FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Sklar, P Ripke, S Scott, LJ Andreassen, OA Cichon, S Craddock, N Edenberg, HJ Nurnberger, JI Rietschel, M Blackwood, D Corvin, A Flickinger, M Guan, WH Mattingsdal, M McQuillin, A Kwan, P Wienker, TF Daly, M Dudbridge, F Holmans, PA Lin, DY Burmeister, M Greenwood, TA Hamshere, ML Muglia, P Smith, EN Zandi, PP Nievergelt, CM McKinney, R Shilling, PD Schork, NJ Bloss, CS Foroud, T Koller, DL Gershon, ES Liu, CY Badner, JA Scheftner, WA Lawson, WB Nwulia, EA Hipolito, M Coryell, W Rice, J Byerley, W McMahon, FJ Schulze, TG Berrettini, W Lohoff, FW Potash, JB Mahon, PB McInnis, MG Zollner, S Zhang, P Craig, DW Szelinger, S Barrett, TB Breuer, R Meier, S Strohmaier, J Witt, SH Tozzi, F Farmer, A McGuffin, P Strauss, J Xu, W Kennedy, JL Vincent, JB Matthews, K Day, R Ferreira, MA O'Dushlaine, C Perlis, R Raychaudhuri, S Ruderfer, D Hyoun, PL Smoller, JW Li, J Absher, D Thompson, RC Meng, FG Schatzberg, AF Bunney, WE Barchas, JD Jones, EG Watson, SJ Myers, RM Akil, H Boehnke, M Chambert, K Moran, J Scolnick, E Djurovic, S Melle, I Morken, G Gill, M Morris, D Quinn, E Muhleisen, TW Degenhardt, FA Mattheisen, M Schumacher, J Maier, W Steffens, M Propping, P Nothen, MM Anjorin, A Bass, N Gurling, H Kandaswamy, R Lawrence, J McGhee, K McIntosh, A McLean, AW Muir, WJ Pickard, BS Breen, G St Clair, D Caesar, S Gordon-Smith, K Jones, L Fraser, C Green, EK Grozeva, D Jones, IR Kirov, G Moskvina, V Nikolov, I O'Donovan, MC Owen, MJ Collier, DA Elkin, A Williamson, R Young, AH Ferrier, IN Stefansson, K Stefansson, H Porgeirsson, P Steinberg, S Gustafsson, O Bergen, SE Nimgaonkar, V Hultman, C Landen, M Lichtenstein, P Sullivan, P Schalling, M Osby, U Backlund, L Frisen, L Langstrom, N Jamain, S Leboyer, M Etain, B Bellivier, F Petursson, H Sigurosson, E Muller-Mysok, B Lucae, S Schwarz, M Schofield, PR Martin, N Montgomery, GW Lathrop, M Oskarsson, H Bauer, M Wright, A Mitchell, PB Hautzinger, M Reif, A Kelsoe, JR Purcell, SM AF Sklar, Pamela Ripke, Stephan Scott, Laura J. Andreassen, Ole A. Cichon, Sven Craddock, Nick Edenberg, Howard J. Nurnberger, John I., Jr. Rietschel, Marcella Blackwood, Douglas Corvin, Aiden Flickinger, Matthew Guan, Weihua Mattingsdal, Morten McQuillin, Andrew Kwan, Phoenix Wienker, Thomas F. Daly, Mark Dudbridge, Frank Holmans, Peter A. Lin, Danyu Burmeister, Margit Greenwood, Tiffany A. Hamshere, Marian L. Muglia, Pierandrea Smith, Erin N. Zandi, Peter P. Nievergelt, Caroline M. McKinney, Rebecca Shilling, Paul D. Schork, Nicholas J. Bloss, Cinnamon S. Foroud, Tatiana Koller, Daniel L. Gershon, Elliot S. Liu, Chunyu Badner, Judith A. Scheftner, William A. Lawson, William B. Nwulia, Evaristus A. Hipolito, Maria Coryell, William Rice, John Byerley, William McMahon, Francis J. Schulze, Thomas G. Berrettini, Wade Lohoff, Falk W. Potash, James B. Mahon, Pamela B. McInnis, Melvin G. Zoellner, Sebastian Zhang, Peng Craig, David W. Szelinger, Szabocls Barrett, Thomas B. Breuer, Rene Meier, Sandra Strohmaier, Jana Witt, Stephanie H. Tozzi, Federica Farmer, Anne McGuffin, Peter Strauss, John Xu, Wei Kennedy, James L. Vincent, John B. Matthews, Keith Day, Richard Ferreira, Manuel A. O'Dushlaine, Colm Perlis, Roy Raychaudhuri, Soumya Ruderfer, Douglas Hyoun, Phil L. Smoller, Jordan W. Li, Jun Absher, Devin Thompson, Robert C. Meng, Fan Guo Schatzberg, Alan F. Bunney, William E. Barchas, Jack D. Jones, Edward G. Watson, Stanley J. Myers, Richard M. Akil, Huda Boehnke, Michael Chambert, Kim Moran, Jennifer Scolnick, Ed Djurovic, Srdjan Melle, Ingrid Morken, Gunnar Gill, Michael Morris, Derek Quinn, Emma Muehleisen, Thomas W. Degenhardt, Franziska A. Mattheisen, Manuel Schumacher, Johannes Maier, Wolfgang Steffens, Michael Propping, Peter Noethen, Markus M. Anjorin, Adebayo Bass, Nick Gurling, Hugh Kandaswamy, Radhika Lawrence, Jacob McGhee, Kevin McIntosh, Andrew McLean, Alan W. Muir, Walter J. Pickard, Benjamin S. Breen, Gerome St Clair, David Caesar, Sian Gordon-Smith, Katherine Jones, Lisa Fraser, Christine Green, Elaine K. Grozeva, Detelina Jones, Ian R. Kirov, George Moskvina, Valentina Nikolov, Ivan O'Donovan, Michael C. Owen, Michael J. Collier, David A. Elkin, Amanda Williamson, Richard Young, Allan H. Ferrier, I. Nicol Stefansson, Kari Stefansson, Hreinn Porgeirsson, Porgeir Steinberg, Stacy Gustafsson, Omar Bergen, Sarah E. Nimgaonkar, Vishwajit Hultman, Christina Landen, Mikael Lichtenstein, Paul Sullivan, Patrick Schalling, Martin Osby, Urban Backlund, Lena Frisen, Louise Langstrom, Niklas Jamain, Stephane Leboyer, Marion Etain, Bruno Bellivier, Frank Petursson, Hannes Sigurosson, Engilbert Mueller-Mysok, Bertram Lucae, Susanne Schwarz, Markus Schofield, Peter R. Martin, Nick Montgomery, Grant W. Lathrop, Mark Oskarsson, Hogni Bauer, Michael Wright, Adam Mitchell, Philip B. Hautzinger, Martin Reif, Andreas Kelsoe, John R. Purcell, Shaun M. CA Psychiat GWAS Consortium Bipolar D TI Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4 SO NATURE GENETICS LA English DT Article ID PSYCHIATRIC-DISORDERS; CACNA1C; SCHIZOPHRENIA; INDIVIDUALS; RISK; PSYCHOSIS; GENETICS; ANK3 AB We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 x 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci. C1 [Sklar, Pamela] Mt Sinai Sch Med, Dept Psychiat, Div Psychiat Genom, New York, NY USA. [Sklar, Pamela; Ripke, Stephan; Daly, Mark; Ferreira, Manuel A.; O'Dushlaine, Colm; Perlis, Roy; Raychaudhuri, Soumya; Ruderfer, Douglas; Hyoun, Phil L.; Smoller, Jordan W.; Bergen, Sarah E.; Purcell, Shaun M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Sklar, Pamela; Ripke, Stephan; Daly, Mark; Ferreira, Manuel A.; O'Dushlaine, Colm; Perlis, Roy; Raychaudhuri, Soumya; Ruderfer, Douglas; Hyoun, Phil L.; Smoller, Jordan W.; Bergen, Sarah E.; Purcell, Shaun M.] Harvard Univ, Sch Med, Boston, MA USA. [Ripke, Stephan; Daly, Mark; Ferreira, Manuel A.; O'Dushlaine, Colm; Perlis, Roy; Raychaudhuri, Soumya; Ruderfer, Douglas; Smoller, Jordan W.; Chambert, Kim; Moran, Jennifer; Scolnick, Ed; Bergen, Sarah E.; Purcell, Shaun M.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Scott, Laura J.; Flickinger, Matthew; Guan, Weihua; Kwan, Phoenix; Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Scott, Laura J.; Flickinger, Matthew; Guan, Weihua; Kwan, Phoenix; Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Andreassen, Ole A.; Mattingsdal, Morten; Djurovic, Srdjan; Melle, Ingrid] Univ Oslo, Inst Clin Med, European Network Bipolar Res Expert Ctr ENBREC Gr, Oslo, Norway. [Andreassen, Ole A.; Melle, Ingrid] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway. [Cichon, Sven; Muehleisen, Thomas W.; Degenhardt, Franziska A.; Mattheisen, Manuel; Schumacher, Johannes; Propping, Peter; Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Cichon, Sven; Muehleisen, Thomas W.; Degenhardt, Franziska A.; Noethen, Markus M.] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany. [Cichon, Sven] Res Ctr Juelich, Inst Neurosci & Med INM 1, Julich, Germany. [Craddock, Nick; Holmans, Peter A.; Hamshere, Marian L.; Gordon-Smith, Katherine; Fraser, Christine; Green, Elaine K.; Grozeva, Detelina; Jones, Ian R.; Kirov, George; Moskvina, Valentina; Nikolov, Ivan; O'Donovan, Michael C.; Owen, Michael J.] Cardiff Univ, Sch Med, Med Res Council MRC Ctr Neuropsychiat Genet & Gen, Cardiff, S Glam, Wales. [Edenberg, Howard J.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Dept Med & Mol Genet, Indianapolis, IN USA. [Nurnberger, John I., Jr.; Foroud, Tatiana; Koller, Daniel L.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN USA. [Rietschel, Marcella; Schulze, Thomas G.; Breuer, Rene; Meier, Sandra; Strohmaier, Jana; Witt, Stephanie H.] Univ Heidelberg, Dept Genet Epidemiol Psychiat, Cent Inst Mental Hlth Mannheim, D-6800 Mannheim, Germany. [Blackwood, Douglas; McGhee, Kevin; McIntosh, Andrew; McLean, Alan W.; Muir, Walter J.; Pickard, Benjamin S.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. [Blackwood, Douglas; McGhee, Kevin; McIntosh, Andrew; McLean, Alan W.; Muir, Walter J.; Pickard, Benjamin S.] Univ Edinburgh, Western Gen Hosp, Mol Med Ctr, Med Genet Sect, Edinburgh, Midlothian, Scotland. [Corvin, Aiden; Gill, Michael; Morris, Derek; Quinn, Emma] Trinity Coll Dublin, Neuropsychiat Genet Res Grp, Dept Psychiat, Dublin, Ireland. [Corvin, Aiden; Gill, Michael; Morris, Derek; Quinn, Emma] Trinity Coll Dublin, Inst Mol Med, Dublin, Ireland. [Mattingsdal, Morten] Sorlandet Hosp HF, Kristiansand, Norway. [McQuillin, Andrew; Anjorin, Adebayo; Bass, Nick; Gurling, Hugh; Kandaswamy, Radhika; Lawrence, Jacob] UCL, Mol Psychiat Lab, Res Dept Mental Hlth Sci, London, England. [Wienker, Thomas F.; Mattheisen, Manuel; Steffens, Michael] Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-5300 Bonn, Germany. [Dudbridge, Frank] Univ London, London Sch Hyg & Trop Med, London, England. [Holmans, Peter A.] Cardiff Univ, Sch Med, Biostat & Bioinformat Unit, Cardiff, S Glam, Wales. [Lin, Danyu] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Burmeister, Margit; Li, Jun] Univ Michigan, Dept Psychiat, Dept Human Genet, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Greenwood, Tiffany A.; Nievergelt, Caroline M.; McKinney, Rebecca; Shilling, Paul D.; Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Hamshere, Marian L.; Muglia, Pierandrea; Tozzi, Federica; Moskvina, Valentina] GlaxoSmithKline Res & Dev Ltd, Neurosci Ctr Excellence Drug Discovery, Verona, Italy. [Smith, Erin N.; Schork, Nicholas J.; Bloss, Cinnamon S.] Scripps Translat Sci Inst, La Jolla, CA USA. [Smith, Erin N.; Schork, Nicholas J.; Bloss, Cinnamon S.] Scripps Hlth, La Jolla, CA USA. [Zandi, Peter P.; Potash, James B.; Mahon, Pamela B.] Johns Hopkins Univ & Hosp, Dept Mental Hlth, Baltimore, MD USA. [Gershon, Elliot S.; Liu, Chunyu; Badner, Judith A.; Reif, Andreas] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Scheftner, William A.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Lawson, William B.; Nwulia, Evaristus A.; Hipolito, Maria] Howard Univ, Coll Med, Dept Psychiat & Behav Sci, Washington, DC USA. [Coryell, William] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Rice, John] Washington Univ, Sch Med, St Louis, MO USA. [Byerley, William] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [McMahon, Francis J.; Schulze, Thomas G.] NIMH, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Schulze, Thomas G.] Univ Gottingen, Dept Psychiat, Gottingen, Germany. [Berrettini, Wade; Lohoff, Falk W.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Craig, David W.; Szelinger, Szabocls] Translat Genom Res Inst, Phoenix, AZ USA. [Barrett, Thomas B.] Portland VA Med Ctr, Portland, OR USA. [Farmer, Anne; McGuffin, Peter; Breen, Gerome; Collier, David A.; Elkin, Amanda; Williamson, Richard] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat SGDP Ctr, London WC2R 2LS, England. [Strauss, John; Vincent, John B.] Ctr Addict & Mental Hlth, Mol Neuropsychiat & Dev Lab, Toronto, ON, Canada. [Xu, Wei] Princess Margaret Hosp, Dept Biostat, Toronto, ON M4X 1K9, Canada. [Kennedy, James L.] Ctr Addict & Mental Hlth, Psychiat Neurogenet Sect, Toronto, ON, Canada. [Matthews, Keith; Young, Allan H.; Ferrier, I. Nicol] Univ Dundee, Sch Med, Dundee, Scotland. [Day, Richard] Royal Victoria Infirm, Sch Neurol Neurobiol & Psychiat, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Ferreira, Manuel A.; Martin, Nick; Montgomery, Grant W.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Absher, Devin; Myers, Richard M.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Thompson, Robert C.; Bunney, William E.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. [Meng, Fan Guo; Barchas, Jack D.] Cornell Univ, Weill Med Coll, Dept Psychiat, New York, NY 10021 USA. [Schatzberg, Alan F.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Jones, Edward G.] Univ Calif Davis, Dept Psychiat & Behav Sci, Ctr Neurosci, Davis, CA 95616 USA. [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Morken, Gunnar] St Olavs Hosp, Dept Psychiat, Trondheim, Norway. [Morken, Gunnar] Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway. [Maier, Wolfgang] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. [Breen, Gerome; St Clair, David] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland. [Caesar, Sian; Gordon-Smith, Katherine; Jones, Lisa] Univ Birmingham, Dept Psychiat, Sch Clin & Expt Med, Birmingham, W Midlands, England. [Young, Allan H.] Univ British Columbia, Inst Mental Hlth, Vancouver, BC V5Z 1M9, Canada. [Stefansson, Kari; Stefansson, Hreinn; Porgeirsson, Porgeir; Steinberg, Stacy; Gustafsson, Omar] deCODE Genet, Reykjavik, Iceland. [Nimgaonkar, Vishwajit] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Hultman, Christina; Landen, Mikael; Lichtenstein, Paul] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Landen, Mikael; Langstrom, Niklas] Univ Gothenburg, Inst Neurosci & Physiol, Gothenburg, Sweden. [Sullivan, Patrick] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC USA. [Schalling, Martin; Osby, Urban; Frisen, Louise] Karolinska Inst, Dept Mol Med, Stockholm, Sweden. [Backlund, Lena] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Jamain, Stephane; Leboyer, Marion; Etain, Bruno; Bellivier, Frank] Hop Henri Mondor, INSERM, U955, F-94010 Creteil, France. [Jamain, Stephane; Leboyer, Marion; Etain, Bruno; Bellivier, Frank] Univ Paris Est, Fac Med, Creteil, France. [Jamain, Stephane; Leboyer, Marion; Etain, Bruno; Bellivier, Frank] Hop H Mondor A Chenevier, AP HP, Dept Psychiat, Creteil, France. [Jamain, Stephane; Leboyer, Marion; Etain, Bruno; Bellivier, Frank] Fdn Fondamental, ENBREC Grp, Creteil, France. [Petursson, Hannes; Sigurosson, Engilbert] Univ Iceland, Div Psychiat, Landspitali Univ Hosp, Reykjavik, Iceland. [Mueller-Mysok, Bertram; Lucae, Susanne] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Schwarz, Markus] Psychiat Ctr Nordbaden, Wiesloch, Germany. [Schofield, Peter R.] Prince Wales Med Inst, Sydney, NSW, Australia. [Wright, Adam; Mitchell, Philip B.] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Lathrop, Mark] Ctr Natl Genotypage, Evry, France. [Bauer, Michael] Univ Hosp Carl Gustav Carus, ENBREC Grp, Dept Psychiat & Psychotherapy, Dresden, Germany. [Wright, Adam; Mitchell, Philip B.] Black Dog Inst, Sydney, NSW, Australia. [Hautzinger, Martin] Univ Tubingen, Dept Clin & Dev Psychol, Inst Psychol, Tubingen, Germany. [Reif, Andreas] Univ Wurzburg, Dept Psychiat, D-8700 Wurzburg, Germany. [Kelsoe, John R.] Vet Affairs San Diego Healthcare Syst, STEP, Dept Psychiat, San Diego, CA USA. RP Sklar, P (reprint author), Mt Sinai Sch Med, Dept Psychiat, Div Psychiat Genom, New York, NY USA. EM pamela.sklar@mssm.edu RI Pickard, Benjamin/K-3923-2014; Breen, Gerome/A-5540-2010; Schalling, Martin/F-1518-2015; Holmans, Peter/F-4518-2015; Montgomery, Grant/B-7148-2008; Mattheisen, Manuel/B-4949-2012; Melle, Ingrid /B-4858-2011; Schumacher, Johannes/F-4970-2015; Ruderfer, Douglas/M-5795-2016; Lohoff, Falk/M-7951-2016; BELLIVIER, FRANK/H-5197-2012; McQuillin, Andrew/C-1623-2008; Cichon, Sven/B-9618-2014; Smith, Erin/E-5933-2011; Liu, Chunyu/G-7561-2012; McInnis, Melvin/F-6963-2012; Bergen, Sarah/I-8313-2012; McIntosh, Andrew/B-9379-2008; Burmeister, Margit/A-3157-2013; Ferreira, Manuel/D-3609-2013; Schulze, Thomas/H-2157-2013; Gurling, Hugh/A-5029-2010; McGuffin, Peter/A-1565-2012; Cichon, Sven/H-8803-2013; Zhang, Peng/N-2920-2014 OI McMahon, Francis/0000-0002-9469-305X; Escott-Price, Valentina/0000-0003-1784-5483; Nothen, Markus/0000-0002-8770-2464; Andreassen, Ole A./0000-0002-4461-3568; Etain, Bruno/0000-0002-5377-1488; Edenberg, Howard/0000-0003-0344-9690; Steffens, Michael/0000-0002-6445-8593; Greenwood, Tiffany/0000-0002-6080-6503; Nurnberger, John/0000-0002-7674-1767; Gill, Michael/0000-0003-0206-5337; Schofield, Peter/0000-0003-2967-9662; lichtenstein, paul/0000-0003-3037-5287; Moran, Jennifer/0000-0002-5664-4716; Mitchell, Philip/0000-0002-7954-5235; Stefansson, Hreinn/0000-0002-9331-6666; Jamain, Stephane/0000-0002-4321-4100; Matthews, Keith/0000-0002-4478-5888; Nievergelt, Caroline/0000-0001-5766-8923; Lawson, William/0000-0002-9324-7090; Corvin, Aiden/0000-0001-6717-4089; O'Donovan, Michael/0000-0001-7073-2379; Backlund, Lena/0000-0001-9399-5024; Morris, Derek/0000-0002-3413-570X; Tozzi, Federica/0000-0002-3536-2920; Pickard, Benjamin/0000-0002-2374-6329; Breen, Gerome/0000-0003-2053-1792; Schalling, Martin/0000-0001-5011-2922; Holmans, Peter/0000-0003-0870-9412; Montgomery, Grant/0000-0002-4140-8139; Mattheisen, Manuel/0000-0002-8442-493X; Melle, Ingrid /0000-0002-9783-548X; Schumacher, Johannes/0000-0001-9217-6457; Ruderfer, Douglas/0000-0002-2365-386X; McQuillin, Andrew/0000-0003-1567-2240; Bergen, Sarah/0000-0002-5888-0034; Cichon, Sven/0000-0002-9475-086X; Liu, Chunyu/0000-0002-5986-4415; McInnis, Melvin/0000-0002-0375-6247; McIntosh, Andrew/0000-0002-0198-4588; Burmeister, Margit/0000-0002-1914-2434; McGuffin, Peter/0000-0002-9888-2907; Cichon, Sven/0000-0002-9475-086X; Zhang, Peng/0000-0003-1182-1392 FU US National Institutes of Health (NIH) [MH078151, MH081804, MH059567, MH59553, MH080372, 1U54RR025204]; Genetic Association Information Network (GAIN); NIMH Intramural Research Program; Tzedakah Foundation; American Philosophical Society; Stardust foundation; National Library of Medicine; Stanley Foundation for Medical Research; Wellcome Trust; Pritzker Neuropsychiatric Disorders Research Fund L.L.C.; GlaxoSmithKline; Research Council of Norway [167153/V50, 163070/V50, 175345/V50]; South-East Norway Health Authority [123-2004]; EU (ENBREC) FX We would like to recognize the contribution of thousands of subjects without whom this work would not be possible. T. Lehner (National Institute of Mental Health (NIMH)) was instrumental in initiating and planning the overall project. D. Posthuma and the Dutch Genetic Cluster Computer provided invaluable computational resources. We also thank the PGC schizophrenia group for allowing us to perform the combined analyses of six loci before publication. This work was supported by many grants from the US National Institutes of Health (NIH) (MH078151, MH081804, MH059567 supplement, MH59553, MH080372 and 1U54RR025204). Other sources of support include: the Genetic Association Information Network (GAIN), the NIMH Intramural Research Program, the Tzedakah Foundation, the American Philosophical Society, the Stardust foundation, the National Library of Medicine, the Stanley Foundation for Medical Research and the Wellcome Trust, the Pritzker Neuropsychiatric Disorders Research Fund L.L.C., GlaxoSmithKline, as well as grants for individual studies (see the Supplemental Note for a full list of Acknowledgements). The TOP Study was supported by grants from the Research Council of Norway (167153/V50, 163070/V50 and 175345/V50), the South-East Norway Health Authority (123-2004) and the EU (ENBREC). Additional acknowledgments can be found in the Supplementary Note. NR 31 TC 248 Z9 252 U1 6 U2 55 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 OCT PY 2011 VL 43 IS 10 BP 977 EP U162 DI 10.1038/ng.943 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 825XT UT WOS:000295316200012 ER PT J AU Wain, LV Verwoert, GC O'Reilly, PF Shi, G Johnson, T Johnson, AD Bochud, M Rice, KM Henneman, P Smith, AV Ehret, GB Amin, N Larson, MG Mooser, V Hadley, D Dorr, M Bis, JC Aspelund, T Esko, T Janssens, ACJW Zhao, JH Heath, S Laan, M Fu, JY Pistis, G Luan, JA Arora, P Lucas, G Pirastu, N Pichler, I Jackson, AU Webster, RJ Zhang, F Peden, JF Schmidt, H Tanaka, T Campbell, H Igl, W Milaneschi, Y Hottenga, JJ Vitart, V Chasman, DI Trompet, S Bragg-Gresham, JL Alizadeh, BZ Chambers, JC Guo, XQ Lehtimaki, T Kuhnel, B Lopez, LM Polasek, O Boban, M Nelson, CP Morrison, AC Pihur, V Ganesh, SK Hofman, A Kundu, S Mattace-Raso, FUS Rivadeneira, F Sijbrands, EJG Uitterlinden, AG Hwang, SJ Vasan, RS Wang, TJ Bergmann, S Vollenweider, P Waeber, G Laitinen, J Pouta, A Zitting, P McArdle, WL Kroemer, HK Volker, U Volzke, H Glazer, NL Taylor, KD Harris, TB Alavere, H Haller, T Keis, A Tammesoo, ML Aulchenko, Y Barroso, I Khaw, KT Galan, P Hercberg, S Lathrop, M Eyheramendy, S Org, E Sober, S Lu, XW Nolte, IM Penninx, BW Corre, T Masciullo, C Sala, C Groop, L Voight, BF Melander, O O'Donnell, CJ Salomaa, V d'Adamo, AP Fabretto, A Faletra, F Ulivi, S Del Greco, MF Facheris, M Collins, FS Bergman, RN Beilby, JP Hung, J Musk, AW Mangino, M Shin, SY Soranzo, N Watkins, H Goel, A Hamsten, A Gider, P Loitfelder, M Zeginigg, M Hernandez, D Najjar, SS Navarro, P Wild, SH Corsi, AM Singleton, A de Geus, EJC Willemsen, G Parker, AN Rose, LM Buckley, B Stott, D Orru, M Uda, M van der Klauw, MM Zhang, WH Li, XZ Scott, J Chen, YDI Burke, GL Kahonen, M Viikari, J Doring, A Meitinger, T Davies, G Starr, JM Emilsson, V Plump, A Lindeman, JH 't Hoen, PAC Konig, IR Felix, JF Clarke, R Hopewell, JC Ongen, H Breteler, M Debette, S DeStefano, AL Fornage, M Mitchell, GF Smith, NL Holm, H Stefansson, K Thorleifsson, G Thorsteinsdottir, U Samani, NJ Preuss, M Rudan, I Hayward, C Deary, IJ Wichmann, HE Raitakari, OT Palmas, W Kooner, JS Stolk, RP Jukema, JW Wright, AF Boomsma, DI Bandinelli, S Gyllensten, UB Wilson, JF Ferrucci, L Schmidt, R Farrall, M Spector, TD Palmer, LJ Tuomilehto, J Pfeufer, A Gasparini, P Siscovick, D Altshuler, D Loos, RJF Toniolo, D Snieder, H Gieger, C Meneton, P Wareham, NJ Oostra, BA Metspalu, A Launer, L Rettig, R Strachan, DP Beckmann, JS Witteman, JCM Erdmann, J van Dijk, KW Boerwinkle, E Boehnke, M Ridker, PM Jarvelin, MR Chakravarti, A Abecasis, GR Gudnason, V Newton-Cheh, C Levy, D Munroe, PB Psaty, BM Caulfield, MJ Rao, DC Tobin, MD Elliott, P van Duijn, CM AF Wain, Louise V. Verwoert, Germaine C. O'Reilly, Paul F. Shi, Gang Johnson, Toby Johnson, Andrew D. Bochud, Murielle Rice, Kenneth M. Henneman, Peter Smith, Albert V. Ehret, Georg B. Amin, Najaf Larson, Martin G. Mooser, Vincent Hadley, David Doerr, Marcus Bis, Joshua C. Aspelund, Thor Esko, Tonu Janssens, A. Cecile J. W. Zhao, Jing Hua Heath, Simon Laan, Maris Fu, Jingyuan Pistis, Giorgio Luan, Jian'an Arora, Pankaj Lucas, Gavin Pirastu, Nicola Pichler, Irene Jackson, Anne U. Webster, Rebecca J. Zhang, Feng Peden, John F. Schmidt, Helena Tanaka, Toshiko Campbell, Harry Igl, Wilmar Milaneschi, Yuri Hottenga, Jouke-Jan Vitart, Veronique Chasman, Daniel I. Trompet, Stella Bragg-Gresham, Jennifer L. Alizadeh, Behrooz Z. Chambers, John C. Guo, Xiuqing Lehtimaki, Terho Kuehnel, Brigitte Lopez, Lorna M. Polasek, Ozren Boban, Mladen Nelson, Christopher P. Morrison, Alanna C. Pihur, Vasyl Ganesh, Santhi K. Hofman, Albert Kundu, Suman Mattace-Raso, Francesco U. S. Rivadeneira, Fernando Sijbrands, Eric J. G. Uitterlinden, Andre G. Hwang, Shih-Jen Vasan, Ramachandran S. Wang, Thomas J. Bergmann, Sven Vollenweider, Peter Waeber, Gerard Laitinen, Jaana Pouta, Anneli Zitting, Paavo McArdle, Wendy L. Kroemer, Heyo K. Voelker, Uwe Voelzke, Henry Glazer, Nicole L. Taylor, Kent D. Harris, Tamara B. Alavere, Helene Haller, Toomas Keis, Aime Tammesoo, Mari-Liis Aulchenko, Yurii Barroso, Ines Khaw, Kay-Tee Galan, Pilar Hercberg, Serge Lathrop, Mark Eyheramendy, Susana Org, Elin Sober, Siim Lu, Xiaowen Nolte, Ilja M. Penninx, Brenda W. Corre, Tanguy Masciullo, Corrado Sala, Cinzia Groop, Leif Voight, Benjamin F. Melander, Olle O'Donnell, Christopher J. Salomaa, Veikko d'Adamo, Adamo Pio Fabretto, Antonella Faletra, Flavio Ulivi, Sheila Del Greco, Fabiola M. Facheris, Maurizio Collins, Francis S. Bergman, Richard N. Beilby, John P. Hung, Joseph Musk, A. William Mangino, Massimo Shin, So-Youn Soranzo, Nicole Watkins, Hugh Goel, Anuj Hamsten, Anders Gider, Pierre Loitfelder, Marisa Zeginigg, Marion Hernandez, Dena Najjar, Samer S. Navarro, Pau Wild, Sarah H. Corsi, Anna Maria Singleton, Andrew de Geus, Eco J. C. Willemsen, Gonneke Parker, Alex N. Rose, Lynda M. Buckley, Brendan Stott, David Orru, Marco Uda, Manuela van der Klauw, Melanie M. Zhang, Weihua Li, Xinzhong Scott, James Chen, Yii-Der Ida Burke, Gregory L. Kahonen, Mika Viikari, Jorma Doering, Angela Meitinger, Thomas Davies, Gail Starr, John M. Emilsson, Valur Plump, Andrew Lindeman, Jan H. 't Hoen, Peter A. C. Koenig, Inke R. Felix, Janine F. Clarke, Robert Hopewell, Jemma C. Ongen, Halit Breteler, Monique Debette, Stephanie DeStefano, Anita L. Fornage, Myriam Mitchell, Gary F. Smith, Nicholas L. Holm, Hilma Stefansson, Kari Thorleifsson, Gudmar Thorsteinsdottir, Unnur Samani, Nilesh J. Preuss, Michael Rudan, Igor Hayward, Caroline Deary, Ian J. Wichmann, H-Erich Raitakari, Olli T. Palmas, Walter Kooner, Jaspal S. Stolk, Ronald P. Jukema, J. Wouter Wright, Alan F. Boomsma, Dorret I. Bandinelli, Stefania Gyllensten, Ulf B. Wilson, James F. Ferrucci, Luigi Schmidt, Reinhold Farrall, Martin Spector, Tim D. Palmer, Lyle J. Tuomilehto, Jaakko Pfeufer, Arne Gasparini, Paolo Siscovick, David Altshuler, David Loos, Ruth J. F. Toniolo, Daniela Snieder, Harold Gieger, Christian Meneton, Pierre Wareham, Nicholas J. Oostra, Ben A. Metspalu, Andres Launer, Lenore Rettig, Rainer Strachan, David P. Beckmann, Jacques S. Witteman, Jacqueline C. M. Erdmann, Jeanette van Dijk, Ko Willems Boerwinkle, Eric Boehnke, Michael Ridker, Paul M. Jarvelin, Marjo-Riitta Chakravarti, Aravinda Abecasis, Goncalo R. Gudnason, Vilmundur Newton-Cheh, Christopher Levy, Daniel Munroe, Patricia B. Psaty, Bruce M. Caulfield, Mark J. Rao, Dabeeru C. Tobin, Martin D. Elliott, Paul van Duijn, Cornelia M. CA LifeLines Cohort Study EchoGen Consortium AortaGen Consortium CHARGE Consortium Heart Failure KidneyGen Consortium CKDGen Consortium Cardiogenics Consortium CardioGram TI Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure SO NATURE GENETICS LA English DT Article ID ADRENERGIC-RECEPTOR TRAFFICKING; CARDIOVASCULAR-DISEASE RISK; BLOOD-PRESSURE; HEART-FAILURE; HYPERTENSION; METAANALYSIS; MORTALITY; GENE; MICE; RELEVANCE AB Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans(1-3). We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 x 10(-8) to P = 2.3 x 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP. C1 [O'Reilly, Paul F.; Chambers, John C.; Zhang, Weihua; Li, Xinzhong; Jarvelin, Marjo-Riitta; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. 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[Preuss, Michael; Erdmann, Jeanette] Univ Lubeck, Med Klin 2, Lubeck, Germany. [Rudan, Igor] Univ Split Med Sch, Croatian Ctr Global Hlth, Split, Croatia. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Palmas, Walter] Columbia Univ, New York, NY USA. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Palmer, Lyle J.] Ontario Canc Inst Res, Toronto, ON, Canada. [Palmer, Lyle J.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Tuomilehto, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki, Finland. [Pfeufer, Arne] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Toniolo, Daniela] CNR, Inst Mol Genet, I-27100 Pavia, Italy. [Meneton, Pierre] Ctr Rech Cordeliers, INSERM, U872, Paris, France. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, Greifswald, Germany. [Beckmann, Jacques S.] CHU Vaudois, Serv Med Genet, Lausanne, Switzerland. [van Dijk, Ko Willems] Leiden Univ Med Ctr, Dept Internal Med, Leiden, Netherlands. [Boerwinkle, Eric] Ctr Human Genet, Houston, TX USA. [Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr, Oulu, Finland. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Rao, Dabeeru C.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Rao, Dabeeru C.] Washington Univ, Dept Math, Sch Med, St Louis, MO 63130 USA. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, MRC Hlth Protect Agcy HPA Ctr Environm & Hlth, London, England. [van Duijn, Cornelia M.] Erasmus MC, Ctr Med Syst Biol, Rotterdam, Netherlands. RP Elliott, P (reprint author), Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. EM mt47@leicester.ac.uk; p.elliott@imperial.ac.uk; c.vanduijn@erasmusmc.nl RI Erdmann, Jeanette/P-7513-2014; Hernandez-Fuentes, Maria/B-5011-2010; Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; Boban, Mladen/E-2777-2017; Feitosa, Mary/K-8044-2012; Gudnason, Vilmundur/K-6885-2015; Mattace- Raso, Francesco/L-2541-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; de Geus, Eco/M-9318-2015; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Shi, Gang/D-3301-2016; Hypponen, Elina/B-2596-2014; Smith, Albert/K-5150-2015; Bochud, Murielle/A-3981-2010; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Aulchenko, Yurii/M-8270-2013; Altshuler, David/A-4476-2009; van der Klauw, Melanie/A-2138-2014; d'Adamo, Adamo Pio/G-4064-2011; Palmer, Lyle/K-3196-2014; Kronenberg, Florian/B-1736-2008; Schalling, Martin/F-1518-2015; Eggermann, Thomas/F-3807-2014; Breteler, Monique /J-5058-2014; Bakker, Stephan/J-4023-2015; Maxwell, Patrick/C-5557-2008; Lopez, Lorna/F-7265-2010; Hadley, David/I-6902-2012; Heath, Simon/J-4138-2012; Rice, Kenneth/A-4150-2013; Stolk, Ronald/B-2341-2013; Pfeufer, Arne/B-6634-2013; Giallauria, Francesco/B-5681-2013; Newman, Anne/C-6408-2013; Johnson, Andrew/G-6520-2013; Ulivi, Sheila/H-3700-2013; Gale, Daniel/D-5594-2013; Colaus, PsyColaus/K-6607-2013; Aspelund, Thor/C-5983-2008; Willems van Dijk, Ko/A-1798-2008; EHRET, Georg/A-9532-2009; Lucas, Gavin/D-4346-2012; Deary, Ian/C-6297-2009; Abecasis, Goncalo/B-7840-2010; Rudan, Igor/I-1467-2012; Singleton, Andrew/C-3010-2009; Pirastu, Nicola/G-4358-2011; Arora, Pankaj/F-3437-2011; Laan, Maris/A-4100-2011; Beckmann, Jacques S /A-9772-2008; 't Hoen, Peter/A-4857-2012; OI Magi, Reedik/0000-0002-2964-6011; Fuchsberger, Christian/0000-0002-5918-8947; Johnson, Toby/0000-0002-5998-3270; Org, Elin/0000-0003-1451-9375; Abecasis, Goncalo/0000-0003-1509-1825; Zgaga, Lina/0000-0003-4089-9703; Ramachandran, Vasan/0000-0001-7357-5970; Janssens, A Cecile/0000-0002-6153-4976; Forouhi, Nita/0000-0002-5041-248X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Wallace, Chris/0000-0001-9755-1703; Ouwehand, Willem/0000-0002-7744-1790; Lawlor, Debbie A/0000-0002-6793-2262; Bergmann, Sven/0000-0002-6785-9034; Kleber, Marcus/0000-0003-0663-7275; Erdmann, Jeanette/0000-0002-4486-6231; Hernandez-Fuentes, Maria/0000-0002-7558-9441; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Ziegler, Andreas/0000-0002-8386-5397; Gillebert, Thierry/0000-0002-3832-919X; Feitosa, Mary/0000-0002-0933-2410; Faletra, Flavio/0000-0003-1483-3612; Esko, Tonu/0000-0003-1982-6569; Larson, Martin/0000-0002-9631-1254; Felix, Janine/0000-0002-9801-5774; Pichler, Irene/0000-0001-8251-0757; Sijbrands, Eric/0000-0001-8857-7389; Gudnason, Vilmundur/0000-0001-5696-0084; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; de Geus, Eco/0000-0001-6022-2666; Rivadeneira, Fernando/0000-0001-9435-9441; Hypponen, Elina/0000-0003-3670-9399; Smith, Albert/0000-0003-1942-5845; Bochud, Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Aulchenko, Yurii/0000-0002-7899-1575; Altshuler, David/0000-0002-7250-4107; van der Klauw, Melanie/0000-0001-7178-009X; d'Adamo, Adamo Pio/0000-0001-9367-4909; Palmer, Lyle/0000-0002-1628-3055; Kronenberg, Florian/0000-0003-2229-1120; Schalling, Martin/0000-0001-5011-2922; Bakker, Stephan/0000-0003-3356-6791; Maxwell, Patrick/0000-0002-0338-2679; Rice, Kenneth/0000-0001-5779-4495; Stolk, Ronald/0000-0002-0518-1205; Giallauria, Francesco/0000-0003-4119-9397; Newman, Anne/0000-0002-0106-1150; Ulivi, Sheila/0000-0003-3606-835X; Gale, Daniel/0000-0002-9170-1579; Aspelund, Thor/0000-0002-7998-5433; Willems van Dijk, Ko/0000-0002-2172-7394; EHRET, Georg/0000-0002-5730-0675; Rudan, Igor/0000-0001-6993-6884; Arora, Pankaj/0000-0003-2420-3550; Laan, Maris/0000-0002-8519-243X; Beckmann, Jacques S /0000-0002-9741-1900; Wain, Louise/0000-0003-4951-1867; Ziad Alizadeh, Behrooz/0000-0002-1415-8007; Pirastu, Nicola/0000-0002-5363-3886; Kundu, Suman/0000-0002-6305-2559 FU US National Institutes of Health; National Heart, Lung, and Blood Institute, European FX A number of the participating studies and authors are members of the CHARGE and Global BPgen consortia. Many funding mechanisms by the US National Institutes of Health and National Heart, Lung, and Blood Institute, European and private funding agencies contributed to this work, and a full list of acknowledgements is provided in the Supplementary Note. NR 33 TC 169 Z9 171 U1 4 U2 53 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 OCT PY 2011 VL 43 IS 10 BP 1005 EP U122 DI 10.1038/ng.922 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 825XT UT WOS:000295316200017 PM 21909110 ER PT J AU Tagawa, ST Milowsky, MI Jeske, S Mazumdar, M Kung, S Sung, M Lehrer, D Matulich, D Selzer, J Wright, JJ Nanus, DM AF Tagawa, Scott T. Milowsky, Matthew I. Jeske, Stephanie Mazumdar, Madhu Kung, Sophia Sung, Max Lehrer, Deborah Matulich, Daniel Selzer, Jodi Wright, John J. Nanus, David M. TI A Phase I Trial of Sorafenib Plus Gemcitabine and Capecitabine for Patients With Advanced Renal Cell Carcinoma New York Cancer Consortium Trial NCI 6981 SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE chemotherapy; renal cell carcinoma; sorafenib; gemcitabine; capecitabine ID CONTINUOUS-INFUSION FLUOROURACIL; WEEKLY INTRAVENOUS GEMCITABINE; METASTATIC COLORECTAL-CANCER; SOLID TUMORS; BEVACIZUMAB; 5-FLUOROURACIL; CHEMOTHERAPY; COMBINATION; PACLITAXEL; LEUCOVORIN AB Objective: To define the safety [dose limiting toxicity (DLT)] and recommended phase II dose of the combination of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC). Methods: In this phase I dose-escalation study, cohorts of 3 to 6 patients with metastatic RCC received sorafenib (200 or 400mg po BID), gemcitabine (750 or 1000 mg/m(2) intravenous on days 1 and 8), and capecitabine (415 or 622 mg/m(2) po BID days 1-14) every 21 days using a standard 3+3 design. Results: Fifteen patients with advanced RCC (93% with clear cell histology and 87% treatment naive) received treatment. The recommended phase II doses for the combination were sorafenib 200 mg/m(2) BID continuously plus gemcitabine 750 mg/m(2) intravenous days 1 and 8 and capecitabine 415 mg/m(2) BID days 1 to 14, every 21 days. Of the 15 patients, 3 developed dose-limiting hand-foot syndrome during the first 2 cycles; 2 additional DLT's were grade 3 mucositis and transaminase elevation. Four of 14 evaluable patients had a partial response by response evaluation criteria in solid tumors (29%; 95% confidence interval (CI): 8, 58%). Median progression-free survival was 7.5 months (95% CI-0, 18.7), and median overall survival has not been reached at a median follow-up of 28.8 months. The median number of treatment cycles given was 7 (range, 2-38+). Conclusions: The combination of sorafenib plus gemcitabine and capecitabine is tolerable, but requires attenuation of sorafenib and capecitabine dosing because of the overlapping toxicity of hand-foot syndrome. Antitumor activity was observed leading to an ongoing phase II trial. C1 [Tagawa, Scott T.; Milowsky, Matthew I.; Jeske, Stephanie; Mazumdar, Madhu; Kung, Sophia; Matulich, Daniel; Selzer, Jodi; Nanus, David M.] Weill Cornell Med Coll, Div Hematol & Med Oncol, New York, NY 10065 USA. [Milowsky, Matthew I.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Sung, Max; Lehrer, Deborah] Mt Sinai Sch Med, Div Oncol, New York, NY USA. [Matulich, Daniel] Montefiore Einstein Canc Ctr, New York, NY USA. [Wright, John J.] Natl Canc Inst, Canc Therapy Evaluat Program, Bethesda, MD USA. RP Tagawa, ST (reprint author), Weill Cornell Med Coll, Div Hematol & Med Oncol, 525 E 68th St,Box 403, New York, NY 10065 USA. EM stt2007@med.cornell.edu FU United States Department of Health and Human Service [N01-CM-62204]; Bayer Pharmaceuticals; David M. Nanus owns Amgen stock FX Supported by United States Department of Health and Human Service contract N01-CM-62204 (P.I. Joseph A. Sparano, MD).; Scott T. Tagawa is a member of the speakers bureau of Bayer and Pfizer Pharmaceuticals and has received honoraria as a member of the speakers bureau of Bayer Pharmaceuticals, manufacturer of Sorafenib. Matthew I. Milowsky receives research funding from Bayer Pharmaceuticals; David M. Nanus owns Amgen stock. The other authors declare no conflicts of interest. NR 27 TC 6 Z9 6 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD OCT PY 2011 VL 34 IS 5 BP 443 EP 448 DI 10.1097/COC.0b013e3181e9c0d7 PG 6 WC Oncology SC Oncology GA 823XP UT WOS:000295161600001 PM 20881475 ER PT J AU Venkataraman, G Aguhar, C Kreitman, RJ Yuan, CM Stetler-Stevenson, M AF Venkataraman, Girish Aguhar, Christine Kreitman, Robert J. Yuan, Constance M. Stetler-Stevenson, Maryalice TI Characteristic CD103 and CD123 Expression Pattern Defines Hairy Cell Leukemia Usefulness of CD123 and CD1O3 in the Diagnosis of Mature B-Cell Lymphoproliferative Disorders SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE CD123; Flow cytometry; Non-Hodgkin lymphoma; CD103; B-cell lymphoproliferative disorders ID RECEPTOR-ALPHA CHAIN; IMMUNOPHENOTYPIC ANALYSIS; FLOW-CYTOMETRY; CONSENSUS RECOMMENDATIONS; VILLOUS LYMPHOCYTES; NEOPLASIA AB By using flow cytometiy, we studied CD103 and CD 123 expression by the malignant cells in 300 B-cell lymphoproliferative disorder (BC-LPD) cases, including 114 hairy cell leukemia (HCL), 20 HCL variant (HCLv), 9 splenic marginal zone lymphoma (SMZL; in 5, only CD103 was evaluated), 133 chronic lymphocytic leukemia (CLL), 3 follicular lymphoma (FL), and 21 mantle cell lymphoma (MCL). All HCLs expressed uniform CD103 and bright CD123. Among the 20 HCLv cases, 20 (100%) were CD103+ and 8 (40%) were CD123+ (partial or dim). CD 103 was negative in all MCL, FL, CLL, and SMZL cases. CD123 was positive in 1(25%) of 4 SMZL, 3.8% of CLL (5/133), 7 (33%) of 21 MCL, and 1 (33%) of 3 FL cases. CD103 is specific for HCL and HCLv. CD123 expression is more widespread in BC-LPDs but is useful in conjunction with CD25 to differentiate HCLv from HCL. These findings support the usefulness of CD123 and CD103 to aid in the differential diagnosis of BC-LPDs. C1 [Venkataraman, Girish; Aguhar, Christine; Yuan, Constance M.; Stetler-Stevenson, Maryalice] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Kreitman, Robert J.] NCI, Clin Immunotherapy Sect, Mol Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Pathol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 2C108E,Mail Stop 1500, Bethesda, MD 20892 USA. FU National Institutes of Health, National Cancer Institute FX Supported by the Intramural Program of the National Institutes of Health, National Cancer Institute. NR 13 TC 17 Z9 18 U1 0 U2 4 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD OCT PY 2011 VL 136 IS 4 BP 625 EP 630 DI 10.1309/AJCPKUM9J4IXCWEU PG 6 WC Pathology SC Pathology GA 822UR UT WOS:000295075600016 PM 21917686 ER PT J AU Lian, M Schootman, M Doubeni, CA Park, Y Major, JM Stone, RAT Laiyemo, AO Hollenbeck, AR Graubard, BI Schatzkin, A AF Lian, Min Schootman, Mario Doubeni, Chyke A. Park, Yikyung Major, Jacqueline M. Stone, Rosalie A. Torres Laiyemo, Adeyinka O. Hollenbeck, Albert R. Graubard, Barry I. Schatzkin, Arthur TI Geographic Variation in Colorectal Cancer Survival and the Role of Small-Area Socioeconomic Deprivation: A Multilevel Survival Analysis of the NIH-AARP Diet and Health Study Cohort SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; colorectal neoplasms; geography; multilevel analysis; residence characteristics; socioeconomic factors; survival ID ISCHEMIC-HEART-DISEASE; LOGISTIC-REGRESSION; MORTALITY; POPULATION; DISPARITIES; IMPACT; INEQUALITIES; ASSOCIATION; COMORBIDITY; ENVIRONMENT AB Adverse socioeconomic conditions, at both the individual and the neighborhood level, increase the risk of colorectal cancer (CRC) death, but little is known regarding whether CRC survival varies geographically and the extent to which area-level socioeconomic deprivation affects this geographic variation. Using data from the National Institutes of Health (NIH)-AARP Diet and Health Study, the authors examined geographic variation and the role of area-level socioeconomic deprivation in CRC survival. CRC cases (n = 7,024), identified during 1995-2003, were followed for their CRC-specific vital status through 2005 and overall vital status through 2006. Bayesian multilevel survival models showed that there was significant geographic variation in overall (variance = 0.2, 95% confidence interval (CI): 0.1, 0.2) and CRC-specific (variance = 0.3, 95% CI: 0.1, 0.4) risk of death. More socioeconomically deprived neighborhoods had a higher overall risk of death (most deprived quartile vs. least deprived: hazard ratio = 1.2, 95% CI: 1.1, 1.4) and a higher CRC-specific risk of death (most deprived quartile vs. least deprived: hazard ratio = 1.2, 95% CI: 1.1, 1.5). However, neighborhood socioeconomic deprivation did not account for the geographic variation in overall and CRC-specific risks of death. In future studies, investigators should evaluate other neighborhood characteristics to help explain geographic heterogeneity in CRC survival. Such research could facilitate interventions for reducing geographic disparity in CRC survival. C1 [Lian, Min; Schootman, Mario] Washington Univ, Sch Med, Dept Med, St Louis, MO 63108 USA. [Doubeni, Chyke A.] Univ Massachusetts, Sch Med, Dept Family Med & Community Hlth, Worcester, MA USA. [Park, Yikyung; Major, Jacqueline M.; Graubard, Barry I.; Schatzkin, Arthur] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Stone, Rosalie A. Torres] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Laiyemo, Adeyinka O.] Howard Univ, Coll Med, Dept Internal Med, Washington, DC USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Lian, M (reprint author), Washington Univ, Sch Med, Dept Med, Campus Box 8504,4444 Forest Pk Ave,Suite 6700, St Louis, MO 63108 USA. EM mlian@dom.wustl.edu OI Schootman, Mario/0000-0003-1162-8824; Doubeni, Chyke/0000-0001-7495-0285; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, National Institutes of Health; National Cancer Institute [R01CA137750, P30CA91842, K01CA127118, R01CA151736]; Florida Department of Health FX This research was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The work of Drs. Min Lian and Mario Schootman was supported in part by a research award (R01CA137750) and a cancer center support award (P30CA91842) from the National Cancer Institute. Dr. Chyke A. Doubeni's work was supported by career development awards (K01CA127118 and R01CA151736) from the National Cancer Institute.; Cancer incidence data from the Atlanta, Georgia, metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit, Michigan, metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract with the Florida Department of Health. (The views expressed herein are solely those of the authors and do not necessarily reflect those of the Florida Cancer Data System or the Florida Department of Health.) Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. (The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions.) Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, Center for Health Data and Research, Bureau of Health Planning and Statistics, State Health Division, State of Nevada Department of Health and Human Services. NR 36 TC 32 Z9 32 U1 2 U2 13 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 OCT 1 PY 2011 VL 174 IS 7 BP 828 EP 838 DI 10.1093/aje/kwr162 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 823ZC UT WOS:000295166500009 PM 21836166 ER PT J AU Matise, TC Ambite, JL Buyske, S Carlson, CS Cole, SA Crawford, DC Haiman, CA Heiss, G Kooperberg, C Le Marchand, L Manolio, TA North, KE Peters, U Ritchie, MD Hindorff, LA Haines, JL AF Matise, Tara C. Ambite, Jose Luis Buyske, Steven Carlson, Christopher S. Cole, Shelley A. Crawford, Dana C. Haiman, Christopher A. Heiss, Gerardo Kooperberg, Charles Le Marchand, Loic Manolio, Teri A. North, Kari E. Peters, Ulrike Ritchie, Marylyn D. Hindorff, Lucia A. Haines, Jonathan L. CA PAGE Study TI The Next PAGE in Understanding Complex Traits: Design for the Analysis of Population Architecture Using Genetics and Epidemiology (PAGE) Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cardiovascular diseases; cohort studies; genome-wide association study; multifactorial inheritance; neoplasms; obesity; population characteristics; reproducibility of results ID GENOME-WIDE ASSOCIATION; DISEASE RISK; CARDIOVASCULAR-DISEASE; AMERICAN-INDIANS; LOCI; HEALTH AB Genetic studies have identified thousands of variants associated with complex traits. However, most association studies are limited to populations of European descent and a single phenotype. The Population Architecture using Genomics and Epidemiology (PAGE) Study was initiated in 2008 by the National Human Genome Research Institute to investigate the epidemiologic architecture of well-replicated genetic variants associated with complex diseases in several large, ethnically diverse population-based studies. Combining DNA samples and hundreds of phenotypes from multiple cohorts, PAGE is well-suited to address generalization of associations and variability of effects in diverse populations; identify genetic and environmental modifiers; evaluate disease subtypes, intermediate phenotypes, and biomarkers; and investigate associations with novel phenotypes. PAGE investigators harmonize phenotypes across studies where possible and perform coordinated cohort-specific analyses and meta-analyses. PAGE researchers are genotyping thousands of genetic variants in up to 121,000 DNA samples from African-American, white, Hispanic/Latino, Asian/Pacific Islander, and American Indian participants. Initial analyses will focus on single nucleotide polymorphisms (SNPs) associated with obesity, lipids, cardiovascular disease, type 2 diabetes, inflammation, various cancers, and related biomarkers. PAGE SNPs are also assessed for pleiotropy using the "phenome-wide association study" approach, testing each SNP for associations with hundreds of phenotypes. PAGE data will be deposited into the National Center for Biotechnology Information's Database of Genotypes and Phenotypes and made available via a custom browser. C1 [Matise, Tara C.; Buyske, Steven] Rutgers State Univ, Dept Genet, Sch Arts & Sci, Piscataway, NJ 08854 USA. [Ambite, Jose Luis] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA. [Buyske, Steven] Rutgers State Univ, Dept Stat, Sch Arts & Sci, Piscataway, NJ 08854 USA. [Cole, Shelley A.] SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. [Crawford, Dana C.; Ritchie, Marylyn D.; Haines, Jonathan L.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Crawford, Dana C.; Ritchie, Marylyn D.; Haines, Jonathan L.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN USA. [Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Heiss, Gerardo; North, Kari E.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Carlson, Christopher S.; Kooperberg, Charles; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr Hawaii, Program Epidemiol, Honolulu, HI 96813 USA. [Manolio, Teri A.; Hindorff, Lucia A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. RP Matise, TC (reprint author), Rutgers State Univ, Dept Genet, Sch Arts & Sci, Life Sci Bldg,145 Bevier Rd, Piscataway, NJ 08854 USA. EM matise@dls.rutgers.edu RI Crawford, Dana/C-1054-2012; Ritchie, Marylyn/C-1114-2012; Haines, Jonathan/C-3374-2012; OI Buyske, Steven/0000-0001-8539-5416 FU National Human Genome Research Institute (NHGRI) [U01HG004798, U01HG004802, U01HG004790, U01HG004803]; National Institutes of Health [U01HG004798, U01HG004802, U01HG004790, U01HG004803, U01HG004801]; Centers for Disease Control and Prevention; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-55015]; US Department of Health and Human Services [N01WH22110]; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; PAGE Coordinating Center [U01HG004801]; Coordinating Center; [N01-HC-85079]; [N01-HC-85086]; [N01-HC-35129]; [N01-HC-15103]; [N01 HC-55222]; [N01-HC-75150]; [N01-HC-45133] FX PAGE is funded by the National Human Genome Research Institute (NHGRI) and is supported by National Institutes of Health grants U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (Multiethnic Cohort Study), U01HG004790 (WHI), and U01HG004801 (Coordinating Center).; The EAGLE Study is funded through the NHGRI PAGE program (grant U01HG004798). The study participants were derived from the National Health and Nutrition Examination Surveys, which are supported by the Centers for Disease Control and Prevention. (The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention).; Characterization of epidemiological architecture in the Multiethnic Cohort Study is funded through the NHGRI PAGE program (grant U01HG004802). The Multiethnic Cohort Study is funded by the National Cancer Institute (grants R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758).; Funding for the study of the epidemiology of putative genetic variants in the WHI is provided through the NHGRI PAGE program (grant U01HG004790). The WHI is funded by the National Heart, Lung, and Blood Institute (NHLBI) and the US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. (The authors thank the WHI investigators and staff for their dedication). A full listing of WHI investigators can be found at http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf.; Funding for the CALiCo consortium was provided through the NHGRI PAGE program (grant U01HG004803). The ARIC Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The CARDIA Study is supported by the following NHLBI contracts: N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, and N01-HC-45205. The Cardiovascular Health Study is supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133 and grants U01HL080295 and R01 HL087652 from the NHLBI, with an additional contribution from the National Institute of Neurological Disorders and Stroke. Genome-wide association study DNA handling and genotyping in the Cardiovascular Health Study was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center genotyping core and by National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The HCHS/SOL is supported by NHLBI contracts N01-HC65233, N01-HC65234, N01-HC65235, N01-HC65236, and N01-HC65237. The following institutes/centers/offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: the National Center on Minority Health and Health Disparities, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. The Strong Heart Study is supported by NHLBI grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, and U01 HL65521. (The opinions expressed in this paper are those of the author(s) and do not necessarily reflect the views of the Indian Health Service).; Assistance with phenotype harmonization; single nucleotide polymorphism selection and annotation; data cleaning; data management, integration, and dissemination; and general study coordination is provided by the PAGE Coordinating Center (grant U01HG004801). The National Institute of Mental Health also provides financial support for the Coordinating Center. NR 30 TC 74 Z9 74 U1 3 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 OCT 1 PY 2011 VL 174 IS 7 BP 849 EP 859 DI 10.1093/aje/kwr160 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 823ZC UT WOS:000295166500011 PM 21836165 ER PT J AU Engels, EA Pfeiffer, RM Ricker, W Wheeler, W Parsons, R Warren, JL AF Engels, Eric A. Pfeiffer, Ruth M. Ricker, Winnie Wheeler, William Parsons, Ruth Warren, Joan L. TI Use of Surveillance, Epidemiology, and End Results-Medicare Data to Conduct Case-Control Studies of Cancer Among the US Elderly SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE aged; case-control studies; data collection; epidemiologic methods; Medicare; neoplasms; risk factors; SEER Program ID POSITIVE PREDICTIVE-VALUE; AUTOIMMUNE CONDITIONS; TRANSPLANT RECIPIENTS; HOSPITAL RECORDS; SUBSEQUENT RISK; MALIGNANCIES; CLAIMS; METAANALYSIS; INFECTION; HEPATITIS AB Cancer is an important cause of morbidity in the elderly, and many medical conditions and treatments influence cancer risk. The Surveillance, Epidemiology, and End Results (SEER)-Medicare database can be used to conduct population-based case-control studies that elucidate the etiology of cancer among the US elderly. SEER-Medicare links data on malignancies ascertained through SEER cancer registries to claims from Medicare, the US government insurance program for people over age 65 years. Under one approach described herein, elderly cancer cases are ascertained from SEER data (1987-2005). Matched controls are selected from a 5% random sample of Medicare beneficiaries. Risk factors of interest, including medical conditions and procedures, are identified by using linked Medicare claims. Strengths of this design include the ready availability of data, representative sampling from the US elderly population, and large sample size (e.g., under one scenario: 1,176,950 cases, including 221,389 prostate cancers, 185,853 lung cancers, 138,041 breast cancers, and 124,442 colorectal cancers; and 100,000 control subjects). Limitations reflect challenges in exposure assessment related to Medicare claims: restricted range of evaluable risk factors, short time before diagnosis/selection for ascertainment, and inaccuracies in claims. With awareness of limitations, investigators have in SEER-Medicare data a valuable resource for epidemiologic research on cancer etiology. C1 [Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ricker, Winnie; Wheeler, William; Parsons, Ruth] Informat Management Serv Inc, Rockville, MD USA. [Warren, Joan L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Engels, EA (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7076, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov FU National Cancer Institute FX This research was supported by the National Cancer Institute. NR 21 TC 45 Z9 46 U1 0 U2 5 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 OCT 1 PY 2011 VL 174 IS 7 BP 860 EP 870 DI 10.1093/aje/kwr146 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 823ZC UT WOS:000295166500012 PM 21821540 ER PT J AU George, RT Arbab-Zadeh, A Cerci, RJ Vavere, AL Kitagawa, K Dewey, M Rochitte, CE Arai, AE Paul, N Rybicki, FJ Lardo, AC Clouse, ME Lima, JAC AF George, Richard T. Arbab-Zadeh, Armin Cerci, Rodrigo J. Vavere, Andrea L. Kitagawa, Kakuya Dewey, Marc Rochitte, Carlos E. Arai, Andrew E. Paul, Narinder Rybicki, Frank J. Lardo, Albert C. Clouse, Melvin E. Lima, Joao A. C. TI Diagnostic Performance of Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320-MDCT: The CT Angiography and Perfusion Methods of the CORE320 Multicenter Multinational Diagnostic Study SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE coronary atherosclerosis; coronary CT angiography; myocardial CT perfusion imaging; myocardial ischemia; SPECT ID EMISSION COMPUTED-TOMOGRAPHY; AMERICAN-HEART-ASSOCIATION; INCREMENTAL PROGNOSTIC VALUE; ARTERY-DISEASE; CLINICAL CARDIOLOGY; ADENOSINE STRESS; ACCURACY; COMMITTEE; QUANTIFICATION; METAANALYSIS AB OBJECTIVE. Coronary MDCT angiography has been shown to be an accurate noninvasive tool for the diagnosis of obstructive coronary artery disease (CAD). Its sensitivity and negative predictive value for diagnosing percentage of stenosis are unsurpassed compared with those of other noninvasive testing methods. However, in its current form, it provides no information regarding the physiologic impact of CAD and is a poor predictor of myocardial ischemia. CORE320 is a multicenter multinational diagnostic study with the primary objective to evaluate the diagnostic accuracy of 320-MDCT for detecting coronary artery luminal stenosis and corresponding myocardial perfusion deficits in patients with suspected CAD compared with the reference standard of conventional coronary angiography and SPECT myocardial perfusion imaging. CONCLUSION. We aim to describe the CT acquisition, reconstruction, and analysis methods of the CORE320 study. C1 [George, Richard T.; Arbab-Zadeh, Armin; Cerci, Rodrigo J.; Vavere, Andrea L.; Lardo, Albert C.; Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Div Cardiol, Dept Med, Baltimore, MD 21287 USA. [Kitagawa, Kakuya] Mie Univ Hosp, Dept Radiol, Tsu, Mie, Japan. [Dewey, Marc] Free Univ Berlin, Berlin, Germany. [Dewey, Marc] Humboldt Univ Berline, Charite Med Sch, Dept Radiol, Berlin, Germany. [Rochitte, Carlos E.] Univ Sao Paulo, InCor Sao Paulo Heart Inst, Sao Paulo, Brazil. [Arai, Andrew E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Paul, Narinder] Univ Toronto, Toronto Gen Hosp, Dept Med Imaging, Toronto, ON M5G 1L7, Canada. [Rybicki, Frank J.] Harvard Univ, Brigham & Womens Hosp, Appl Imaging Sci Lab, Boston, MA 02115 USA. [Clouse, Melvin E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP George, RT (reprint author), Johns Hopkins Univ, Sch Med, Div Cardiol, Dept Med, 600 N Wolfe St,Carnegie Bldg 565C, Baltimore, MD 21287 USA. EM rgeorge3@jhmi.edu OI Dewey, Marc/0000-0002-4402-2733 FU Toshiba Medical Systems FX This study was supported by a research grant from Toshiba Medical Systems. NR 36 TC 60 Z9 63 U1 0 U2 5 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD OCT PY 2011 VL 197 IS 4 BP 829 EP 837 DI 10.2214/AJR.10.5689 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 822WL UT WOS:000295081000052 PM 21940569 ER PT J AU Mandelblatt, J Cronin, K AF Mandelblatt, Jeanne Cronin, Kathleen CA CISNET Breast Canc Working Grp TI Response to Hendrick and Helvie by the Cancer Intervention Surveillance Modeling Network (CISNET) Breast Working Group SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Letter C1 [Mandelblatt, Jeanne] Lombardi Canc Ctr, Washington, DC USA. [Cronin, Kathleen] NCI, Bethesda, MD 20892 USA. RP Mandelblatt, J (reprint author), Lombardi Canc Ctr, Washington, DC USA. NR 3 TC 1 Z9 1 U1 0 U2 3 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD OCT PY 2011 VL 197 IS 4 BP W792 EP W792 DI 10.2214/AJR.11.6749 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 822WL UT WOS:000295081000042 PM 21940561 ER PT J AU Carney, JA Stratakis, CA AF Carney, J. Aidan Stratakis, Constantine A. TI Virilizing Ovarian Stromal Tumor in a Young Woman With Carney Complex SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE Carney complex; ovarian tumor; virilizing tumor; myeloid metaplasia; PRKAR1A gene ID HYALINIZING ANGIECTATIC TUMOR; PEUTZ-JEGHERS-SYNDROME; ENDOCRINE OVERACTIVITY; SPOTTY PIGMENTATION; CELL TUMORS; CLINICOPATHOLOGICAL ANALYSIS; CUTANEOUS MYXOMAS; FEATURES; GENETICS; LESION AB A woman with Carney complex presented at the age of 22 years with abdominal pain and hirsutism. As a baby, she had undergone excision of a right eyelid lesion, and at age 14 years she had undergone removal of a left lower eyelid nodule that subsequently recurred. Investigation revealed an elevated level of serum testosterone and a 2-cm left ovarian tumor. A left salpingo-oophorectomy was performed. Postoperatively, she experienced relief from abdominal pain, the serum level of testosterone normalized, and the hirsutism ameliorated. The tumor featured sheets of eosinophilic cells with lipochrome pigment, myeloid metaplasia, stromal metaplasia, and markedly abnormal blood vessels. Immunocytochemically, the tumor cells were positive for vimentin, synaptophysin, inhibin-A, and calrenin. Because of the clinical setting in which the neoplasm occurred, it is likely that is occurrence was related to Carney complex. C1 [Carney, J. Aidan] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Stratakis, Constantine A.] NICHD, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. RP Carney, JA (reprint author), Mayo Clin, Dept Lab Med & Pathol, 200 1st St SW, Rochester, MN 55905 USA. EM carney.aidan@mayo.edu FU NICHD, NIH [Z01 HD000642-04] FX Intramural Program, NICHD, NIH, project: Z01 HD000642-04. NR 25 TC 4 Z9 5 U1 0 U2 2 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 OCT PY 2011 VL 35 IS 10 BP 1592 EP 1599 DI 10.1097/PAS.0b013e31822a24a6 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 822WK UT WOS:000295080800019 PM 21934476 ER PT J AU Bland, KI Hoyt, DB Polk, HC Niederhuber, JE AF Bland, Kirby I. Hoyt, David B. Polk, Hiram C., Jr. Niederhuber, John E. TI Comparative Effectiveness Research Relative and Efficient Outcomes in Surgery Patients SO ANNALS OF SURGERY LA English DT Article; Proceedings Paper CT 131st Annual Scientific Meeting of the American-Surgical-Association CY APR 11-16, 2011 CL Boca Raton, FL SP Amer Surg Assoc ID GENOMIC MEDICINE; QUALITY; CARE; HEALTH; SAFETY; POLICY; COST C1 [Bland, Kirby I.] Univ Alabama, Dept Surg, UAB Comprehens Canc Ctr, Birmingham, AL 35294 USA. [Hoyt, David B.] Amer Coll Surg, Chicago, IL USA. [Hoyt, David B.] Univ Calif Irvine, Dept Surg, Irvine, CA 92717 USA. [Polk, Hiram C., Jr.] Univ Louisville, Dept Surg, Price Inst Surg Res, Louisville, KY 40292 USA. [Polk, Hiram C., Jr.] Inova Hlth Syst, Inova Translat Med Inst, Falls Church, VA USA. [Niederhuber, John E.] Johns Hopkins Sch Med, Dept Oncol, Bethesda, MD USA. [Niederhuber, John E.] Johns Hopkins Clin Res Network, Bethesda, MD USA. [Niederhuber, John E.] NCI, NIH, Bethesda, MD 20892 USA. RP Bland, KI (reprint author), Univ Alabama, Dept Surg, UAB Comprehens Canc Ctr, 1530 3rd Ave S,502 BDB, Birmingham, AL 35294 USA. EM Kirby.Bland@ccc.uab.edu NR 32 TC 3 Z9 3 U1 1 U2 4 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 OCT PY 2011 VL 254 IS 4 BP 550 EP 557 DI 10.1097/SLA.0b013e3182314074 PG 8 WC Surgery SC Surgery GA 823XX UT WOS:000295162400002 PM 21946216 ER PT J AU Agurs-Collins, T Fuemmeler, BF AF Agurs-Collins, Tanya Fuemmeler, Bernard F. TI Dopamine polymorphisms and depressive symptoms predict foods intake. Results from a nationally representative sample SO APPETITE LA English DT Article DE Adolescent; Diet; Dopamine; Depression ID BODY-MASS INDEX; RECEPTOR GENE; CONSUMPTION FREQUENCY; TRANSPORTER DENSITY; GENDER-DIFFERENCES; ADOLESCENT HEALTH; PERCEIVED STRESS; MAJOR DEPRESSION; OBESITY; GENOTYPE AB Depression and variation in dopamine related genes have both independently been associated with food consumption. Depressive symptoms could synergistically interact with genetic variation to influence food intake. We examined the interaction between high depressive symptoms and functional polymorphisms of dopamine transporter (SLC6A3), monoamine oxidase A (MAOA), dopamine receptor D2 (DRD2) and dopamine receptor 04 (DRD4) on intake of high-calorie sweet, high-calorie non-sweet, and low-calorie foods in the National Longitudinal Study of Adolescent Health (Add Health). Multivariate linear regression analyses were used to examine main effects of gene and depression symptoms and their interaction (genotype-by-high depression symptoms) on food categories. Applying a false discovery rate criterion for multiple comparisons indicated a statistically significant interaction for females with high depressive symptoms and the SLC6A3 gene, such that those with the SLC6A3 10/10 allele reported greater intake of high-calorie sweet foods than their counterparts high in depressive symptoms with the SLC6A3 any 9 allele (LS mean 10/10 allele = 2.5, SE =.13; LS mean any 9 allele = 1.8, SE =.13,p < .05). These findings highlight that the relationship between depression and food intake may vary as a function of genetic polymorphism. Further research is needed to confirm these findings. Published by Elsevier Ltd. C1 [Agurs-Collins, Tanya] NCI, Hlth Behav Res Branch, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Fuemmeler, Bernard F.] Dept Community & Family Med & Psychol & Neurosci, Durham, NC 27710 USA. RP Agurs-Collins, T (reprint author), NCI, Hlth Behav Res Branch, Div Canc Control & Populat Sci, 6130 Execut Blvd, Rockville, MD 20852 USA. EM collinsta@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [P01-HD31921]; NCI [1K07CA124905] FX This research uses data from Add Health, a program project directed by Kathleen Mullan Harris and designed by J. Richard Udry, Peter S. Bearman, and Kathleen Mullan Harris at the University of North Carolina at Chapel Hill, and funded by Grant P01-HD31921 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cooperative funding from 23 other federal agencies and foundations. Special acknowledgment is due Ronald R. Rindfuss and Barbara1 Entwisle for assistance in the original design. Information on how to obtain the Add Health data files is available on the Add Health website (http://www.cpc.unc.edu/addhealth). No direct support was received from Grant P01-HD31921 for this analysis. Support to complete analyses was funded in part by a grant from NCI: 1K07CA124905 awarded to BFF. NR 62 TC 11 Z9 11 U1 4 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 J9 APPETITE JI Appetite PD OCT PY 2011 VL 57 IS 2 BP 339 EP 348 DI 10.1016/j.appet.2011.05.325 PG 10 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA 823IH UT WOS:000295115200005 PM 21672565 ER PT J AU Mathur, A Moses, W Rahbari, R Khanafshar, E Duh, QY Clark, O Kebebew, E AF Mathur, Aarti Moses, Willeford Rahbari, Reza Khanafshar, Elham Duh, Quan-Yang Clark, Orlo Kebebew, Electron TI Higher Rate of BRAF Mutation in Papillary Thyroid Cancer Over Time A Single-Institution Study SO CANCER LA English DT Article DE thyroid cancer; somatic mutations; incidence; prevalence; molecular changes ID INCREASED PATHOLOGICAL DETECTION; INCREASING INCIDENCE; UNITED-STATES; CARCINOMA; TRENDS AB BACKGROUND: The incidence of thyroid cancer has doubled over the past decade. The reason for this dramatic increase in incidence is controversial. Some investigators have suggested that the increased incidence is because of increased detection of small primary tumors as a result of diagnostic scrutiny. Conversely, some investigators have demonstrated an increased incidence across all tumor sizes, suggesting that other factors may play a role. This study was undertaken to investigate the clinical, pathologic, and molecular changes present in papillary thyroid cancer over a 15-year period during which the incidence of papillary thyroid cancer doubled. METHODS: A total of 628 patients with conventional papillary thyroid cancer and 228 tumor samples from a single institution were analyzed from 1991 to 2005. Time-trend analyses of demographic, clinical, pathologic, and tumor genotype were performed over three 5-year time periods: group I (1991-1995), group II (1996-2000), and group III (2001-2005). RESULTS: The authors found no differences in age, sex, ethnicity, primary tumor size, rate of extrathyroidal invasion, or overall TNM cancer stage among the 3 time groups. The rate of BRAF V600E mutation was significantly higher in group III (88% BRAF V600E positive) as compared with groups I and II (51% and 43%, respectively) (P < .001). The rate of all the common somatic mutations was also significantly higher in group III (92% positive) as compared with groups I and II (68% and 64%, respectively) (P < .002). CONCLUSIONS: The rate of BRAF V600E mutation increased significantly over a 15-year period at the authors' institution. The findings suggest that a higher rate of BRAF mutation in papillary thyroid cancer may contribute to the increasing incidence of thyroid cancer. Cancer 2011; 117: 4390-5. (C) 2011 American Cancer Society. C1 [Mathur, Aarti; Rahbari, Reza; Kebebew, Electron] NCI, Endocrine Oncol Sect, Surg Branch, Bethesda, MD 20892 USA. [Moses, Willeford; Duh, Quan-Yang; Clark, Orlo] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Khanafshar, Elham] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. RP Kebebew, E (reprint author), 10 Ctr Dr,MSC 1201,CRC Room 4-5952, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov FU American Cancer Society; National Cancer Institute; University of California, San Francisco Helen Diller Comprehensive Cancer Center FX This study was supported, in part, by grants from the American Cancer Society, National Cancer Institute, and University of California, San Francisco Helen Diller Comprehensive Cancer Center. NR 19 TC 47 Z9 49 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD OCT 1 PY 2011 VL 117 IS 19 BP 4390 EP 4395 DI 10.1002/cncr.26072 PG 6 WC Oncology SC Oncology GA 824TN UT WOS:000295225200010 PM 21412762 ER PT J AU Schmid, T Bajer, MM Blees, JS Eifler, LK Milke, L Rubsamen, D Schulz, K Weigert, A Baker, AR Colburn, NH Brune, B AF Schmid, Tobias Bajer, Magdalena M. Blees, Johanna S. Eifler, Lisa K. Milke, Larissa Ruebsamen, Daniela Schulz, Kathrin Weigert, Andreas Baker, Alyson R. Colburn, Nancy H. Bruene, Bernhard TI Inflammation-induced loss of Pdcd4 is mediated by phosphorylation-dependent degradation SO CARCINOGENESIS LA English DT Article ID TUMOR-SUPPRESSOR PDCD4; CELL-DEATH 4; CANCER-RELATED INFLAMMATION; COLON-CARCINOMA CELLS; PROGRAMMED CELL-DEATH-4; BREAST-CANCER; COLORECTAL-CANCER; PROGNOSTIC-FACTOR; STRUCTURAL BASIS; DOWN-REGULATION AB The tumor suppressor programmed cell death 4 (Pdcd4) is lost in various tumor tissues. Loss of Pdcd4 has been associated with increased tumorigenic potential and tumor progression. While various mechanisms of Pdcd4 regulation have been described, the effect of an inflammatory tumor microenvironment on Pdcd4 protein expression has not been characterized so far. In the present study, we aimed to elucidate the molecular mechanisms of Pdcd4 protein regulation in tumor cells under inflammatory conditions. 12-O-tetradecanoylphorbol 13-acetate-induced differentiation of human U937 monocytes increased the expression and secretion of inflammatory cytokines such as tumor necrosis factor alpha, interleukin (IL)-6 and IL-8. Exposure to conditioned medium (CM) of these activated macrophages markedly decreased Pdcd4 protein expression in various tumor cells. Similarly, indirect coculture with such activated U937 monocyte-derived macrophages resulted in the loss of Pdcd4 protein in tumor cells. Decreased Pdcd4 protein levels were attributable to enhanced proteasomal degradation, diminishing Pdcd4 protein half-life. Proteasomal degradation required activation of phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling. Since macrophage-CM sufficed to induce Pdcd4 degradation, Pdcd4 downregulation was determined to be an indirect unidirectional effect of the macrophages on the tumor cells. Pdcd4 protein expression was also attenuated in vivo in mouse colon tissue in response to dextran sodium sulfate-induced colitis. In summary, we characterized PI3K-mTOR-dependent proteasome-mediated Pdcd4 degradation in tumor cells in the inflammatory tumor microenvironment. Consequently, stabilization of Pdcd4 protein could provide a promising novel avenue for therapeutics targeting inflammation-associated tumors. C1 [Schmid, Tobias; Bajer, Magdalena M.; Blees, Johanna S.; Eifler, Lisa K.; Milke, Larissa; Ruebsamen, Daniela; Schulz, Kathrin; Weigert, Andreas; Bruene, Bernhard] Goethe Univ Frankfurt, Inst Biochem 1, Fac Med, D-60590 Frankfurt, Germany. [Baker, Alyson R.; Colburn, Nancy H.] NCI, Lab Canc Prevent, Frederick, MD 21702 USA. RP Schmid, T (reprint author), Goethe Univ Frankfurt, Inst Biochem 1, Fac Med, D-60590 Frankfurt, Germany. EM t.schmid@biochem.uni-frankfurt.de RI Weigert, Andreas/E-6540-2010 FU DFG [BR999, GRK1172]; LOEWE Schwerpunkt OSF [III L 4-518/55.004 (2009)]; Hessian Ministry of Higher Education, Research and Arts; National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This work was supported by the DFG (BR999, GRK1172); LOEWE Schwerpunkt OSF [III L 4-518/55.004 (2009)] funded by the Hessian Ministry of Higher Education, Research and Arts. Part of the work was supported by the Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research. NR 45 TC 22 Z9 22 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD OCT PY 2011 VL 32 IS 10 BP 1427 EP 1433 DI 10.1093/carcin/bgr131 PG 7 WC Oncology SC Oncology GA 824BE UT WOS:000295173200004 PM 21771721 ER PT J AU Coulouarn, C Factor, VM Conner, EA Thorgeirsson, SS AF Coulouarn, Cedric Factor, Valentina M. Conner, Elizabeth A. Thorgeirsson, Snorri S. TI Genomic modeling of tumor onset and progression in a mouse model of aggressive human liver cancer SO CARCINOGENESIS LA English DT Article ID GROWTH-FACTOR-ALPHA; EXPRESSING C-MYC; TRANSGENIC MICE; HEPATOCELLULAR-CARCINOMA; NKT CELLS; IMMUNITY; HEPATOCARCINOGENESIS; IMMUNOSURVEILLANCE; DISRUPTION; MODULATION AB A comprehensive understanding of molecular mechanisms driving cancer onset and progression should provide a basis for improving early diagnosis, biomarker discovery and treatment options. A key value of genetically engineered mice for modeling human cancer is the possibility to analyze the entire process of tumor development. Here, we applied functional genomics approach to study step-by-step development of hepatocellular carcinoma (HCC) in the c-Myc/Tgf alpha transgenic mouse model of aggressive human liver cancer. We report that coexpression of c-Myc and Tgf alpha induces progressive and cumulative transcriptional alterations in the course of liver oncogenesis. Functional analysis of deregulated genes at the early stage of HCC disease supports a model of active hepatocyte proliferation on the background of chronic oxidative stress generated by a general metabolic disorder. In addition, early and persistent deregulation of numerous immune-related genes suggested that disruption of immune microenvironment may contribute to oncogenic process in this model of accelerated liver carcinogenesis. In particularly, by flow cytometry analysis, we found loss of the major histocompatibility complex class I expression in dysplastic hepatocytes followed by upregulation of numerous activating ligands for natural killer (NK) cells concomitant with a drastic decrease in hepatic NK cell frequency. In conclusion, our study provides a comprehensive characterization of sequential molecular changes during a stepwise progression of preneoplastic lesions toward HCC and highlights a critical role of metabolic disorders and innate immunity at the early stages of liver cancer. C1 [Coulouarn, Cedric; Factor, Valentina M.; Conner, Elizabeth A.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Coulouarn, Cedric] Univ Rennes 1, INSERM, UMR991, Hop Pontchaillou, F-35033 Rennes, France. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov RI Coulouarn, Cedric/E-5472-2011 FU NIH/CCR/NCI, USA; NIH; Association pour la Recherche sur le Cancer, France FX This research was supported by the intramural research program of the NIH/CCR/NCI, USA. C. C. is a recipient of a fellowship from NIH and Association pour la Recherche sur le Cancer, France. NR 37 TC 15 Z9 16 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD OCT PY 2011 VL 32 IS 10 BP 1434 EP 1440 DI 10.1093/carcin/bgr133 PG 7 WC Oncology SC Oncology GA 824BE UT WOS:000295173200005 PM 21771728 ER PT J AU Tang, L Yao, S Till, C Goodman, PJ Tangen, CM Wu, Y Kristal, AR Platz, EA Neuhouser, ML Stanczyk, FZ Reichardt, JKV Santella, RM Hsing, A Hoque, A Lippman, SM Thompson, IM Ambrosone, CB AF Tang, Li Yao, Song Till, Cathee Goodman, Phyllis J. Tangen, Catherine M. Wu, Yue Kristal, Alan R. Platz, Elizabeth A. Neuhouser, Marian L. Stanczyk, Frank Z. Reichardt, Juergen K. V. Santella, Regina M. Hsing, Ann Hoque, Ashraful Lippman, Scott M. Thompson, Ian M. Ambrosone, Christine B. TI Repeat polymorphisms in estrogen metabolism genes and prostate cancer risk: results from the Prostate Cancer Prevention Trial SO CARCINOGENESIS LA English DT Article ID ENDOGENOUS SEX-HORMONES; AROMATASE; ANDROGEN; CYP19; BREAST; CARCINOGENESIS; BIOSYNTHESIS; ASSOCIATION; COMBINATION; MALIGNANCY AB The etiology of prostate cancer remains elusive, although steroid hormones probably play a role. Considering the carcinogenic potential of estrogen metabolites as well as altered intraprostatic estrogen biosynthesis during the development of prostate cancer, we investigated associations between repeat polymorphisms of three key estrogen-related genes (CYP11A1, CYP19A1, UGT1A1) and risk of prostate cancer in the Prostate Cancer Prevention Trial (PCPT), designed to test finasteride versus placebo as a chemoprevention agent. Using data and specimens from 1154 cases and 1351 controls who were frequency matched on age, family history of prostate cancer and PCPT treatment arm, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) separately in the placebo and finasteride arms. Among men in the placebo arm, CYP19A1 7/8 genotype carriers had a significantly higher risk of prostate cancer compared with those with the 7/7 genotype (OR = 1.70, 95% CI = 1.16-2.5), regardless of Gleason grade. This genotype was also associated with elevated serum estrogen levels. For the (TA)(n) repeat polymorphism in UGT1A1, the heterozygous short (< 7 repeats)/long (>= 7 repeats) genotype was significantly associated with the risk of low-grade prostate cancer (OR = 1.34, 95% CI = 1.05-1.70) compared with the short/short genotype. No significant association was found with CYP11A1. These associations were not observed among men in the finasteride arm. The results indicate that repeat polymorphisms in genes involved in estrogen biosynthesis and metabolism may influence risk of prostate cancer but that their effects may be modified by factors altering hormone metabolism, such as finasteride treatment. C1 [Tang, Li; Yao, Song; Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Till, Cathee; Goodman, Phyllis J.; Tangen, Catherine M.; Kristal, Alan R.; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Stanczyk, Frank Z.] Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. [Reichardt, Juergen K. V.] James Cook Univ, Sch Pharm & Mol Sci, Townsville, Qld 4811, Australia. [Santella, Regina M.] Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Hsing, Ann] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hoque, Ashraful] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. [Lippman, Scott M.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. RP Tang, L (reprint author), Roswell Pk Canc Inst, Dept Canc Prevent & Control, Elm & Carlton St,Carlton House Room 342, Buffalo, NY 14263 USA. EM li.tang@roswellpark.org RI Yao, Song/A-2534-2012; OI Kristal, Alan/0000-0002-7329-1617; Reichardt, Juergen/0000-0001-6458-2773 FU National Cancer Institute [P01 CA108964] FX National Cancer Institute (P01 CA108964). NR 38 TC 11 Z9 11 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD OCT PY 2011 VL 32 IS 10 BP 1500 EP 1506 DI 10.1093/carcin/bgr139 PG 7 WC Oncology SC Oncology GA 824BE UT WOS:000295173200013 PM 21771722 ER PT J AU Choudhury, SR Balasubramanian, S Chew, YC Han, BS Marquez, VE Eckert, RL AF Choudhury, Subhasree Roy Balasubramanian, Sivaprakasam Chew, Yap Ching Han, Bingshe Marquez, Victor E. Eckert, Richard L. TI (-)-Epigallocatechin-3-gallate and DZNep reduce polycomb protein level via a proteasome-dependent mechanism in skin cancer cells SO CARCINOGENESIS LA English DT Article ID TEA POLYPHENOL (-)-EPIGALLOCATECHIN-3-GALLATE; HISTONE METHYLTRANSFERASE ACTIVITY; GREEN TEA; HDAC INHIBITORS; PROSTATE-CANCER; COMPLEX; GENE; REPRESSION; BMI-1; H3 AB Polycomb group (PcG) protein-dependent histone methylation and ubiquitination drives chromatin compaction leading to reduced tumor suppressor expression and increased cancer cell survival. Green tea polyphenols and S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors are important candidate chemopreventive agents. Previous studies indicate that (-)-epigallocatechin-3-gallate (EGCG), a potent green tea polyphenol, suppresses PcG protein level and skin cancer cell survival. Inhibition of AdoHcy hydrolase with 3-deazaneplanocin A (DZNep) inhibits methyltransferases by reducing methyl group availability. In the present study, we examine the impact of EGCG and DZNep cotreatment on skin cancer cell function. EGCG and DZNep, independently and in combination, reduce the level of PcG proteins including Ezh2, eed, Suz12, Mel18 and Bmi-1. This is associated with reduced H3K27me3 and H2AK119ub formation, histone modifications associated with closed chromatin. Histone deacetylase 1 level is also reduced and acetylated H3 formation is increased. These changes are associated with increased tumor suppressor expression and reduced cell survival and are partially reversed by vector-mediated maintenance of Bmi-1 level. The reduction in PcG protein level is associated with increased ubiquitination and is reversed by proteasome inhibitors, suggesting proteasome-associated degradation. C1 [Choudhury, Subhasree Roy; Balasubramanian, Sivaprakasam; Chew, Yap Ching; Han, Bingshe; Eckert, Richard L.] Univ Maryland, Dept Biochem & Mol Biol, Sch Med, Baltimore, MD 21201 USA. [Eckert, Richard L.] Univ Maryland, Dept Dermatol, Sch Med, Baltimore, MD 21201 USA. [Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Eckert, Richard L.] Univ Maryland, Dept Obstet Gynecol & Reprod Sci, Sch Med, Baltimore, MD 21201 USA. RP Eckert, RL (reprint author), Univ Maryland, Dept Biochem & Mol Biol, Sch Med, 108 N Greene St,Room 103, Baltimore, MD 21201 USA. EM reckert@umaryland.edu FU National Institutes of Health [AR053851, CA131074] FX National Institutes of Health (AR053851 and CA131074 to R.L.E.). NR 62 TC 55 Z9 55 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD OCT PY 2011 VL 32 IS 10 BP 1525 EP 1532 DI 10.1093/carcin/bgr171 PG 8 WC Oncology SC Oncology GA 824BE UT WOS:000295173200017 PM 21798853 ER PT J AU Yeshayahu, Y Tallett, S Pacak, K De Souza, C Palmert, MR AF Yeshayahu, Yonatan Tallett, Susan Pacak, Karel De Souza, Claire Palmert, Mark R. TI When is a phaeo not a phaeo? Depression in an adolescent leading to a phaeochromocytoma-like biochemical profile SO CLINICAL ENDOCRINOLOGY LA English DT Letter ID DIAGNOSIS C1 [Yeshayahu, Yonatan; Tallett, Susan; De Souza, Claire; Palmert, Mark R.] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Yeshayahu, Yonatan; Tallett, Susan; Palmert, Mark R.] Univ Toronto, Dept Paediat, Toronto, ON M5S 1A1, Canada. [Pacak, Karel] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [De Souza, Claire] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. RP Yeshayahu, Y (reprint author), Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. EM yonniy@gmail.com FU Intramural NIH HHS [ZIA HD008735-11] NR 5 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD OCT PY 2011 VL 75 IS 4 BP 567 EP 568 DI 10.1111/j.1365-2265.2011.04063.x PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 822LO UT WOS:000295048600024 PM 21521331 ER PT J AU Naiche, LA Arora, R Kania, A Lewandoski, M Papaioannou, VE AF Naiche, L. A. Arora, Ripla Kania, Artur Lewandoski, Mark Papaioannou, Virginia E. TI Identity and Fate of Tbx4-Expressing Cells Reveal Developmental Cell Fate Decisions in the Allantois, Limb, and External Genitalia SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Tbx4; allantois; limb; hindlimb; lung; genital tubercle; mouse; development ID T-BOX GENES; HEMATOPOIETIC STEM-CELLS; MURINE ALLANTOIS; EMBRYONIC-DEVELOPMENT; VERTEBRATE LIMBS; MOUSE EMBRYOS; TBX4 GENE; EXPRESSION; SPECIFICATION; OUTGROWTH AB T-box gene Tbx4 is critical for the formation of the umbilicus and the initiation of the hindlimb. Previous studies show broad expression in the allantois, hindlimb, lung and proctodeum. We have examined the expression of Tbx4 in detail and used a Tbx4-Cre line to trace the fates of Tbx4-expressing cells. Tbx4 expression and lineage reveal that various distinct appendages, such as the allantois, hindlimb, and external genitalia, all arise from a single mesenchymal expression domain. Additionally, although Tbx4 is associated primarily with the hindlimb, we find two forelimb expression domains. Most notably, we find that, despite the requirement for Tbx4 in allantoic vasculogenesis, the presumptive endothelial cells of the allantois do not express Tbx4 and lineage tracing reveals that the umbilical vasculature never expresses Tbx4. These results suggest that endothelial lineages are segregated before the onset of vasculogenesis, and demonstrate a role for the peri-vascular tissue in vasculogenesis. Developmental Dynamics 240:2290-2300, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Arora, Ripla; Papaioannou, Virginia E.] Columbia Univ, Dept Genet & Dev, Coll Phys & Surg, New York, NY 10032 USA. [Naiche, L. A.; Lewandoski, Mark] NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. [Kania, Artur] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada. [Kania, Artur] Inst Rech Clin Montreal, Neural Circuit Dev Lab, Montreal, PQ H2W 1R7, Canada. RP Papaioannou, VE (reprint author), Columbia Univ, Dept Genet & Dev, Coll Phys & Surg, HHSC 1402,701 W 168th St, New York, NY 10032 USA. EM Lewandom@mail.nih.gov; vep1@columbia.edu OI Papaioannou, Virginia/0000-0001-7558-8601 FU NIH [RO1-HD033082, HD033082]; NCI FX Grant sponsor: NIH; Grant number: RO1-HD033082.; We thank Thomas Jessell for material and mentoring assistance, Xin Sun and Bin Zhou for pathology assistance, Jeremy Gibson-Brown for commenting on the manuscript, and the NCI histopathology lab for their help with sectioning. M. L. was funded by NCI intramural funding and V. E. P. was funded by the NIH (HD033082). NR 51 TC 21 Z9 21 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD OCT PY 2011 VL 240 IS 10 BP 2290 EP 2300 DI 10.1002/dvdy.22731 PG 11 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 823VQ UT WOS:000295155100007 PM 21932311 ER PT J AU Deng, XM Xiong, XM Khomenko, T Sandor, Z Osapay, K Tolstanova, G Shiloach, J Chen, LC Folkman, J Szabo, S AF Deng, Xiaoming Xiong, Ximing Khomenko, Tetyana Sandor, Zsuzsanna Osapay, Klara Tolstanova, Ganna Shiloach, Joseph Chen, Longchuan Folkman, Judah Szabo, Sandor TI Inappropriate Angiogenic Response as a Novel Mechanism of Duodenal Ulceration and Impaired Healing SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Duodenal ulcer; Angiogenic imbalance; VEGF; Endostatin; Angiostatin; MMP2; TIMP-1 ID ENDOTHELIAL GROWTH-FACTOR; VENOUS LEG ULCERS; MATRIX METALLOPROTEINASES; PEPTIC-ULCER; EXTRACELLULAR-MATRIX; HUMAN ENDOSTATIN; GASTRIC-ULCER; UNITED-STATES; TUMOR-GROWTH; IN-VITRO AB Background Despite recent advances and better understanding of the etiology and the pathogenesis of gastrointestinal ulcer diseases, e.g., duodenal ulcer, the molecular events leading to ulcer development, delayed healing, and recurrence remain poorly elucidated. Aims After we found that duodenal ulcers did not heal despite increased levels of vascular endothelial growth factor (VEGF), we tested the hypothesis that an imbalance in angiogenic VEGF and anti-angiogenic endostatin and angiostatin might be important in the development and delayed healing of experimental duodenal ulcers. Methods Levels of VEGF, endostatin, and angiostatin, and the expression and activity of related matrix metalloproteinases (MMP) 2 and 9 were measured in scrapings of rat proximal duodenal mucosa in the early and late stages of chemically induced duodenal ulceration. Furthermore, animals were treated with recombinant endostatin and MMP 2 inhibitor to test the relationship between MMP2 and endostatin and their involvement in healing of experimental duodenal ulcers. Results A concurrent increase of duodenal VEGF, endostatin, and angiostatin was noted during duodenal ulceration. Endostatin treatment aggravated duodenal ulcer. Levels of MMP2, but not MMP9, were increased. Inhibition of MMP2 reduced levels of endostatin and angiostatin, and attenuated duodenal ulcers. Conclusions Increased levels of endostatin and angiostatin induced by MMP2 delayed healing of duodenal ulcers despite concurrently increased VEGF. Thus, an inappropriate angiogenic response or "angiogenic imbalance" may be an important new mechanism in ulcer development and impaired healing. C1 [Sandor, Zsuzsanna; Szabo, Sandor] VA Med Ctr, Med Hlth Care Grp, Long Beach, CA 90822 USA. [Deng, Xiaoming; Khomenko, Tetyana; Tolstanova, Ganna; Szabo, Sandor] Univ Calif Irvine, Dept Pathol, Irvine, CA 92697 USA. [Sandor, Zsuzsanna] Univ Calif Irvine, Dept Med, Irvine, CA 92697 USA. [Shiloach, Joseph] NIDDK, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. [Folkman, Judah] Harvard Univ, Sch Med, Childrens Hosp, Dept Pediat Surg, Boston, MA 02115 USA. [Folkman, Judah] Harvard Univ, Sch Med, Childrens Hosp, Dept Cell Biol, Boston, MA 02115 USA. [Szabo, Sandor] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92697 USA. RP Szabo, S (reprint author), VA Med Ctr, Med Hlth Care Grp, 5901 E 7th St, Long Beach, CA 90822 USA. EM sandor.szabo@va.gov FU Department of Veterans Affairs, Veterans Health Administration FX This study was supported by a Department of Veterans Affairs, Veterans Health Administration Merit Review grant and by contributions from CPRC, Inc. NR 49 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD OCT PY 2011 VL 56 IS 10 BP 2792 EP 2801 DI 10.1007/s10620-011-1753-4 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 823YP UT WOS:000295164600023 PM 21735086 ER PT J AU Maudsley, S Martin, B Egan, JM AF Maudsley, Stuart Martin, Bronwen Egan, Josephine M. TI To Be or Not To Be-Obese SO ENDOCRINOLOGY LA English DT Editorial Material ID CANNABINOID-1 RECEPTOR BLOCKER; MU-OPIOID-RECEPTOR; FOOD-INTAKE; CB1 RECEPTOR; RISK-FACTORS; BODY-WEIGHT; OVERWEIGHT PATIENTS; ENERGY-BALANCE; DOUBLE-BLIND; RIMONABANT C1 [Maudsley, Stuart; Martin, Bronwen; Egan, Josephine M.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Egan, JM (reprint author), NIA, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM eganj@vax.grc.nia.nih.gov FU Intramural NIH HHS NR 41 TC 3 Z9 3 U1 1 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2011 VL 152 IS 10 BP 3592 EP 3596 DI 10.1210/en.2011-1615 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 822WN UT WOS:000295081200003 PM 21937750 ER PT J AU Zemkova, H Stojilkovic, SS Klein, DC AF Zemkova, Hana Stojilkovic, Stanko S. Klein, David C. TI Norepinephrine Causes a Biphasic Change in Mammalian Pinealocye Membrane Potential: Role of alpha(1B)-Adrenoreceptors, Phospholipase C, and Ca2+ SO ENDOCRINOLOGY LA English DT Article ID ARYLALKYLAMINE N-ACETYLTRANSFERASE; PROTEIN-KINASE-C; RAT PINEALOCYTES; CALCIUM-CHANNELS; ALPHA-1-ADRENERGIC STIMULATION; DEPENDENT MECHANISM; DISSOCIATED CELLS; IONIC CURRENTS; IN-VITRO; GLAND AB Perforated patch clamp recording was used to study the control of membrane potential (V-m) and spontaneous electrical activity in the rat pinealocyte by norepinephrine. Norepinephrine did not alter spiking frequency. However, it was found to act through alpha(1B)-adrenoreceptors in a concentration-dependent manner(0.1-10 mu M) to produce a biphasic change in V-m. The initial response was a hyperpolarization (similar to 13 mV from a resting potential of -46 mV) due to a transient (similar to 5 sec) outward K+ current (similar to 50 pA). This current appears to be triggered by Ca2+ released from intracellular stores, based on the observation that it was also seen in cells bathed in Ca2+-deficient medium. In addition, pharmacological studies indicate that this current was dependent on phospholipase C (PLC) activation and was in part mediated by bicuculline methiodide and apamin-sensitive Ca2+-controlled K+ channels. The initial transient hyperpolarization was followed by a sustained depolarization (similar to 4mV) due to an inward current (similar to 10 pA). This response was dependent on PLC-dependent activation of Na+/Ca2+ influx but did not involve nifedipine-sensitive voltage-gated Ca2+ channels. Together, these results indicate for the first time that activation of alpha(1B)-adrenoreceptors initiates a PLC-dependent biphasic change in pinealocyte V-m characterized by an initial transient hyperpolarization mediated by a mixture of Ca2+-activated channels followed by a sustained depolarization mediated by a Ca2+ -conducting nonselective cation channel. These observations indicate that both continuous elevation of intracellular Ca2+ and sustained depolarization at approximately -40mV are associated with and are likely to be required for activation of the pinealocyte. (Endocrinology 152: 3842-3851, 2011) C1 [Stojilkovic, Stanko S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Zemkova, Hana] Acad Sci Czech Republic, Inst Physiol, CR-14220 Prague 4, Czech Republic. [Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), Natl Inst Hlth 49 6A82, Bethesda, MD 20892 USA. EM kleind@mail.nih.gov RI Zemkova, Hana/C-1844-2012 FU The National Institute of Child Health and Human Development, National Institutes of Health; Grant Agency of the Czech Republic [305/07/0681] FX This work was supported by funds from the Intramural Research Program of The National Institute of Child Health and Human Development, National Institutes of Health, and by a Grant Agency of the Czech Republic (Grant 305/07/0681) NR 49 TC 6 Z9 6 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2011 VL 152 IS 10 BP 3842 EP 3851 DI 10.1210/en.2011-1180 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 822WN UT WOS:000295081200029 PM 21828176 ER PT J AU Yu, W Yesupriya, A Wulf, A Hindorff, LA Dowling, N Khoury, MJ Gwinn, M AF Yu, Wei Yesupriya, Ajay Wulf, Anja Hindorff, Lucia A. Dowling, Nicole Khoury, Muin J. Gwinn, Marta TI GWAS Integrator: a bioinformatics tool to explore human genetic associations reported in published genome-wide association studies SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE genome-wide association studies; database; bioinformatics ID EPIDEMIOLOGY; KNOWLEDGE; DISEASE AB Genome-wide association studies (GWAS) have successfully identified numerous genetic loci that are associated with phenotypic traits and diseases. GWAS Integrator is a bioinformatics tool that integrates information on these associations from the National Human Genome Research institute (NHGRI) Catalog, SNAP (SNP Annotation and Proxy Search), and the Human Genome Epidemiology (HuGE) Navigator literature database. This tool includes robust search and data mining functionalities that can be used to quickly identify relevant associations from GWAS, as well as proxy single-nucleotide polymorphisms (SNPs) and potential candidate genes. Query-based University of California Santa Cruz (UCSC) Genome Browser custom tracks are generated dynamically on the basis of users' selected GWAS hits or candidate genes from HuGE Navigator literature database (http://www.hugenavigator.net/HuGENavigator/gWAHitStartPage.do). The GWAS Integrator may help enhance inference on potential genetic associations identified from GWAS studies. European Journal of Human Genetics (2011) 19, 1095-1099; doi:10.1038/ejhg.2011.91; published online 25 May 2011 C1 [Yu, Wei; Yesupriya, Ajay; Wulf, Anja; Dowling, Nicole; Khoury, Muin J.; Gwinn, Marta] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30341 USA. [Hindorff, Lucia A.] NHGRI, Office Populat Genom, NIH, Bethesda, MD 20892 USA. RP Yu, W (reprint author), Ctr Dis Control & Prevent, Off Publ Hlth Genom, 4770 Buford Highway,MS K-89, Atlanta, GA 30341 USA. EM wby0@cdc.gov NR 6 TC 21 Z9 21 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD OCT PY 2011 VL 19 IS 10 BP 1095 EP 1099 DI 10.1038/ejhg.2011.91 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 823KG UT WOS:000295120500016 PM 21610748 ER PT J AU Karargyris, A Bourbakis, N AF Karargyris, Alexandros Bourbakis, Nikolaos TI Detection of Small Bowel Polyps and Ulcers in Wireless Capsule Endoscopy Videos SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Bleeding; blood based; data mining; endoscopy; medical imaging; polyps; protrusions; small bowel; SUSAN edge detector; ulcers; wireless capsule ID SPATIAL-FREQUENCY; SEGMENTATION; FEATURES; CELLS AB Over the last decade, wireless capsule endoscopy (WCE) technology has become a very useful tool for diagnosing diseases within the human digestive tract. Physicians using WCE can examine the digestive tract in a minimally invasive way searching for pathological abnormalities such as bleeding, polyps, ulcers, and Crohn's disease. To improve effectiveness of WCE, researchers have developed software methods to automatically detect these diseases at a high rate of success. This paper proposes a novel synergistic methodology for automatically discovering polyps (protrusions) and perforated ulcers in WCE video frames. Finally, results of the methodology are given and statistical comparisons are also presented relevant to other works. C1 [Karargyris, Alexandros] NIH, Natl Lib Med, Bethesda, MD 20894 USA. [Bourbakis, Nikolaos] Wright State Univ, Assist Technol Res Ctr, Coll Engn, Dayton, OH 45435 USA. [Bourbakis, Nikolaos] AIIS, Dayton, OH 45458 USA. RP Karargyris, A (reprint author), NIH, Natl Lib Med, Bethesda, MD 20894 USA. EM akarargyris@gmail.com; nikolaos.bourbakis@wright.edu FU American Institute of Indian Studies FX Manuscript received December 14, 2010; revised March 3, 2011 and April 18, 2011; accepted April 27, 2011. Date of publication May 16, 2011; date of current version September 21, 2011. This work was supported in part by the American Institute of Indian Studies. Asterisk indicates corresponding author. NR 35 TC 36 Z9 36 U1 1 U2 9 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD OCT PY 2011 VL 58 IS 10 BP 2777 EP 2786 DI 10.1109/TBME.2011.2155064 PN 1 PG 10 WC Engineering, Biomedical SC Engineering GA 823JR UT WOS:000295119000009 PM 21592915 ER PT J AU Frangi, AF Coatrieux, JL Peng, GCY D'Argenio, DZ Marmarelis, VZ Michailova, A AF Frangi, Alejandro F. Coatrieux, Jean-Louis Peng, Grace C. Y. D'Argenio, David Z. Marmarelis, Vasilis Z. Michailova, Anushka TI Special Issue on Multiscale Modeling and Analysis in Computational Biology and Medicine-Part-1 SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Editorial Material ID VIRTUAL PHYSIOLOGICAL HUMAN; HUMAN-COMPUTER SIMULATION; PHYSIOME PROJECT; II INTRODUCTION; HUMAN TOOLS; BIOMEDICINE; FRAMEWORK; CELLML C1 [Frangi, Alejandro F.] Univ Pompeu Fabra, E-08018 Barcelona, Spain. [Frangi, Alejandro F.] Univ Sheffield, Sheffield S10 2TN, S Yorkshire, England. [Coatrieux, Jean-Louis] Univ Rennes 1, INSERM, U642, F-35042 Rennes, France. [Peng, Grace C. Y.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. [D'Argenio, David Z.; Marmarelis, Vasilis Z.] Univ So Calif, Los Angeles, CA 90089 USA. [Michailova, Anushka] Univ Calif San Diego, La Jolla, CA 92093 USA. RP Frangi, AF (reprint author), Univ Pompeu Fabra, E-08018 Barcelona, Spain. EM alejandro.frangi@upf.edu; jean-louis.coatrieux@univ-rennes1.fr; grace.peng@nih.gov; dargenio@bmsr.usc.edu; vzm@bmsr.usc.edu; amihaylo@bioeng.ucsd.edu OI Frangi, Alejandro/0000-0002-2675-528X NR 29 TC 4 Z9 4 U1 0 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD OCT PY 2011 VL 58 IS 10 BP 2936 EP 2942 DI 10.1109/TBME.2011.2165151 PN 2 PG 7 WC Engineering, Biomedical SC Engineering GA 823DN UT WOS:000295102600002 PM 21937299 ER PT J AU Medeiros, MN Logullo, R Ramos, IB Sorgine, MHF Paiva-Silva, GO Mesquita, RD Machado, EA Coutinho, MA Masuda, H Capurro, ML Ribeiro, JMC Braz, GRC Oliveira, PL AF Medeiros, Marcelo N. Logullo, Raquel Ramos, Isabela B. Sorgine, Marcos H. F. Paiva-Silva, Gabriela O. Mesquita, Rafael D. Machado, Ednildo Alcantara Coutinho, Maria Alice Masuda, Hatisaburo Capurro, Margareth L. Ribeiro, Jose M. C. Cardoso Braz, Gloria Regina Oliveira, Pedro L. TI Transcriptome and gene expression profile of ovarian follicle tissue of the triatomine bug Rhodnius prolixus SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Reticulum stress; Rhodnius prolixus; Transcriptome; Chorion; Oocyte; Apoptosis ID ENDOPLASMIC-RETICULUM STRESS; PROGRAMMED CELL-DEATH; UNFOLDED PROTEIN RESPONSE; ADULT FEMALE MOSQUITO; HEME-BINDING PROTEIN; KAR2 BIP GENE; DROSOPHILA-MELANOGASTER; AEDES-AEGYPTI; CROSS-LINKING; OOGENESIS AB Insect oocytes grow in close association with the ovarian follicular epithelium (OFE), which escorts the oocyte during oogenesis and is responsible for synthesis and secretion of the eggshell. We describe a transcriptome of OFE of the triatomine bug Rhodnius prolixus, a vector of Chagas disease, to increase our knowledge of the role of FE in egg development. Random clones were sequenced from a cDNA library of different stages of follicle development. The transcriptome showed high commitment to transcription, protein synthesis, and secretion. The most abundant cDNA was a secreted (S) small, proline-rich protein with maximal expression in the vitellogenic follicle, suggesting a role in oocyte maturation. We also found Rp45, a chorion protein already described, and a putative chitin-associated cuticle protein that was an eggshell component candidate. Six transcripts coding for proteins related to the unfolded-protein response (UPR) by were chosen and their expression analyzed. Surprisingly, transcripts related to UPR showed higher expression during early stages of development and downregulation during late stages, when transcripts coding for S proteins participating in chorion formation were highly expressed. Several transcripts with potential roles in oogenesis and embryo development are also discussed. We propose that intense protein synthesis at the FE results in reticulum stress (RS) and that lowering expression of a set of genes related to cell survival should lead to degeneration of follicular cells at oocyte maturation. This paradoxical suppression of UPR suggests that ovarian follicles may represent an interesting model for studying control of RS and cell survival in professional S cell types. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Medeiros, Marcelo N.; Ramos, Isabela B.; Machado, Ednildo Alcantara] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, BR-21941 Rio De Janeiro, Brazil. [Logullo, Raquel; Coutinho, Maria Alice; Cardoso Braz, Gloria Regina] Univ Fed Rio de Janeiro, Inst Quim, Dept Bioquim, BR-21941 Rio De Janeiro, Brazil. [Sorgine, Marcos H. F.; Paiva-Silva, Gabriela O.; Masuda, Hatisaburo] Univ Fed Rio de Janeiro, Inst Bioquim Med, BR-21941 Rio De Janeiro, Brazil. [Mesquita, Rafael D.; Oliveira, Pedro L.] Inst Fed Educ Rio de Janeiro, Rio De Janeiro, Brazil. [Capurro, Margareth L.] Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, BR-05508 Sao Paulo, Brazil. [Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Medeiros, Marcelo N.; Logullo, Raquel; Ramos, Isabela B.; Sorgine, Marcos H. F.; Paiva-Silva, Gabriela O.; Mesquita, Rafael D.; Machado, Ednildo Alcantara; Coutinho, Maria Alice; Masuda, Hatisaburo; Capurro, Margareth L.; Cardoso Braz, Gloria Regina; Oliveira, Pedro L.] Inst Nacl Ciencia & Tecnol Entomol Mol, Rio De Janeiro, Brazil. RP Braz, GRC (reprint author), Av Athos da Silveira Ramos 149,Bl A CT,Sala 536-A, BR-21941909 Rio De Janeiro, Brazil. EM gbraz@iq.ufrj.br RI Capurro, Margareth/F-8679-2012; Entomologiamolecular, Inct/J-8214-2013; OI Capurro, Margareth/0000-0002-7480-2116; Ribeiro, Jose/0000-0002-9107-0818; Oliveira, Pedro/0000-0003-0307-354X FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Fundacao de Amparo a Pesquisa de Estado do Rio de Janeiro (FAPERJ); Fundacao Universitaria Jose Bonifacio (FUJB); INCT-Entomologia Molecular; Howard Hughes Medical Institute (HHMI); Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank S.R. Cassia for technical assistance and NIAID intramural editor B. R. Marshall. This work was supported by grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Fundacao de Amparo a Pesquisa de Estado do Rio de Janeiro (FAPERJ), Fundacao Universitaria Jose Bonifacio (FUJB), INCT-Entomologia Molecular, and Howard Hughes Medical Institute (HHMI, to PLO). JMCR was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 70 TC 9 Z9 9 U1 2 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD OCT PY 2011 VL 41 IS 10 BP 823 EP 831 DI 10.1016/j.ibmb.2011.06.004 PG 9 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 824DW UT WOS:000295183400008 PM 21736942 ER PT J AU Esser, L Xia, D AF Esser, Lothar Xia, Di TI CrysPage: a program for displaying images of crystallization trials, rapid comparisons and analysis SO JOURNAL OF APPLIED CRYSTALLOGRAPHY LA English DT Article AB CrysPage is a program to facilitate the rapid evaluation of high-throughput crystallization trials by experienced crystallographers. Emphasis is placed on a clear overview and the display of individual drops. Chemical space can be searched and selected drops can be displayed for detailed inspection, allowing the user to narrow down the range of trial conditions for further optimization. C1 [Esser, Lothar; Xia, Di] NCI, NIH, Bethesda, MD 20892 USA. RP Esser, L (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM lesser@helix.nih.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-8898 J9 J APPL CRYSTALLOGR JI J. Appl. Crystallogr. PD OCT PY 2011 VL 44 BP 1130 EP 1131 DI 10.1107/S0021889811029608 PN 5 PG 2 WC Chemistry, Multidisciplinary; Crystallography SC Chemistry; Crystallography GA 823BW UT WOS:000295097800029 ER PT J AU Gonzalez-Perez, M Murcia, MI Landsman, D Jordan, IK Marino-Ramirez, L AF Gonzalez-Perez, Monica Murcia, Martha I. Landsman, David Jordan, I. King Marino-Ramirez, Leonardo TI Genome Sequence of the Mycobacterium colombiense Type Strain, CECT 3035 SO JOURNAL OF BACTERIOLOGY LA English DT Article ID LYMPHADENOPATHY AB We report the first whole-genome sequence of the Mycobacterium colombiense type strain, CECT 3035, which was initially isolated from Colombian HIV-positive patients and causes respiratory and disseminated infections. Preliminary comparative analyses indicate that the M. colombiense lineage has experienced a substantial genome expansion, possibly contributing to its distinct pathogenic capacity. C1 [Gonzalez-Perez, Monica; Landsman, David; Marino-Ramirez, Leonardo] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Gonzalez-Perez, Monica; Murcia, Martha I.; Jordan, I. King; Marino-Ramirez, Leonardo] PanAmer Bioinformat Inst, Santa Marta, Magdalena, Colombia. [Gonzalez-Perez, Monica; Murcia, Martha I.; Marino-Ramirez, Leonardo] Univ Nacl Colombia, Fac Med, Dept Microbiol, Bogota, Colombia. [Jordan, I. King] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. RP Marino-Ramirez, L (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,Room 6S614M,8600 Rockville Pike,MSC 6075, Bethesda, MD 20894 USA. EM marino@ncbi.nlm.nih.gov RI Marino-Ramirez, Leonardo/I-5759-2013; OI Marino-Ramirez, Leonardo/0000-0002-5716-8512; Landsman, David/0000-0002-9819-6675 FU Alfred P. Sloan Research Fellowship in Computational and Evolutionary Molecular Biology [BR-4839]; NCBI; NIH, NLM, NCBI FX This work was supported by an Alfred P. Sloan Research Fellowship in Computational and Evolutionary Molecular Biology (BR-4839 to I.K.J.) and the NCBI Scientific Visitors Program (ORISE to M.G.-P.). The research was supported in part by the Intramural Research Program of the NIH, NLM, NCBI. NR 8 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2011 VL 193 IS 20 BP 5866 EP 5867 DI 10.1128/JB.05928-11 PG 2 WC Microbiology SC Microbiology GA 825FJ UT WOS:000295256100035 PM 21952541 ER PT J AU McDermott, DH Lopez, J Deng, F Liu, Q Ojode, T Chen, HQ Ulrick, J Kwatemaa, N Kelly, C Anaya-O'Brien, S Garofalo, M Marquesen, M Hilligoss, D DeCastro, R Malech, HL Murphy, PM AF McDermott, David H. Lopez, Joseph Deng, Francis Liu, Qian Ojode, Teresa Chen, Haoqian Ulrick, Jean Kwatemaa, Nana Kelly, Corin Anaya-O'Brien, Sandra Garofalo, Mary Marquesen, Martha Hilligoss, Dianne DeCastro, Rosamma Malech, Harry L. Murphy, Philip M. TI AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE Plerixafor; immunodeficiency; neutropenia; human; genetics; warts; hypogammaglobulinemia; human papillomavirus ID COLONY-STIMULATING FACTOR; TERMINUS-TRUNCATED CXCR4; SIGNAL-TRANSDUCTION; SEVERE NEUTROPENIA; MYELOKATHEXIS; INTERNALIZATION; DISORDER; HYPOGAMMAGLOBULINEMIA; PHOSPHORYLATION; DESENSITIZATION AB WHIM is an acronym for a rare immunodeficiency syndrome (OMIM # 193670) caused by autosomal dominant mutations truncating the C-terminus of the chemokine receptor CXC chemokine receptor 4 (CXCR4). WHIM mutations may potentiate CXCR4 signalling, suggesting that the United States Food and Drug Administration (FDA)-approved CXCR4 antagonist AnorMED3100 (AMD3100) (also known as Plerixafor) may be beneficial in WHIM syndrome. We have tested this at the preclinical level by comparing Chinese hamster ovary (CHO) and K562 cell lines matched for expression of recombinant wild-type CXCR4 (CXCR4(WT)) and the most common WHIM variant of CXCR4 (CXCR4(R334X)), as well as leucocytes from a WHIM patient with the CXCR4(R334X) mutation versus healthy controls. We found that CXCR4(R334X) mediated modestly increased signalling (similar to 2-fold) in all functional assays tested, but strongly resisted ligand-dependent down-regulation. AMD3100 was equipotent and equieffective as an antagonist at CXCR4(R334X) and CXCR4(WT). Together, our data provide further evidence that CXCR4(R334X) is a gain-of-function mutation, and support clinical evaluation of AMD3100 as mechanism-based treatment in patients with WHIM syndrome. C1 [McDermott, David H.; Lopez, Joseph; Deng, Francis; Liu, Qian; Ojode, Teresa; Chen, Haoqian; Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Ulrick, Jean; Kwatemaa, Nana; Kelly, Corin; Anaya-O'Brien, Sandra; Garofalo, Mary; Marquesen, Martha; Hilligoss, Dianne; DeCastro, Rosamma; Malech, Harry L.] NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. RP McDermott, DH (reprint author), NIAID, Lab Mol Immunol, NIH, Bldg 10,Room 11N113, Bethesda, MD 20892 USA. EM dmcdermot@niaid.nih.gov OI Lopez, Joseph/0000-0003-3001-1109; Deng, Francis/0000-0003-3117-5076; Malech, Harry/0000-0001-5874-5775; McDermott, David/0000-0001-6978-0867 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH. NR 30 TC 22 Z9 22 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD OCT PY 2011 VL 15 IS 10 BP 2071 EP 2081 DI 10.1111/j.1582-4934.2010.01210.x PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 824RD UT WOS:000295218800006 PM 21070597 ER PT J AU Koshimizu, H Cawley, NX Yergy, AL Loh, YP AF Koshimizu, Hisatsugu Cawley, Niamh X. Yergy, Alfred L. Loh, Y. Peng TI Role of pGlu-Serpinin, a Novel Chromogranin A-Derived Peptide in Inhibition of Cell Death SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Serpinin; Chromogranin A; Neuroprotection; Protease nexin-1; Pyroglutamination ID SECRETORY GRANULE BIOGENESIS; PROPROTEIN CONVERTASES; PYROGLUTAMYL-PEPTIDES; CHROMAFFIN GRANULES; CARBOXYPEPTIDASE-E; PROTEASE NEXIN-1; ADRENAL-MEDULLA; RAT PITUITARY; IDENTIFICATION; GLUTAMINYL AB Chromogranin A (CgA) is a member of the granin family of molecules found in secretory granules of endocrine and neuro-endocrine cells. Here, we have identified a new 23-mer CgA-derived peptide secreted from pituitary AtT-20 cells, which we named pyroGlu-serpinin (pGlu-serpinin). LC-MS studies of peptides in conditioned medium of AtT-20 cells indicate that pGlu-serpinin is derived from initial processing of mouse CgA at paired basic residues, Arg461-Arg462 and Arg433-Arg434, to yield a previously described 26 amino acid peptide, serpinin. Three amino acids are then cleaved from the N terminus of serpinin, yielding a peptide with an N-terminal glutamine, which is then subsequently pyroglutaminated. Immunocytochemistry showed co-localization of pGlu-serpinin with adrenocorticotropic hormone in secretory granules of AtT-20 cells, and it was released in an activity-dependent manner. Functional studies demonstrated that pGlu-serpinin was able to prevent radical oxygen species (hydrogen peroxide)-induced cell death of AtT-20 cells and cultured rat cerebral cortical neurons at a concentration of 1 and 10 nM, respectively. These data indicate that pGlu-serpinin has anti-apoptotic effects that may be important in neuroprotection of central nervous system neurons and pituitary cells. Furthermore, pGlu-serpinin added to the media of AtT-20 cells up-regulated the transcription of the serine protease inhibitor, protease nexin-1 (PN-1) mRNA. pGlu-serpinin's ability to increase levels of PN-1, a potent inhibitor of plasmin released during inflammatory processes causing cell death, may play a role in protecting cells under adverse pathophysiological conditions. C1 [Koshimizu, Hisatsugu; Cawley, Niamh X.; Loh, Y. Peng] NICHD, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Yergy, Alfred L.] NICHD, Sect Metab Anal & Mass Spectrometry, NIH, Bethesda, MD 20892 USA. RP Loh, YP (reprint author), NICHD, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX We would like to thank Dr. Hong Lou for technical assistance, and Chip Dye and Dr. Vincent Schram (Microscopy and Imaging Core, NICHD, NIH) for assistance with microscopic imaging. This work was supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health intramural research program. NR 31 TC 9 Z9 11 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD OCT PY 2011 VL 45 IS 2 BP 294 EP 303 DI 10.1007/s12031-011-9521-7 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 824BH UT WOS:000295173600026 PM 21537909 ER PT J AU Haque, R Chong, NW Ali, F Chaurasia, SS Sengupta, T Chun, E Howell, JC Klein, DC Iuvone, PM AF Haque, Rashidul Chong, Nelson W. Ali, Fatima Chaurasia, Shyam S. Sengupta, Trisha Chun, Euguene Howell, Jennifer C. Klein, David C. Iuvone, P. Michael TI Melatonin synthesis in retina: cAMP-dependent transcriptional regulation of chicken arylalkylamine N-acetyltransferase by a CRE-like sequence and a TTATT repeat motif in the proximal promoter SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Aanat; AP1; CRE; CREB; melatonin; retina ID LIGHT-DARK CYCLE; PHOTORECEPTOR CELLS; MESSENGER-RNA; PINEAL-GLAND; CIRCADIAN REGULATION; GENE-TRANSCRIPTION; SOMATOSTATIN GENE; RESPONSE ELEMENT; BINDING PROTEIN; EXPRESSION AB Arylalkylamine N-acetyltransferase (AANAT) is the key regulatory enzyme controlling the daily rhythm of melatonin biosynthesis. In chicken retinal photoreceptor cells, Aanat transcription and AANAT activity are regulated in part by cAMP-dependent mechanisms. The purpose of this study was to identify regulatory elements within the chicken Aanat promoter responsible for cAMP-dependent induction. Photoreceptor-enriched retinal cell cultures were transfected with a luciferase reporter construct containing up to 4 kb of 5'-flanking region and the first exon of Aanat. Forskolin treatment stimulated luciferase activity driven by the similar to 4 kb promoter construct and by all 5'-deletion constructs except the smallest, Aanat (-217 to +120)luc. Maximal basal and forskolin-stimulated expression levels were generated by the Aanat (-484 to +120)luc construct. This construct lacks a canonical cyclic AMP-response element (CRE), but contains two other potentially important elements in its sequence: an eight times TTATT repeat (TTATT(8)) and a CRE-like sequence. Electrophoretic mobility shift assays, luciferase reporter assays, chromatin immunoprecipitation, and siRNA experiments provide evidence that these elements bind c-Fos, JunD, and CREB to enhance basal and forskolin-stimulated Aanat transcription. We propose that the CRE-like sequence and TTATT(8) elements in the 484 bp proximal promoter interact to mediate cAMP-dependent transcriptional regulation of Aanat. C1 [Haque, Rashidul; Ali, Fatima; Chaurasia, Shyam S.; Sengupta, Trisha; Chun, Euguene; Howell, Jennifer C.; Iuvone, P. Michael] Emory Univ, Sch Med, Dept Ophthalmol, Atlanta, GA 30322 USA. [Chong, Nelson W.] Univ Leicester, Glenfield Gen Hosp, Dept Cardiovasc Sci, Cardiol Grp, Leicester, Leics, England. [Klein, David C.] Eunice Shriver Kennedy Natl Inst Child Hlth & Hum, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. RP Iuvone, PM (reprint author), Emory Univ, Sch Med, Dept Ophthalmol, Atlanta, GA 30322 USA. EM miuvone@pharm.emory.edu FU NIH [R01EY004864, P30EY006360]; Eunice Shriver Kennedy National Institute of Child Health and Human Development; Research to Prevent Blindness (RPB); BBSRC UK [G18273] FX The research was supported by NIH grants R01EY004864 (PMI), P30EY006360 (PMI), funds from the Intramural Research Program of the Eunice Shriver Kennedy National Institute of Child Health and Human Development (DCK), and an unrestricted departmental grant from Research to Prevent Blindness (RPB). PMI is a recipient of the Senior Scientific Investigator Award from RPB. NWS is supported by the BBSRC UK (G18273). The authors gratefully thank Dr Beatriz Caputto and Dr Ourania Andrisani for donating c-Fos and D-CREB antisera, respectively. The authors also thank Zhuping Xu, Jane Abey, and Aamra Thazyeen, for providing technical assistance. The authors declare no conflict of interest with respect to the research reported herein. NR 42 TC 10 Z9 11 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2011 VL 119 IS 1 BP 6 EP 17 DI 10.1111/j.1471-4159.2011.07397.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 822NE UT WOS:000295054300002 PM 21790603 ER PT J AU Stroth, N Liu, Y Aguilera, G Eiden, LE AF Stroth, N. Liu, Y. Aguilera, G. Eiden, L. E. TI Pituitary Adenylate Cyclase-Activating Polypeptide Controls Stimulus-Transcription Coupling in the Hypothalamic-Pituitary-Adrenal Axis to Mediate Sustained Hormone Secretion During Stress SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE pituitary adenylate cyclase-activating polypeptide; stress; hypothalamic-pituitary-adrenal axis; corticotropin-releasing hormone; Nr4a ID IMMEDIATE-EARLY GENES; ORPHAN NUCLEAR RECEPTORS; PARAVENTRICULAR NUCLEUS; NGFI-B; GLUCOCORTICOID-RECEPTOR; CRH GENE; C-FOS; EXPRESSION; RAT; NUR77 AB External and internal stimuli that threaten homeostasis trigger coordinated stress responses through activation of specialised neuroendocrine circuits. In mammals, the hypothalamic-pituitary-adrenal (HPA) axis mediates responses to stressors such as restraint, ultimately enhancing adrenocortical hormone secretion. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in central control of the HPA axis, and we have recently shown PACAP-dependent expression of corticotropin-releasing hormone (CRH) and secretion of corticosterone in response to restraint. We now provide a more detailed analysis of PACAP-dependent HPA axis stimulation in the mouse, indicating that the hypothalamic paraventricular nucleus (PVN) is the primary site of action. We demonstrate by quantitative polymerase chain reaction and in situ hybridisation that up-regulation of mRNAs encoding CRH and inducible transcription factors, from the Nr4a family (Nur77, Nor1) in the PVN is PACAP-dependent. Furthermore, CRH hnRNA is rapidly up-regulated in cultured hypothalamic neurones after treatment with PACAP. Induction of Nr4a factors (Nur77, Nurr1) in response to restraint is attenuated in the pituitary gland of PACAP-deficient mice. In the adrenal glands, restraint elicits a marked PACAP-dependent increase in adrenocortical mRNA levels of all three Nr4a transcription factors, steroidogenic factor 1 (Nr5a1), steroidogenic acute regulatory protein and steroid 21-hydroxylase. Taken together, our results show that PACAP controls HPA responses to restraint primarily at the level of the hypothalamus by up-regulating CRH, possibly involving transcription factors such as Nur77 and Nor1. Subsequent adrenocortical steroidogenesis also appears to involve PACAP-dependent stimulus-transcription coupling, suggesting a mechanism by which PACAP exerts control over HPA axis function during stress. C1 [Stroth, N.; Eiden, L. E.] NIMH, Sect Mol Neurosci, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. [Liu, Y.; Aguilera, G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrine Physiol, PDEGEN, Bethesda, MD USA. RP Eiden, LE (reprint author), NIMH, Sect Mol Neurosci, Lab Cellular & Mol Regulat, Bldg 49,Room 5A-38,9000 Rockville Pike, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov OI Eiden, Lee/0000-0001-7524-944X FU NIMH; NICHD [Z01-MH002386-23, Z01-HD000631-21] FX This work was supported by NIMH and NICHD Intramural Research Program Projects Z01-MH002386-23 (Lee E. Eiden) and Z01-HD000631-21 (Greti Aguilera), respectively. NR 39 TC 20 Z9 20 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD OCT PY 2011 VL 23 IS 10 BP 944 EP 955 DI 10.1111/j.1365-2826.2011.02202.x PG 12 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 824NU UT WOS:000295209400010 PM 21824204 ER PT J AU Nicastro, HL Seifried, HE Milner, JA AF Nicastro, Holly L. Seifried, Harold E. Milner, John A. TI Opportunities for Small Nutrition-Related Cancer Research Grants (R03) from the National Cancer Institute SO JOURNAL OF NUTRITION LA English DT Editorial Material AB Small research grants, or R03 grants, provide limited, short-term support for individual research projects. R03s may be an excellent means of support for projects by nutrition scientists at all stages in their careers. The National Cancer Institute (NCI) has awarded roughly one-half of all nutrition-related NIH R03 grants in the period from 2005 to 2010. A detailed review of the recent NCI grant portfolio identified potential strategies for successful applications. Projects that addressed important nutrition and cancer issues had feasible and appropriate specific aims, were innovative, and were based on sound concepts were most positively viewed by reviewers. Furthermore, applicants with suitable expertise, training, mentorship, and records of accomplishment who, when appropriate, collaborated with investigators with complementary knowledge and skills were more likely to receive higher priority scores. J. Nutr. 141: 1765-1768, 2011. C1 [Nicastro, Holly L.; Seifried, Harold E.; Milner, John A.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Rockville, MD USA. RP Milner, JA (reprint author), NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Rockville, MD USA. EM milnerj@mail.nih.gov RI Nicastro, Humberto/I-7936-2012 NR 3 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD OCT PY 2011 VL 141 IS 10 BP 1765 EP 1768 DI 10.3945/jn.111.144261 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 824HM UT WOS:000295193000001 PM 21865560 ER PT J AU Kant, AK Graubard, BI AF Kant, Ashima K. Graubard, Barry I. TI 20-Year Trends in Dietary and Meal Behaviors Were Similar in U.S. Children and Adolescents of Different Race/Ethnicity SO JOURNAL OF NUTRITION LA English DT Article ID BODY-MASS INDEX; NUTRITION EXAMINATION SURVEYS; SOFT DRINK CONSUMPTION; MULTIPLE-PASS METHOD; 2 DECADES 1973-1994; US CHILDREN; SECULAR TRENDS; UNITED-STATES; NATIONAL-HEALTH; AFRICAN-AMERICAN AB Recent survey data reveal persistent race/ethnic disparities in prevalence of adiposity in U.S. children and adolescents. We examined race/ethnic differentials in time trends in dietary behaviors of Americans 2-19 y of age to understand if these trends track those observed for body weight. We used dietary data from the NHANES 1988-1994, 1999-2002, and 2003 2008 (n = 24,131) to examine changes in reported energy intake, amount of foods and beverages, number of eating occasions, and percent of energy from foods and beverages, among non-Hispanic white, non-Hispanic black, and Mexican American 2-19 y olds. Multivariable regression analyses appropriate for complex surveys were used to examine these associations. The secular increase in mean number of eating occasions was significant (P-trend < 0.0001) in all age and race/ethnic groups; however, a corresponding increase in the amount of foods and beverages, or total energy intake was not observed. In non-Hispanic black and Mexican American 2-5 and 12-19 y olds, the secular increase in number of eating occasions, and in non-Hispanic black 12-19 y olds, the increase in percent of energy from all beverages or non-nutritive beverages were greater relative to non-Hispanic whites. In conclusion, the observed race/ethnic differences in trajectory of changes in dietary behaviors over past 20 y were modest and were not accompanied by a significant increase in energy intake. Cautious interpretation is urged due to potential underreporting of dietary intake in national surveys. There was a suggestion of convergence in some race/ethnic differentials in dietary behaviors due to greater relative changes in possibly adverse behaviors in non-Hispanic blacks, especially adolescents. J. Nutr, 141: 1880-1888, 2011. C1 [Kant, Ashima K.] CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. [Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. EM ashima.kant@qc.cuny.edu FU NIH [HD060217]; Department of Health and Human Services, National Cancer Institute, NIH FX Supported in part by an NIH grant award (HD060217) (A.K.K.) and the intramural research program of the Department of Health and Human Services, National Cancer Institute, NIH (B.I.G.). NR 62 TC 13 Z9 13 U1 1 U2 10 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD OCT PY 2011 VL 141 IS 10 BP 1880 EP 1888 DI 10.3945/jn.111.144915 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 824HM UT WOS:000295193000017 PM 21865567 ER PT J AU Osborne, TS Ren, L Healey, JH Shapiro, LQ Chou, AJ Gorlick, RG Hewitt, SM Khanna, C AF Osborne, Tanasa S. Ren, Ling Healey, John H. Shapiro, Lauren Q. Chou, Alexander J. Gorlick, Richard G. Hewitt, Stephen M. Khanna, Chand TI Evaluation of eIF4E Expression in an Osteosarcoma-Specific Tissue Microarray SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE tissue microarray; osteosarcoma; eIF4E; immunohistochemistry ID INITIATION-FACTOR 4E; MURAMYL TRIPEPTIDE; TRANSLATION; GROWTH; CELL; CHEMOTHERAPY; SURVIVAL; CANCER; EZRIN AB The ability to define osteosarcoma (OS) patients at greatest risk for metastatic progression and nonresponsiveness to conventional therapy is currently not possible. Such biomarkers are needed to predict overall prognosis, probability of metastases at diagnosis, and response to chemotherapy. The tissue microarray (TMA) serves as a powerful tool for detecting and validating protein biomarkers across a variety of patients. We constructed a novel outcome-linked TMA to add to and address shortcomings of currently available OS tissue resources. To test the use of our TMA, we surveyed the expression of eukaryotic initiation factor 4E (eIF4E) in OS patients using immunohistochemistry. Aberrant regulation of translation initiation is a feature of many cancers. eIF4E is central to initiation of protein synthesis. Its expression and activity have been implicated in tumor formation and potentially malignant and/or metastatic progression in some carcinomas. We found that eIF4E was uniformly expressed in OS patient samples. No association was found between eIF4E and outcome in OS patients. This novel OS TMA provided a facile mechanism to assess the role of a relevant protein biomarker in OS. C1 [Osborne, Tanasa S.] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, NIH,Ctr Canc Res, Bethesda, MD 20892 USA. [Khanna, Chand] NCI, Comparat Oncol Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Hewitt, Stephen M.] NCI, Tarp Lab, Appl Mol Pathol Lab, Adv Technol Ctr, Bethesda, MD 20892 USA. [Healey, John H.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Chou, Alexander J.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. [Gorlick, Richard G.] Montefiore Med Ctr, Bronx, NY 10467 USA. RP Osborne, TS (reprint author), NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, NIH,Ctr Canc Res, 37 Convent Dr,Rm 2144, Bethesda, MD 20892 USA. EM osbornet@mail.nih.gov OI Chou, Alexander/0000-0002-7926-3326; Hewitt, Stephen/0000-0001-8283-1788 FU National Institutes of Health, National Cancer Institute FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 21 TC 12 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD OCT PY 2011 VL 33 IS 7 BP 524 EP 528 DI 10.1097/MPH.0b013e318223d0c1 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 823WM UT WOS:000295157900025 PM 21941146 ER PT J AU Yu, YD Kim, KH Lee, SG Choi, SY Kim, YC Byun, KS Cha, IH Park, KY Cho, CH Choi, DH AF Yu, Young-Dong Kim, Ki-Hun Lee, Sung-Gyu Choi, Sang-Yong Kim, Young-Chul Byun, Kwan-Su Cha, In-Ho Park, Kye-Yoon Cho, Cheul-Hyung Choi, Dong-Ho TI Hepatic Differentiation from Human Embryonic Stem Cells Using Stromal Cells SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE stromal cells; human embryonic stem cells; hepatocytes ID ACUTE LIVER-FAILURE; HEPATOCYTE TRANSPLANTATION; HEPATOCELLULAR TRANSPLANTATION; DEFINITIVE ENDODERM; GLYCOGEN-CONTENT; DONOR LIVER; RAT-LIVER; MOUSE; DISEASE; STORAGE AB Objective. The derivation of hepatocytes from human embryonic stem (hES) cells is of value both in the study of early human liver organogenesis and in the creation of an unlimited source of donor cells for hepatocyte transplantation therapy. Here, we report the generation of hepatocyte-like cells derived from hES cells. Methods. Hepatic endoderm cells were generated by adding activin A for 5 d- to 1-d-old embryoid bodies formed from hES cells. The hepatic endoderm cells were cocultured with mitomycin treated 3T3-J2 feeder cells. Results. After co-culture with mitomycin treated 3T3-J2 feeder cells, these hepatic endodermal cells yielded hepatocyte-like cell colonies, which possessed the proliferation potential to be cultured for an extended period of more than 30 d. With extensive expansion, they co-expressed the hepatic marker AFP and albumin, indicating that they were hepatocyte-like cells. Conclusions. We report the generation of proliferative hepatocyte-like cells from hES cells. These hES cell derived hepatic cells can effectively be used as in vitro model for studying the mechanisms of hepatic stem/progenitor cell origin, self-renewal and differentiation. (C) 2011 Elsevier Inc. All rights reserved. C1 [Choi, Dong-Ho] Soonchunhyang Univ Hosp, Dept Surg, Seoul 140743, South Korea. [Yu, Young-Dong; Kim, Ki-Hun; Lee, Sung-Gyu] Univ Ulsan, Coll Med, Div Hepatobiliary Surg & Liver Transplantat, Dept Surg,Asan Med Ctr, Seoul, South Korea. [Choi, Sang-Yong; Kim, Young-Chul] Korea Univ, Dept Surg, Med Ctr, Seoul, South Korea. [Byun, Kwan-Su] Korea Univ, Med Ctr, Dept Internal Med, Seoul, South Korea. [Cha, In-Ho] Korea Univ, Med Ctr, Dept Radiol, Seoul, South Korea. [Park, Kye-Yoon] NINDS, Stem Cell Unit, NIH, Bethesda, MD 20892 USA. [Cho, Cheul-Hyung] New Jersey Inst Technol, Dept Biomed Engn, Newark, NJ 07102 USA. RP Choi, DH (reprint author), Soonchunhyang Univ Hosp, Dept Surg, Seoul 140743, South Korea. EM dhchoi@schmc.ac.kr FU Glaxo Smith Kline of the Korean Association FX This research was supported in part by The Glaxo Smith Kline Research Fund of the Korean Association for the study of the Liver. NR 29 TC 10 Z9 12 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 0022-4804 J9 J SURG RES JI J. Surg. Res. PD OCT PY 2011 VL 170 IS 2 BP E253 EP E261 DI 10.1016/j.jss.2011.06.032 PG 9 WC Surgery SC Surgery GA 823NH UT WOS:000295128600007 PM 21816427 ER PT J AU Pinto, PA Chung, PH Rastinehad, AR Baccala, AA Kruecker, J Benjamin, CJ Xu, S Yan, PK Kadoury, S Chua, C Locklin, JK Turkbey, B Shih, JH Gates, SP Buckner, C Bratslavsky, G Linehan, WM Glossop, ND Choyke, PL Wood, BJ AF Pinto, Peter A. Chung, Paul H. Rastinehad, Ardeshir R. Baccala, Angelo A., Jr. Kruecker, Jochen Benjamin, Compton J. Xu, Sheng Yan, Pingkun Kadoury, Samuel Chua, Celene Locklin, Julia K. Turkbey, Baris Shih, Joanna H. Gates, Stacey P. Buckner, Carey Bratslavsky, Gennady Linehan, W. Marston Glossop, Neil D. Choyke, Peter L. Wood, Bradford J. TI Magnetic Resonance Imaging/Ultrasound Fusion Guided Prostate Biopsy Improves Cancer Detection Following Transrectal Ultrasound Biopsy and Correlates With Multiparametric Magnetic Resonance Imaging SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; biopsy; magnetic resonance imaging; ultrasonography; early detection of cancer ID SATURATION BIOPSY; STRATEGY; SEXTANT; SYSTEM; IMPACT AB Purpose: A novel platform was developed that fuses pre-biopsy magnetic resonance imaging with real-time transrectal ultrasound imaging to identify and biopsy lesions suspicious for prostate cancer. The cancer detection rates for the first 101 patients are reported. Materials and Methods: This prospective, single institution study was approved by the institutional review board. Patients underwent 3.0 T multiparametric magnetic resonance imaging with endorectal coil, which included T2-weighted, spectroscopic, dynamic contrast enhanced and diffusion weighted magnetic resonance imaging sequences. Lesions suspicious for cancer were graded according to the number of sequences suspicious for cancer as low (2 or less), moderate (3) and high (4) suspicion. Patients underwent standard 12-core transrectal ultrasound biopsy and magnetic resonance imaging/ultrasound fusion guided biopsy with electromagnetic tracking of magnetic resonance imaging lesions. Chi-square and within cluster resampling analyses were used to correlate suspicion on magnetic resonance imaging and the incidence of cancer detected on biopsy. Results: Mean patient age was 63 years old. Median prostate specific antigen at biopsy was 5.8 ng/ml and 90.1% of patients had a negative digital rectal examination. Of patients with low, moderate and high suspicion on magnetic resonance imaging 27.9%, 66.7% and 89.5% were diagnosed with cancer, respectively (p < 0.0001). Magnetic resonance imaging/ultrasound fusion guided biopsy detected more cancer per core than standard 12-core transrectal ultrasound biopsy for all levels of suspicion on magnetic resonance imaging. Conclusions: Prostate cancer localized on magnetic resonance imaging may be targeted using this novel magnetic resonance imaging/ultrasound fusion guided biopsy platform. Further research is needed to determine the role of this platform in cancer detection, active surveillance and focal therapy, and to determine which patients may benefit. C1 [Pinto, Peter A.; Chung, Paul H.; Rastinehad, Ardeshir R.; Baccala, Angelo A., Jr.; Benjamin, Compton J.; Chua, Celene; Bratslavsky, Gennady; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NIH, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Locklin, Julia K.; Gates, Stacey P.; Buckner, Carey; Wood, Bradford J.] NIH, Ctr Intervent Oncol, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Glossop, Neil D.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Rockville, MD USA. [Kruecker, Jochen; Xu, Sheng; Yan, Pingkun; Kadoury, Samuel; Shih, Joanna H.] Philips Res N Amer, Briarcliff Manor, NY USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W 5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research, Center for Interventional Oncology; National Institutes of Health; Philips Healthcare FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Center for Interventional Oncology, and a Cooperative Research and Development Agreement between the National Institutes of Health and Philips Healthcare. NR 27 TC 231 Z9 241 U1 2 U2 32 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD OCT PY 2011 VL 186 IS 4 BP 1281 EP 1285 DI 10.1016/j.juro.2011.05.078 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 827BE UT WOS:000295399500029 PM 21849184 ER PT J AU Dodson, JL Jerry-Fluker, JV Ng, DK Moxey-Mims, M Schwartz, GJ Dharnidharka, VR Warady, BA Furth, SL AF Dodson, Jennifer L. Jerry-Fluker, Judith V. Ng, Derek K. Moxey-Mims, Marva Schwartz, George J. Dharnidharka, Vikas R. Warady, Bradley A. Furth, Susan L. TI Urological Disorders in Chronic Kidney Disease in Children Cohort: Clinical Characteristics and Estimation of Glomerular Filtration Rate SO JOURNAL OF UROLOGY LA English DT Article DE congenital, hereditary, and neonatal diseases and abnormalities; glomerular filtration rate; kidney failure, chronic; pediatrics; urology ID CHRONIC-RENAL-FAILURE; VESICOURETERAL REFLUX; RISK-FACTORS; ADOLESCENTS; CYSTATIN; RACE AB Purpose: Urological disorders are the most common cause of pediatric chronic kidney disease. We determined the characteristics of children with urological disorders and assessed the agreement between the newly developed bedside glomerular filtration rate estimating formula with measured glomerular filtration rate in 586 patients in the Chronic Kidney Disease in Children study. Materials and Methods: The Chronic Kidney Disease in Children study is a prospective, observational cohort of children recruited from 48 sites in the United States and Canada. Eligibility requirements include age 1 to 16 years and estimated glomerular filtration rate by original Schwartz formula 30 to 90 ml/min/1.73 m(2). Baseline demographics, clinical variables and glomerular filtration rate were assessed. Bland-Altman analysis was conducted to assess agreement between estimated and measured glomerular filtration rates. Results: Of the 586 participants with at least 1 glomerular filtration rate measurement 348 (59%) had an underlying urological diagnosis (obstructive uropathy in 118, aplastic/hypoplastic/dysplastic kidneys in 104, reflux in 87 and other condition in 39). Among these patients median age was 9 years, duration of chronic kidney disease was 7 years and age at first visit with a urologist was less than 1 year. Of the patients 67% were male, 67% were white and 21% had a low birth weight. Median height was in the 24th percentile. Median glomerular filtration rate as measured by iohexol plasma disappearance was 44.8 ml/min/1.73 m2. Median glomerular filtration rate as estimated by the Chronic Kidney Disease in Children bedside equation was 44.3 ml/min/1.73 m(2) (bias = -0.5, 95% CI -1.7 to 0.7, p = 0.44). Conclusions: Underlying urological causes of chronic kidney disease were present in 59% of study participants. These children were diagnosed early in life, and many had low birth weight and growth delay. There is good agreement between the newly developed Chronic Kidney Disease in Children estimating equations and measured glomerular filtration rate in this population. C1 [Dodson, Jennifer L.] Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA. [Jerry-Fluker, Judith V.; Ng, Derek K.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Moxey-Mims, Marva] NIDDK, NIH, Bethesda, MD USA. [Schwartz, George J.] Univ Rochester, Div Pediat Nephrol, New York, NY USA. [Dharnidharka, Vikas R.] Univ Florida, Div Pediat Nephrol, Gainesville, FL USA. [Warady, Bradley A.] Childrens Mercy Hosp, Sect Pediat Nephrol, Dept Pediat, Kansas City, MO 64108 USA. [Furth, Susan L.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Dodson, JL (reprint author), Johns Hopkins Med Inst, Dept Urol, Marburg 144,600 N Wolfe St, Baltimore, MD 21287 USA. EM jdodson@jhmi.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute [U01-DK-66143, U01-DK-66174, U01-CK-82194, U01-DK-66116]; National Institute of Diabetes and Digestive and Kidney Diseases [1K23DK078671]; AUA Foundation; National Cancer Institute and National Kidney Foundation of Maryland FX Data in this manuscript were created by the Chronic Kidney Disease in Children prospective cohort study (CKiD) with clinical coordinating centers (Principal Investigators) at Children's Mercy Hospital and the University of Missouri-Kansas City (BAW), Children's Hospital of Pennsylvania (SLF), Central Biochemistry Laboratory at the University of Rochester Medical Center (GJS), and data coordinating center (Principal Investigator) at the Johns Hopkins Bloomberg School of Public Health (Alvaro Munoz, Ph.D.). The CKiD study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases, with additional funding from the National Institute of Neurological Disorders and Stroke, the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute (U01-DK-66143, U01-DK-66174, U01-CK-82194, U01-DK-66116). The project was also supported by grant 1K23DK078671 from the National Institute of Diabetes and Digestive and Kidney Diseases, AUA Foundation, National Cancer Institute and National Kidney Foundation of Maryland Professional Development Award (JLD). The CKiD website is located at http://www.statepi.jhsph.edu/ckid. NR 26 TC 5 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD OCT PY 2011 VL 186 IS 4 BP 1460 EP 1466 DI 10.1016/j.juro.2011.05.059 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 827BE UT WOS:000295399500103 PM 21855938 ER PT J AU Gharib, AM Abd-Elmoniem, KZ Herzka, DA Ho, VB Locklin, J Tzatha, E Stuber, M Pettigrew, RI AF Gharib, Ahmed M. Abd-Elmoniem, Khaled Z. Herzka, Daniel A. Ho, Vincent B. Locklin, Julie Tzatha, Efstathia Stuber, Matthias Pettigrew, Roderic I. TI Optimization of coronary whole-heart MRA free-breathing technique at 3 Tesla SO MAGNETIC RESONANCE IMAGING LA English DT Article ID MAGNETIC-RESONANCE ANGIOGRAPHY; STATE-FREE-PRECESSION; NAVIGATOR LOCATIONS; TIME; CONTRAST; MINUTES AB Four different techniques for 3-T whole-heart coronary magnetic resonance angiography (MRA) using free-breathing three-dimensional segmented parallel imaging and adiabatic T2-preparation were assessed. Coronary MRA at 3 T is improved by shortening the acquisition window more than employing the highest spatial resolution. Double-oblique whole-heart acquisitions result in better overall image quality and allow for better delineation of the left anterior descending coronary artery. It is possible to attain shorter acquisition windows and a smaller voxel size at 3 T than previously reported at 1.5 T. Published by Elsevier Inc. C1 [Gharib, Ahmed M.] NIDDK, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. [Herzka, Daniel A.] Philips Res N Amer, Clin Sites Res Program, Bethesda, MD 20892 USA. [Ho, Vincent B.] Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20892 USA. [Locklin, Julie] NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Stuber, Matthias] Johns Hopkins Univ, Baltimore, MD 21287 USA. [Pettigrew, Roderic I.] NIBIB, NIH, Bethesda, MD 20892 USA. RP Gharib, AM (reprint author), NIDDK, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. EM agharib@niddk.nih.gov RI Gharib, Ahmed/O-2629-2016; Abd-Elmoniem, Khaled/B-9289-2008; OI Gharib, Ahmed/0000-0002-2476-481X; Abd-Elmoniem, Khaled/0000-0002-1001-1702; Stuber, Matthias/0000-0001-9843-2028; Herzka, Daniel/0000-0002-9400-7814 FU Intramural NIH HHS [Z99 DK999999] NR 22 TC 9 Z9 10 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD OCT PY 2011 VL 29 IS 8 BP 1125 EP 1130 DI 10.1016/j.mri.2011.07.008 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 824IP UT WOS:000295195900012 PM 21871751 ER PT J AU Yang, IV Rutledge, HR Yang, J Warg, LA Sevilla, SD Schwartz, DA AF Yang, Ivana V. Rutledge, Holly R. Yang, Jun Warg, Laura A. Sevilla, Sergio D. Schwartz, David A. TI A locus on chromosome 9 is associated with differential response of 129S1/SvImJ and FVB/NJ strains of mice to systemic LPS SO MAMMALIAN GENOME LA English DT Article ID SALMONELLA-ENTERITIDIS; INFLAMMATORY RESPONSE; BACTERIAL CLEARANCE; CONGENIC STRAINS; GENE-EXPRESSION; LIPOPOLYSACCHARIDE; SEPSIS; PCR; IDENTIFICATION; RECOGNITION AB Although polymorphisms in TLR receptors and downstream signaling molecules affect the innate immune response, these variants account for only a portion of the ability of the host to respond to microorganisms. To identify novel genes that regulate the host response to systemic lipopolysaccharide (LPS), we created an F2 intercross between susceptible (FVB/NJ) and resistant (129S1/SvImJ) strains, challenged F2 progeny with LPS via intraperitoneal injection, and phenotyped 605 animals for survival and another 500 mice for serum concentrations of IL-1 beta and IL-6. Genome-wide scans were performed on pools of susceptible and resistant mice for survival, IL-1 beta, and IL-6. This approach identified a locus on the telomeric end of the q arm of chromosome 9 (0-40 Mb) that was associated with the differences in morbidity and serum concentrations of IL-1 beta and IL-6 following systemic LPS in FVB/NJ and 129S1/SvImJ strains of mice. Fine mapping narrowed the locus to 3.7 Mb containing 11 known genes, among which are three inflammatory caspases. We studied expression of genes within the locus by quantitative RT-PCR and showed that Casp1 and Casp12 levels are unaffected by LPS in both strains, whereas Casp4 is highly induced by LPS in FVB/NJ but not in 129S1/SvImJ mice. In conclusion, our mapping results indicate that a 3.7-Mb region on chromosome 9 contains a gene that regulates differential response to LPS in 129S1/SvImJ and FVB/NJ strains of mice. Differences in the induction of Casp4 expression by LPS in the two strains suggest that Casp4 is the most likely candidate gene in this region. C1 [Yang, Ivana V.; Warg, Laura A.; Schwartz, David A.] Natl Jewish Hlth, Ctr Genes Environm & Hlth, Denver, CO 80206 USA. [Yang, Ivana V.; Warg, Laura A.; Schwartz, David A.] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. [Yang, Ivana V.; Schwartz, David A.] Univ Colorado, Dept Med, Sch Med, Aurora, CO 80010 USA. [Rutledge, Holly R.; Yang, Jun] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC 27709 USA. [Sevilla, Sergio D.] Kendle Int, Project Management, Buenos Aires, DF, Argentina. RP Yang, IV (reprint author), Natl Jewish Hlth, Ctr Genes Environm & Hlth, 1400 Jackson St,A650, Denver, CO 80206 USA. EM yangi@njhealth.org FU NIH/NHLBI; NIEHS [ES11375, ES101946] FX We thank Rachel Burton for technical assistance in the laboratory. This research was supported by the funding from the Intramural Program of the NIH/NHLBI and NIEHS extramural grants ES11375 and ES101946. NR 30 TC 3 Z9 3 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD OCT PY 2011 VL 22 IS 9-10 BP 518 EP 529 DI 10.1007/s00335-011-9340-8 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 823OD UT WOS:000295130800003 PM 21720866 ER PT J AU Tominaga, K Srikantan, S Lee, EK Subaran, SS Martindale, JL Abdelmohsen, K Gorospe, M AF Tominaga, Kumiko Srikantan, Subramanya Lee, Eun Kyung Subaran, Sarah S. Martindale, Jennifer L. Abdelmohsen, Kotb Gorospe, Myriam TI Competitive Regulation of Nucleolin Expression by HuR and miR-494 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-BINDING PROTEIN; POSTTRANSCRIPTIONAL GENE-REGULATION; PRE-RIBOSOMAL-RNA; APP MESSENGER-RNA; TRANSLATIONAL REPRESSION; CELL-PROLIFERATION; P53 TRANSLATION; P-BODIES; GROWTH; STABILIZATION AB The RNA-binding protein (RBP) nucleolin promotes the expression of several proliferative proteins. Nucleolin levels are high in cancer cells, but the mechanisms that control nucleolin expression are unknown. Here, we show that nucleolin abundance is controlled posttranscriptionally via factors that associate with its 3'untranslated region (3'UTR). The RBP HuR was found to interact with the nucleolin (NCL) 3'UTR and specifically promoted nucleolin translation without affecting nucleolin mRNA levels. In human cervical carcinoma HeLa cells, analysis of a traceable NCL 3'UTR bearing MS2 RNA hairpins revealed that NCL RNA was mobilized to processing bodies (PBs) after silencing HuR, suggesting that the repression of nucleolin translation may occur in PBs. Immunoprecipitation of MS2-tagged NCL 3'UTR was used to screen for endogenous repressors of nucleolin synthesis. This search identified miR-494 as a microRNA that potently inhibited nucleolin expression, enhanced NCL mRNA association with argonaute-containing complexes, and induced NCL RNA transport to PBs. Importantly, miR-494 and HuR functionally competed for modulation of nucleolin expression. Moreover, the promotion of cell growth previously attributed to HuR was due in part to the HuR-elicited increase in nucleolin expression. Our collective findings indicate that nucleolin expression is positively regulated by HuR and negatively regulated via competition with miR-494. C1 [Tominaga, Kumiko; Srikantan, Subramanya; Lee, Eun Kyung; Martindale, Jennifer L.; Abdelmohsen, Kotb; Gorospe, Myriam] NIA IRP, LMBI, NIH, Baltimore, MD 21224 USA. [Subaran, Sarah S.] NIA IRP, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. RP Abdelmohsen, K (reprint author), NIA IRP, LMBI, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM abdelmohsenk@grc.nia.nih.gov; myriam-gorospe@nih.gov OI srikantan, subramanya/0000-0003-1810-6519; abdelmohsen, Kotb/0000-0001-6240-5810 FU National Institute on Aging-National Institutes of Health FX This work was supported in its entirety by the National Institute on Aging-Intramural Research Program of the National Institutes of Health. NR 65 TC 46 Z9 47 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2011 VL 31 IS 20 BP 4219 EP 4231 DI 10.1128/MCB.05955-11 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 822VO UT WOS:000295078300006 PM 21859890 ER PT J AU Ferreira, Z Hurle, B Rocha, J Seixas, S AF Ferreira, Zelia Hurle, Belen Rocha, Jorge Seixas, Susana TI Differing Evolutionary Histories of WFDC8 (Short-Term Balancing) in Europeans and SPINT4 (Incomplete Selective Sweep) in Africans SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE WFDC; natural selection; innate immunity; serine protease inhibitor; reproduction ID FACTOR-BINDING SITES; POSITIVE SELECTION; PROTEASE INHIBITOR; GENETIC-VARIATION; HUMAN GENOME; HAPLOTYPE RECONSTRUCTION; DARWINIAN SELECTION; STATISTICAL-METHOD; POLYMORPHISM; DIVERSITY AB The whey acidic protein four-disulfide core (WFDC) gene cluster on human chromosome 20q13, harbors 15 small serine protease inhibitor genes with roles in innate immunity, reproduction, and regulation of endogenous proteases kallikreins. The WFDC cluster has emerged as a prime example of rapid diversification and adaptive evolution in primates. This study sought a better understanding of the evolutionary history of WFDC genes in humans and focused on exploring the adaptive selection signatures found in populations of European (Utah residents with ancestry from northern and western Europe [CEU]) and African (Yoruba from Ibadan, in Nigeria [YRI]) ancestry in a genome-wide scan for putative targets of recent adaptive selection. Our approach included resequencing coding and noncoding regions of WFDC6, EPPIN, and WFDC8 in 20 CEU and of SPINT4 in 20 YRI individuals. We generated 302 kb and 60 kb of high-quality sequence data from CEU and of YRI populations, respectively, enabling the identification of 72 single nucleotide polymorphisms. Using classic neutrality tests, empirical and haplotype-based analysis, we pinpointed WFDC8 and SPINT4 as the likely targets of short-term balancing selection in the CEU population, and recent positive selection (incomplete selective sweep) in the YRI population. Putative candidate variants targeted by selection include 44A (rs7273669A) for WFDC8, which may downregulate gene expression by abolishing the binding site of two transcription factors; and a haplotype configuration [Ser73+98A] (rs6017667A-rs6032474A) for SPINT4, which may simultaneously affect protein function and gene regulation. We propose that the evolution of WFDC8 and SPINT4 has been shaped by complex selective scenarios due to the interdependence of variant fitness and ecological variables. C1 [Ferreira, Zelia; Rocha, Jorge; Seixas, Susana] Univ Porto, Inst Mol Pathol & Immunol, P-4100 Oporto, Portugal. [Ferreira, Zelia; Rocha, Jorge] Univ Porto, Fac Sci, Dept Zool & Anthropol, P-4100 Oporto, Portugal. [Ferreira, Zelia; Hurle, Belen] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Seixas, S (reprint author), Univ Porto, Inst Mol Pathol & Immunol, Rua Campo Alegre 823, P-4100 Oporto, Portugal. EM sseixas@ipatimup.pt RI Seixas, Susana /I-5084-2013; OI Seixas, Susana /0000-0002-7035-7422; rocha, jorge/0000-0001-5460-7615 FU Portuguese Foundation for Science and Technology (FCT) [PTDC/SAU-GMG/64043/2006, SFRH/BD/45907/2008]; POPH-QREN-Promotion of scientific employment; European Social Fund; Ministry of Science, Technology and Higher Education FX We would like to thank Aida Andres, Max Planck Institute, for critically reading the manuscript and for insightful discussions; Jacquelyn K. Beals for the editing; and the two anonymous reviewers for their helpful feedback. This research was supported by the Portuguese Foundation for Science and Technology (FCT), project grant to S. Seixas-PTDC/SAU-GMG/64043/2006. Z. Ferreira is supported by SFRH/BD/45907/2008 fellowship from FCT, supported by POPH-QREN-Promotion of scientific employment, supported by the European Social Fund and national funds of the Ministry of Science, Technology and Higher Education. S. Seixas is supported by POPH-QREN-Promotion of scientific employment, supported by the European Social Fund and national funds of the Ministry of Science, Technology and Higher Education. IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by FCT. NR 71 TC 6 Z9 6 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD OCT PY 2011 VL 28 IS 10 BP 2811 EP 2822 DI 10.1093/molbev/msr106 PG 12 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 824EC UT WOS:000295184200010 PM 21536719 ER PT J AU Hare, S Smith, SJ Metifiot, M Jaxa-Chamiec, A Pommier, Y Hughes, SH Cherepanov, P AF Hare, Stephen Smith, Steven J. Metifiot, Mathieu Jaxa-Chamiec, Albert Pommier, Yves Hughes, Stephen H. Cherepanov, Peter TI Structural and Functional Analyses of the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572) SO MOLECULAR PHARMACOLOGY LA English DT Article ID HIV-1 INTEGRASE; IN-VITRO; RESISTANCE MUTATIONS; RALTEGRAVIR; PROTEIN; IDENTIFICATION; BINDING; VIRUS; COMPLEXES; MECHANISM AB Raltegravir (RAL) and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) efficiently block viral replication in vitro and suppress viremia in patients. These small molecules bind to the IN active site, causing it to disengage from the deoxyadenosine at the 3' end of viral DNA. The emergence of viral strains that are highly resistant to RAL underscores the pressing need to develop INSTIs with improved resistance profiles. Herein, we show that the candidate second-generation drug dolutegravir (DTG, S/GSK1349572) effectively inhibits a panel of HIV-1 IN variants resistant to first-generation INSTIs. To elucidate the structural basis for the increased potency of DTG against RAL-resistant INs, we determined crystal structures of wild-type and mutant prototype foamy virus intasomes bound to this compound. The overall IN binding mode of DTG is strikingly similar to that of the tricyclic hydroxypyrrole MK-2048. Both second-generation INSTIs occupy almost the same physical space within the IN active site and make contacts with the beta 4-alpha 2 loop of the catalytic core domain. The extended linker region connecting the metal chelating core and the halobenzyl group of DTG allows it to enter farther into the pocket vacated by the displaced viral DNA base and to make more intimate contacts with viral DNA, compared with those made by RAL and other INSTIs. In addition, our structures suggest that DTG has the ability to subtly readjust its position and conformation in response to structural changes in the active sites of RAL-resistant INs. C1 [Hare, Stephen; Cherepanov, Peter] Univ London Imperial Coll Sci Technol & Med, Div Infect Dis, London W2 1PG, England. [Smith, Steven J.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Metifiot, Mathieu; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jaxa-Chamiec, Albert] Univ London Imperial Coll Sci Technol & Med, Ctr Drug Discovery, London W2 1PG, England. RP Cherepanov, P (reprint author), Univ London Imperial Coll Sci Technol & Med, Div Infect Dis, St Marys Campus,Norfolk Pl, London W2 1PG, England. EM p.cherepanov@imperial.ac.uk RI Cherepanov, Peter/F-6859-2010; OI Cherepanov, Peter/0000-0002-0634-538X; Hare, Stephen/0000-0003-2951-1595 FU UK Medical Research Council [G1000917]; National Institutes of Health, Center for Cancer Research, National Cancer Institute; National Institutes of Health; Wellcome Trust FX This work was supported by the UK Medical Research Council [Grant G1000917]; the National Institutes of Health Intramural Program, Center for Cancer Research, National Cancer Institute; the National Institutes of Health Intramural AIDS Targeted Program; and the Wellcome Trust Value in People Award. NR 41 TC 113 Z9 116 U1 4 U2 20 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 2011 VL 80 IS 4 BP 565 EP 572 DI 10.1124/mol.111.073189 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 822XQ UT WOS:000295084300003 PM 21719464 ER PT J AU Li, J Schiller, D Schoenbaum, G Phelps, EA Daw, ND AF Li, Jian Schiller, Daniela Schoenbaum, Geoffrey Phelps, Elizabeth A. Daw, Nathaniel D. TI Differential roles of human striatum and amygdala in associative learning SO NATURE NEUROSCIENCE LA English DT Article ID HUMAN BRAIN; REWARD; PREDICTION; STIMULI; WORLD AB Although the human amygdala and striatum have both been implicated in associative learning, only the striatum's contribution has been consistently computationally characterized. Using a reversal learning task, we found that amygdala blood oxygen level-dependent activity tracked associability as estimated by a computational model, and dissociated it from the striatal representation of reinforcement prediction error. These results extend the computational learning approach from striatum to amygdala, demonstrating their complementary roles in aversive learning. C1 [Li, Jian; Phelps, Elizabeth A.; Daw, Nathaniel D.] NYU, Dept Psychol, New York, NY 10003 USA. [Li, Jian; Phelps, Elizabeth A.; Daw, Nathaniel D.] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Schiller, Daniela] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Schiller, Daniela] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. [Schiller, Daniela] Mt Sinai Sch Med, Friedman Brain Inst, New York, NY USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. RP Li, J (reprint author), NYU, Dept Psychol, 6 Washington Pl, New York, NY 10003 USA. EM lijian@nyu.edu FU McKnight Foundation; Human Frontiers Science Program [RGP0036/2009-C]; US National Institutes of Health (NIH) [MH087882]; James S. McDonnell Foundation; NIH [MH080756, DA015718, AG027097]; Seaver Foundation FX We thank P. Glimcher, R. Rutledge and E. DeWitt for discussions and comments. This research was supported by a McKnight Foundation Scholar Award, Human Frontiers Science Program grant RGP0036/2009-C, US National Institutes of Health (NIH) grant MH087882 (part of the CRCNS program, to N.D.D.), a James S. McDonnell Foundation grant and NIH grant MH080756 to E. A. P., and NIH grants DA015718 and AG027097 to G. S. This work was also supported by a Seaver Foundation grant to the Center for Brain Imaging. NR 15 TC 91 Z9 92 U1 5 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD OCT PY 2011 VL 14 IS 10 BP 1250 EP 1252 DI 10.1038/nn.2904 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 825EQ UT WOS:000295254200012 PM 21909088 ER PT J AU Massad, LS Xie, XH Darragh, T Minkoff, H Levine, AM Watts, DH Wright, RL D'Souza, G Colie, C Strickler, HD AF Massad, L. Stewart Xie, Xianhong Darragh, Teresa Minkoff, Howard Levine, Alexandra M. Watts, D. Heather Wright, Rodney L. D'Souza, Gypsyamber Colie, Christine Strickler, Howard D. CA Womens Interagency HIV Study Colla TI Genital Warts and Vulvar Intraepithelial Neoplasia Natural History and Effects of Treatment and Human Immunodeficiency Virus Infection SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID WOMENS INTERAGENCY HIV; HUMAN-PAPILLOMAVIRUS; RISK; MODELS; COHORT AB OBJECTIVE: To describe the natural history of genital warts and vulvar intraepithelial neoplasia (VIN) in women with human immunodeficiency virus (HIV). METHODS: A cohort of 2,791 HIV-infected and 953 uninfected women followed for up to 13 years had genital examinations at 6-month intervals with biopsy for lesions suspicious for VIN. RESULTS: The prevalence of warts was 4.4% (5.3% for HIV-seropositive women and 1.9% for HIV-seronegative women, P<.001). The cumulative incidence of warts was 33% (95% confidence interval [CI] 30-36%) in HIV-seropositive and 9% (95% CI 6-12%) in HIV-seronegative women (P<.001). In multivariable analysis, lower CD4 lymphocyte count, younger age, and current smoking were strongly associated with risk for incident warts. Among 501 HIV-seropositive and 43 HIV-seronegative women, warts regressed in 410 (82%) seropositive and 41 (95%) seronegative women (P=.02), most in the first year after diagnosis. In multivariable analysis, regression was negatively associated with HIV status and lower CD4 count as well as older age. Incident VIN of any grade occurred more frequently among HIV-seropositive than HIV-seronegative women: 0.42 (0.33-0.53) compared with 0.07 (0.02-0.18) per 100 person-years (P<.001). Positivity for VIN 2 was found in 58 women (55 with and three without HIV, P<.001). Two women with HIV developed stage IB squamous cell vulvar cancers. CONCLUSION: Although genital warts and VIN are more common among HIV-seropositive than HIV-seronegative women, wart regression is common even in women with HIV, and cancers are infrequent. C1 [Massad, L. Stewart] Washington Univ, Sch Med, Div Gynecol Oncol, St Louis, MO 63110 USA. Albert Einstein Coll Med, New York, NY USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. SUNY, Maimonides Med Ctr, New York, NY USA. City Hope Med Ctr, Duarte, CA USA. Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Georgetown Univ, Sch Med, Washington, DC USA. RP Massad, LS (reprint author), Washington Univ, Sch Med, Div Gynecol Oncol, 4911 Barnes Jewish Hosp Plaza, St Louis, MO 63110 USA. EM massadl@wudosis.wustl.edu FU National Institute of Allergy and Infectious Diseases [U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993, U01-AI-42590]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources (UCSF-CTSI) [UL1 RR024131]; [R01-CA-085178] FX The Women's Interagency HIV Study is funded by the National Institute of Allergy and Infectious Diseases (U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993, and U01-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01-HD-32632). The study is cofunded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. Analysis was funded through R01-CA-085178. NR 19 TC 11 Z9 11 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD OCT PY 2011 VL 118 IS 4 BP 831 EP 839 DI 10.1097/AOG.0b013e31821a0f4d PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 823JJ UT WOS:000295118000010 PM 21934446 ER PT J AU Hasni, S Ippolito, A Illei, GG AF Hasni, S. Ippolito, A. Illei, G. G. TI Helicobacter pylori and autoimmune diseases SO ORAL DISEASES LA English DT Review DE autoimmunity; etiology; infection; lymphoma ID GASTRIC EPITHELIAL-CELLS; IDIOPATHIC THROMBOCYTOPENIC PURPURA; SYSTEMIC-LUPUS-ERYTHEMATOSUS; LYMPHOID-TISSUE LYMPHOMA; RHEUMATOID-ARTHRITIS; SJOGRENS-SYNDROME; MEDICAL PROGRESS; CONSENSUS REPORT; INFECTION; ERADICATION AB Helicobacter pylori (H. pylori) is a widely prevalent microbe, with between 50 and 80% of the population infected worldwide. Clinically, infection with H. pylori is commonly associated with peptic ulcer disease, but many of those infected remain asymptomatic. H. pylori has evolved a number of means to affect the host immune response and has been implicated in many diseases mitigated by immune dysregulation, such as immune thrombocytopenic purpura (ITP), atrophic gastritis, and mucosa associated lymphoid tissue (MALT) lymphoma. Autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrome, are the result of a dysregulated host immune system which targets otherwise healthy tissues. The exact etiology of autoimmune diseases is unclear, but it has long been suggested that exposure to certain environmental agents, such as viral and bacterial infection or chemical exposures, in genetically susceptible individuals may be the catalyst for the initiation of autoimmune processes. Because of its prevalence and ability to affect human immune function, many researchers have hypothesized that H. pylori might contribute to the development of autoimmune diseases. In this article, we review the available literature regarding the role of chronic H. pylori infection in various autoimmune disease states. Oral Diseases (2011) 17, 621-627 C1 [Hasni, S.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Illei, G. G.] Natl Inst Dent & Craniofacial Res & Hlth, Bethesda, MD USA. RP Hasni, S (reprint author), NIAMSD, NIH, 9000 Rockville Pike,Bldg 10,Room 5-5521, Bethesda, MD 20892 USA. EM hasnisa@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institutes of Dental and Craniofacial Research, National Institutes of Health FX This study was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institutes of Dental and Craniofacial Research, National Institutes of Health. NR 69 TC 14 Z9 15 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD OCT PY 2011 VL 17 IS 7 BP 621 EP 627 DI 10.1111/j.1601-0825.2011.01796.x PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 822MO UT WOS:000295052100001 PM 21902767 ER PT J AU Michael, D Soi, S Cabera-Perez, J Weller, M Alexander, S Alevizos, I Illei, GG Chiorini, JA AF Michael, D. Soi, S. Cabera-Perez, J. Weller, M. Alexander, S. Alevizos, I. Illei, G. G. Chiorini, J. A. TI Microarray analysis of sexually dimorphic gene expression in human minor salivary glands SO ORAL DISEASES LA English DT Article DE Genetics; microarray; salivary gland ID MOUSE LACRIMAL GLAND; SJOGRENS-SYNDROME; ANDROGEN RECEPTOR; GROWTH; SEX; GLUTAMINASE; PROSTATE; UTERUS; CELLS AB OBJECTIVE: We hypothesized that differential mRNA transcription between the sexes may be linked to the 9:1 female-to-male gender-related relative risk for the development of Sjogren's syndrome (SS), an autoimmune disease that leads to inflammation and dysfunction in the lachrymal and salivary glands. SUBJECTS AND METHODS: RNA from minor salivary glands was collected from nine healthy volunteers (four men and five women) and analyzed using the Agilent 4 x 44K human microarray platform. Differential expression was confirmed by qRT-PCR. RESULTS: Comparison of the transcriptome of minor salivary glands from normal male and female volunteers with that of salivary glands and secretory epithelia identified a number of gender, species, and tissue-specific gene expression patterns. These differences include, but are not limited to, a diverse set of genes involved in immune modulation, chemotactic control, inhibition of complement, metabolism, and neurogenesis. CONCLUSION: Analysis of these changes provides insight into the protective and predisposing molecular factors that may be involved in the development of Sjogren's syndrome. Some of the gene changes observed in this study correlate with previously observed sexual dimorphisms in salivary gland function and also illustrate several new targets for further investigation. Oral Diseases (2011) 17, 653-661 C1 [Michael, D.; Cabera-Perez, J.; Weller, M.; Alexander, S.; Alevizos, I.; Illei, G. G.; Chiorini, J. A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Michael, D.] Washington Univ, St Louis Sch Med, Mol Cell Biol Program, St Louis, MO USA. [Soi, S.] Univ Penn, Grad Program Genom & Computat Biol, Philadelphia, PA 19104 USA. RP Chiorini, JA (reprint author), Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jchiorini@dir.nidcr.nih.gov FU NIH NIDCR FX The research in this manuscript was supported by an NIH NIDCR intramural research grant to JAC. NR 26 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD OCT PY 2011 VL 17 IS 7 BP 653 EP 661 DI 10.1111/j.1601-0825.2011.01816.x PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 822MO UT WOS:000295052100005 PM 21819492 ER PT J AU Hughes, GB AF Hughes, Gordon B. TI Evidence-Based Medicine in Health Care Reform SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE evidence-based medicine; health care reform ID DEVELOPMENT COSTS; DRUG DEVELOPMENT; GRADE; RECOMMENDATIONS; QUALITY; GLOBALIZATION; CONSENSUS; STRENGTH AB The Patient Protection and Affordable Care Act of 2010 mandates a national comparative outcomes research project agenda. Comparative effectiveness research includes both clinical trials and observational studies and is facilitated by electronic health records. A national network of electronic health records will create a vast electronic data "warehouse" with exponential growth of observational data. High-quality associations will identify research topics for pragmatic clinical trials, and systematic reviews of clinical trials will provide optimal evidence-based medicine. Evidence-based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. Thus, health care reform will provide a robust environment for comparative effectiveness research, systematic reviews, and evidence-based medicine, and implementation of evidence-based medicine should lead to improved quality of care. C1 Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Hughes, GB (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 6120 Execut Blvd,EPS 400C,MSC 7180, Bethesda, MD 20892 USA. EM hughesg@nidcd.nih.gov NR 24 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 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD OCT PY 2011 VL 145 IS 4 BP 526 EP 529 DI 10.1177/0194599811419458 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 824VR UT WOS:000295230800002 PM 21860057 ER PT J AU Tai, BH Nhut, ND Nhiem, NX Quang, TH Nguyen, TTN Bui, TTL Huong, TT Wilson, J Beutler, JA Ban, NK Cuong, NM Kim, YH AF Bui Huu Tai Nguyen Duy Nhut Nguyen Xuan Nhiem Tran Hong Quang Nguyen Thi Thanh Ngan Bui Thi Thuy Luyen Tran Thu Huong Wilson, Jennifer Beutler, John A. Ninh Khac Ban Nguyen Manh Cuong Kim, Young Ho TI An evaluation of the RNase H inhibitory effects of Vietnamese medicinal plant extracts and natural compounds SO PHARMACEUTICAL BIOLOGY LA English DT Article DE HIV; RNase H; cytopathic; antivirus; Vietnamese medicinal plants; organic compounds ID HIV-1 REVERSE-TRANSCRIPTASE; PHYLLANTHUS-RETICULATUS; ASSAY AB Context: Acquired immune deficiency syndrome (AIDS) is a severe pandemic disease especially prevalent in poor and developing countries. Thus, developing specific, potent antiviral drugs that restrain infection by human immunodeficiency virus type 1 (HIV-1), a major cause of AIDS, remains an urgent priority. Objective: This study evaluated 32 extracts and 23 compounds from Vietnamese medicinal plants for their inhibitory effects against HIV-1 ribonuclease H (RNase H) and their role in reversing the cytopathic effects of HIV. Materials and methods: The plants were air-dried and extracted in different solvent systems to produce plant extracts. Natural compounds were obtained as previously published. Samples were screened for RNase H inhibition followed by a cytopathic assay. Data were analyzed using the Microsoft Excel. Results and discussion: At 50 mu g/mL, 11 plant extracts and five compounds inhibited over 90% of RNase H enzymatic activity. Methanol extracts from Phyllanthus reticulatus and Aglaia aphanamixis leaves inhibited RNase H activity by 99 and 98%, respectively, whereas four extracts showed modest protection against the cytopathic effects of HIV. Conclusion: The screening results demonstrated that the butanol (BuOH) extract of Celastrus orbiculata leaves, methanol (MeOH) extracts of Glycosmis stenocarpa stems, Eurya ciliata leaves, and especially P. reticulatus leaves showed potential RNase H inhibition and protection against the viral cytopathic effects of HIV-1. Further chemical investigations should be carried out to find the active components of these extracts and compounds as potential anti-HIV drug candidates. C1 [Bui Huu Tai; Nguyen Xuan Nhiem; Tran Hong Quang; Nguyen Thi Thanh Ngan; Bui Thi Thuy Luyen; Kim, Young Ho] Chungnam Natl Univ, Coll Pharm, Taejon 305764, South Korea. [Bui Huu Tai; Tran Thu Huong; Nguyen Manh Cuong] VAST, Inst Nat Prod Chem, Hanoi, Vietnam. [Nguyen Duy Nhut] Nhatrang Inst Technol Res & Applicat, Nhatrang, Vietnam. [Nguyen Xuan Nhiem; Tran Hong Quang; Ninh Khac Ban] VAST, Inst Marine Biochem, Hanoi, Vietnam. [Wilson, Jennifer; Beutler, John A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Kim, YH (reprint author), Chungnam Natl Univ, Coll Pharm, Taejon 305764, South Korea. EM nmcuong@inpc.vast.ac.vn; yhk@cnu.ac.kr RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU Ministry of Science and Technology, Vietnam [30/823/2007/HD-NDT]; National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology, Republic of Korea [2009-0093815]; NIH, National Cancer Institute, Center for Cancer Research FX We would like to thank the Ministry of Science and Technology, Vietnam, for financial support in form of the Vietnam-Korea International Collaboration Project (No. 30/823/2007/HD-NDT). This work was supported partly by Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0093815), Republic of Korea. This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 24 TC 2 Z9 2 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1388-0209 J9 PHARM BIOL JI Pharm. Biol. PD OCT PY 2011 VL 49 IS 10 BP 1046 EP 1051 DI 10.3109/13880209.2011.563316 PG 6 WC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy SC Plant Sciences; Medical Laboratory Technology; Pharmacology & Pharmacy GA 822XR UT WOS:000295084400008 PM 21595586 ER PT J AU Meschia, JF Nalls, M Matarin, M Brott, TG Brown, RD Hardy, J Kissela, B Rich, SS Singleton, A Hernandez, D Ferrucci, L Pearce, K Keller, M Worrall, BB AF Meschia, James F. Nalls, Michael Matarin, Mar Brott, Thomas G. Brown, Robert D., Jr. Hardy, John Kissela, Brett Rich, Stephen S. Singleton, Andrew Hernandez, Dena Ferrucci, Luigi Pearce, Kerra Keller, Margaret Worrall, Bradford B. CA Siblings Ischemic Stroke Study TI Siblings With Ischemic Stroke Study Results of a Genome-Wide Scan for Stroke Loci SO STROKE LA English DT Article DE cerebral infarct; genetics ID NITRIC-OXIDE SYNTHASE; ATRIAL-FIBRILLATION; BRAIN INFARCTS; ASSOCIATION; VARIANTS; RISK; CLASSIFICATION; POPULATION; GENETICS AB Background and Purpose-Ischemic stroke has a strong familial component to risk. The Siblings With Ischemic Stroke Study (SWISS) is a genome-wide, family-based analysis that included use of imputed genotypes. The Siblings With Ischemic Stroke Study was conducted to examine the associations between single-nucleotide polymorphisms (SNPs) and risk of stroke and stroke subtypes within pairs. Methods-The Siblings With Ischemic Stroke Study enrolled 312 probands with ischemic stroke from 70 US and Canadian centers. Affected siblings were ascertained by centers and confirmed by central record review; unaffected siblings were ascertained by telephone contact. Ischemic stroke was subtyped according to Trial of Org 10172 in Acute Stroke Treatment criteria. Genotyping was performed with an Illumina 610 quad array (probands) and an Illumina linkage V array (affected siblings). SNPs were imputed by using 1000 Genomes Project data and MACH software. Family-based association analyses were conducted by using the sibling transmission-disequilibrium test. Results-For all pairs, the correlation of age at stroke within pairs of affected siblings was r = 0.83 (95% CI, 0.78-0.86; P < 2.2 x 10(-16)). The correlation did not differ substantially by subtype. The concordance of stroke subtypes among affected pairs was 33.8% (kappa = 0.13; P = 5.06 x 10(-4)) and did not differ by age at stroke in the proband. Although no SNP achieved genome-wide significance for risk of ischemic stroke, there was clustering of the most associated SNPs on chromosomes 3p (neuronal nitric oxide synthase) and 6p. Conclusions-Stroke subtype and age at stroke in affected sibling pairs exhibit significant clustering. No individual SNP reached genome-wide significance. However, 2 promising candidate loci were identified, including 1 that contains neuronal nitric oxide synthase, although these risk loci warrant further examination in larger sample collections. (Stroke. 2011; 42: 2726-2732.) C1 [Meschia, James F.; Brott, Thomas G.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Brown, Robert D., Jr.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Hardy, John] UCL, Dept Mol Neurosci, Inst Neurol, London, England. [Kissela, Brett] Univ Cincinnati, Dept Neurol, Cincinnati, OH USA. [Nalls, Michael; Singleton, Andrew; Hernandez, Dena; Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. [Pearce, Kerra] Univ Coll London Genom, London, England. [Pearce, Kerra] Inst Child Hlth, London, England. [Keller, Margaret] Coriell Inst Med Res, Camden, NJ USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Worrall, Bradford B.] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Worrall, Bradford B.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Matarin, Mar] UCL Inst Neurol, Dept Clin & Expt Epilepsy, London, England. RP Meschia, JF (reprint author), Mayo Clin, Dept Neurol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM meschia.james@mayo.edu RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Matarin, Mar/F-1771-2016; OI Matarin, Mar/0000-0002-4717-5735; Kissela, Brett/0000-0002-9773-4013 FU National Institute for Neurological Disorders and Stroke (NINDS) [R01 NS39987]; IRB (Mayo Clinic) [1082-99]; National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000015-50, 2003-078, Z01 AG000954-06]; MRC FX SWISS is funded by the National Institute for Neurological Disorders and Stroke NINDS) through grant number R01 NS39987 J.F.M., PI), IRB 1082-99 Mayo Clinic). The inclusion of BLSA samples was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000015-50, human subjects protocol number 2003-078. Dr Hardy is supported by an MRC Returning Scientist award. The Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000954-06. NR 29 TC 14 Z9 16 U1 0 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 OCT PY 2011 VL 42 IS 10 BP 2726 EP U83 DI 10.1161/STROKEAHA.111.620484 PG 12 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824QM UT WOS:000295217100020 PM 21940970 ER PT J AU Tsai, LK Wang, ZF Munasinghe, J Leng, Y Leeds, P Chuang, DM AF Tsai, Li-Kai Wang, Zhifei Munasinghe, Jeeva Leng, Yan Leeds, Peter Chuang, De-Maw TI Mesenchymal Stem Cells Primed With Valproate and Lithium Robustly Migrate to Infarcted Regions and Facilitate Recovery in a Stroke Model SO STROKE LA English DT Article DE cerebral ischemia; lithium; mesenchymal stem cells; transplantation; valproate; MRI ID MARROW STROMAL CELLS; HISTONE DEACETYLASE INHIBITORS; FOCAL CEREBRAL-ISCHEMIA; RAT MODEL; TRANSPLANTATION; BRAIN; ACID; THERAPY; DIFFERENTIATION; DISORDERS AB Background and Purpose-The migratory efficiency of mesenchymal stem cells (MSC) toward cerebral infarct after transplantation is limited. Valproate (VPA) and lithium enhance in vitro migration of MSC by upregulating CXC chemokine receptor 4 and matrix metalloproteinase-9, respectively. Ability of VPA and lithium to promote MSC homing and to improve functional recovery was assessed in a rat model of cerebral ischemia. Methods-MSC primed with VPA (2.5 mmol/L, 3 hours) and/or lithium chloride (2.5 mmol/L, 24 hours) were transplanted into rats 24 hours after transient middle cerebral artery occlusion (MCAO). Neurological function was assessed via rotarod test, Neurological Severity Score, and body asymmetry test for 2 weeks. Infarct volume was analyzed by MRI. The number of homing MSC and microvessel density in the infarcted regions were measured 15 days after MCAO using immunohistochemistry. Results-Priming with VPA or lithium increased the number of MSC homing to the cerebral infarcted regions, and copriming with VPA and lithium further enhanced this effect. MCAO rats receiving VPA-primed and/or lithium-primed MSC showed improved functional recovery, reduced infarct volume, and enhanced angiogenesis in the infarcted penumbra regions. These beneficial effects of VPA or lithium priming were reversed by AMD3100, a CXC chemokine receptor 4 antagonist, and GM6001, a matrix metalloproteinase inhibitor, respectively. Conclusions-Priming with VPA and/or lithium promoted the homing and migration ability of MSC, improved functional recovery, reduced brain infarct volume, and enhanced angiogenesis in a rat MCAO model. These effects were likely mediated by VPA-induced CXC chemokine receptor 4 overexpression and lithium-induced matrix metalloproteinase-9 upregulation. (Stroke. 2011;42:2932-2939.) C1 [Tsai, Li-Kai; Wang, Zhifei; Leng, Yan; Leeds, Peter; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Munasinghe, Jeeva] NINDS, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Tsai, Li-Kai] Natl Taiwan Univ Hosp, Dept Neurol, Taipei, Taiwan. [Tsai, Li-Kai] Natl Taiwan Univ Hosp, Stroke Ctr, Taipei, Taiwan. Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. [Tsai, Li-Kai] Natl Taiwan Univ Hosp, Dept Neurol, Yun Lin Branch, Yunlin, Taiwan. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, 10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov RI Wang, Zhifei/I-2787-2013; OI Tsai, Li-Kai/0000-0001-8420-6951 FU National Institute of Mental Health; NIH; Hsu family gift fund; National Taiwan University Hospital [100-N1673]; NINDS, NIH FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, NIH, the Hsu family gift fund, and National Taiwan University Hospital (100-N1673).; The authors thank Dr Alan Koretsky of NINDS, NIH for his support and discussions in the MRI studies, Dave Lukenbaugh and Dr Chi-Tso Chiu for their assistance in statistical analysis, and Dr Fengshan Yu for his assistance in hematoxylin and eosin staining. The authors also thank Ioline Henter, Emily Fessler, and Dr Joshua Hunsberger for their assistance in the preparation of this paper. NR 29 TC 55 Z9 59 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD OCT PY 2011 VL 42 IS 10 BP 2932 EP U406 DI 10.1161/STROKEAHA.110.612788 PG 18 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824QM UT WOS:000295217100053 PM 21836090 ER PT J AU Longstreth, WT Arnold, AM Kuller, LH Bernick, C Lefkowitz, DS Beauchamp, NJ Manolio, TA AF Longstreth, W. T., Jr. Arnold, Alice M. Kuller, Lewis H. Bernick, Charles Lefkowitz, David S. Beauchamp, Norman J., Jr. Manolio, Teri A. TI Progression of Magnetic Resonance Imaging-Defined Brain Vascular Disease Predicts Vascular Events in Elderly The Cardiovascular Health Study SO STROKE LA English DT Article DE brain infarction; death; leukoaraiosis; stroke ID WHITE-MATTER; STROKE; MANIFESTATIONS; INFARCTS; PEOPLE; MRI AB Background and Purpose-To determine whether progression of MRI-defined vascular disease predicts subsequent vascular events in the elderly. Methods-The Cardiovascular Health Study, a longitudinal cohort study of vascular disease in the elderly, allows us to address this question because its participants had 2 MRI scans approximate to 5 years apart and have been followed for approximate to 9 years since the follow-up scan for incident vascular events. Results-Both MRI-defined incident infarcts and worsened white matter grade were significantly associated with heart failure, stroke, and death, but not transient ischemic attacks, angina, or myocardial infarction. Strongest associations occurred when both incident infarcts and worsened white matter grade were present for heart failure (hazard ratio, 1.79; 95% confidence interval, 1.18-2.73), stroke (hazard ratio, 2.58; 95% confidence interval, 1.53-4.36), death (hazard ratio, 1.69; 95% confidence interval, 1.28-2.24), and cardiovascular death (hazard ratio, 1.97; 95% confidence interval, 1.24-3.14). Conclusions-Progression of MRI-defined vascular disease identifies elderly people at increased risk for subsequent heart failure, stroke, and death. Whether aggressive risk factor management would reduce risk is unknown. (Stroke. 2011;42:2970-2972.) C1 [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Arnold, Alice M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Beauchamp, Norman J., Jr.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Kuller, Lewis H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Bernick, Charles] Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Las Vegas, NV USA. [Lefkowitz, David S.] Wake Forest Univ, Bowman Gray Sch Med, Dept Neurol, Winston Salem, NC 27103 USA. [Manolio, Teri A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. RP Longstreth, WT (reprint author), Harborview Med Ctr, Dept Neurol, Box 359775,325 9th Ave, Seattle, WA 98104 USA. EM wl@uw.edu FU National Heart Lung and Blood Institute [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL080295, HL-075366]; National Institute of Aging [AG-023269, AG-15928, AG-20098, AG-027058]; University of Pittsburgh Claude D. Pepper Older Americans Independence Center [P30-AG-024827] FX This research was supported by National Heart Lung and Blood Institute Grant/Contract numbers N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133; HL080295, HL-075366; National Institute of Aging Grant/Contract numbers AG-023269, AG-15928, AG-20098, and AG-027058; University of Pittsburgh Claude D. Pepper Older Americans Independence Center grant number P30-AG-024827; with additional contribution from National Institute of Neurological Disorders and Stroke. See also http://www.chs-nhlbi.org/pi.htm. NR 8 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD OCT PY 2011 VL 42 IS 10 BP 2970 EP U468 DI 10.1161/STROKEAHA.111.622977 PG 9 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824QM UT WOS:000295217100063 PM 21817135 ER PT J AU Cheung, K Kaufmann, P AF Cheung, Ken Kaufmann, Petra TI Efficiency Perspectives on Adaptive Designs in Stroke Clinical Trials SO STROKE LA English DT Review DE continual reassessment method; futility interim analysis; Internal pilot; prospective planning ID ACUTE ISCHEMIC-STROKE; PLAY-WINNER RULE; TESTS; SIZE AB An adaptive design allows the modifications of various features, such as sample size and treatment assignments, in a clinical study based on the analysis of interim data. The goal is to enhance statistical efficiency by maximizing relevant information obtained from the clinical data. The promise of efficiency, however, comes with a cost, per se, that is seldom made explicit in the literature. This article reviews some commonly used adaptive strategies in early-phase stroke trials and discusses their associated costs. Specifically, we illustrate the trade-offs in several clinical contexts, including dose-finding in the Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART), futility analyses and internal pilot in Phase 2 proof-of-concept trials, and sample size considerations in an imaging-based dose-selection trial. Through these illustrations, we demonstrate the potential tension between the perspectives of an individual investigator and that of the broader community of stakeholders. This understanding is critical to appreciate the limitations, as well as the full promise, of adaptive designs, so that investigators can deploy an appropriate statistical design-be it adaptive or not-in a clinical study. (Stroke. 2011;42:2990-2994.) C1 [Cheung, Ken] Columbia Univ, Dept Biostat, New York, NY 10032 USA. [Kaufmann, Petra] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Cheung, K (reprint author), Columbia Univ, Dept Biostat, 722 W 168th St, New York, NY 10032 USA. EM yc632@columbia.edu FU National Institutes of Health FX This work was supported by the National Institutes of Health. NR 27 TC 9 Z9 10 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD OCT PY 2011 VL 42 IS 10 BP 2990 EP U502 DI 10.1161/STROKEAHA.111.620765 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 824QM UT WOS:000295217100067 PM 21885845 ER PT J AU Gibson, TM Weinstein, SJ Pfeiffer, RM Hollenbeck, AR Subar, AF Schatzkin, A Mayne, ST Stolzenberg-Solomon, R AF Gibson, Todd M. Weinstein, Stephanie J. Pfeiffer, Ruth M. Hollenbeck, Albert R. Subar, Amy F. Schatzkin, Arthur Mayne, Susan T. Stolzenberg-Solomon, Rachael TI Pre- and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the United States SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID FOLIC-ACID FORTIFICATION; HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; MULTIVITAMIN USE; COLON-CANCER; CARDIOVASCULAR-DISEASE; NATIONAL-INSTITUTES; FOOD FORTIFICATION; RECTAL-CANCER; PLASMA FOLATE AB Background: A higher folate intake is associated with a decreased colorectal cancer risk in observational studies, but recent evidence suggests that excessive folate supplementation may increase colorectal cancer risk in some individuals. Therefore, mandatory folic acid fortification of grain products in the United States may have unintended negative consequences. Objective: We examined the association between folate intake and colorectal cancer risk, including 8.5 y of postfortification follow-up. Design: We examined the association between folate intake and colorectal cancer in the NIH-AARP Diet and Health Study-a US cohort study of 525,488 individuals aged 50-71 y initiated in 1995-1996. Dietary, supplemental, and total folate intakes were calculated for the pre- and postfortification periods (before and after 1 July 1997) based on a baseline food-frequency questionnaire. HRs and 95% CIs were calculated by using multivariable Cox proportional hazards regression models. Results: During follow-up through 31 December 2006 (mean follow-up: 9.1 y), 7212 incident colorectal cancer cases were identified. In the postfortification analysis (6484 cases), a higher total folate intake was associated with a decreased colorectal cancer risk (HR for >= 900 compared with <200 mu g/d: 0.70; 95% CI: 0.58, 0.84). The highest intakes specifically from supplements (HR: 0.82; 95% CI: 0.72, 0.92) or from diet (HR: 0.81; 95% CI: 0.67, 0.97) were also protective. The pattern of associations was similar for the prefortification period, and no significant differences between time periods were observed. Conclusions: In this large prospective cohort study that included 8.5 y of postfortification follow-up, folate intake was associated with a decreased colorectal cancer risk. Given that the adenomacarcinoma sequence may take >= 10 y, additional follow-up time is needed to fully examine the effect of folic acid fortification. Am J Clin Nutr 2011;94:1053-62. C1 [Gibson, Todd M.; Mayne, Susan T.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Gibson, Todd M.; Weinstein, Stephanie J.; Pfeiffer, Ruth M.; Schatzkin, Arthur; Stolzenberg-Solomon, Rachael] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Subar, Amy F.] NCI, Div Canc Control & Populat Sci, NIH, US Dept HHS, Rockville, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Gibson, TM (reprint author), EPS 7091,6120 Execut Blvd, Rockville, MD 20852 USA. EM gibsontm@mail.nih.gov FU NIH; National Cancer Institute [TU2-CA-105666]; Florida Department of Health FX Supported in part by the Intramural Research Program of the NIH and the National Cancer Institute and by grant TU2-CA-105666.; Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract with the Florida Department of Health. The views expressed herein are solely those of the authors and do not necessarily reflect those of the Florida Cancer Data System or Florida Department of Health. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, PA. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. NR 58 TC 33 Z9 35 U1 0 U2 14 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD OCT PY 2011 VL 94 IS 4 BP 1053 EP 1062 DI 10.3945/ajcn.110.002659 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 822GN UT WOS:000295032100014 PM 21813806 ER PT J AU Blasbalg, TL Hibbeln, JR AF Blasbalg, Tanya L. Hibbeln, Joseph R. TI Waste and hydrogenation lower omega-3 and omega-6 fat intake estimates for soybean oil Reply SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter C1 [Blasbalg, Tanya L.; Hibbeln, Joseph R.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Blasbalg, TL (reprint author), NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, 5625 Fishers Lane,Room 3N, Rockville, MD 20852 USA. EM jhibbeln@mail.nih.gov NR 5 TC 0 Z9 0 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 OCT PY 2011 VL 94 IS 4 BP 1153 EP 1155 DI 10.3945/ajcn.111.022178 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 822GN UT WOS:000295032100028 ER PT J AU Giaccone, G Wang, YS AF Giaccone, Giuseppe Wang, Yisong TI Strategies for overcoming resistance to EGFR family tyrosine kinase inhibitors SO CANCER TREATMENT REVIEWS LA English DT Review DE Epidermal growth factor receptor; Tyrosine kinase inhibitor; Non-small cell lung cancer; Afatinib; BIBW 2992; PF-00299804; Resistance ID GROWTH-FACTOR-RECEPTOR; CELL LUNG-CANCER; PHASE-II TRIAL; C-MET ANTIBODY; ACQUIRED-RESISTANCE; T790M MUTATION; MEDIATES RESISTANCE; 1ST-LINE GEFITINIB; ANTITUMOR-ACTIVITY; RANDOMIZED-TRIAL AB The first-generation epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib have been incorporated into treatment paradigms for patients with advanced non-small cell lung cancer. These agents are particularly effective in a subset of patients whose tumors harbor activating epidermal growth factor receptor mutations. However, most patients do not respond to these tyrosine kinase inhibitors, and those who do will eventually acquire resistance that typically results from a secondary epidermal growth factor receptor mutation (e.g., T790M), mesenchymal-epithelial transition factor amplification, or activation of other signaling pathways. For patients whose tumors have wild-type epidermal growth factor receptor, there are several known mechanisms of initial resistance (e.g., Kirsten rat sarcoma viral oncogene homolog mutations) but these do not account for all cases, suggesting that unknown mechanisms also contribute. To potentially overcome the issue of resistance, next-generation tyrosine kinase inhibitors are being developed, which irreversibly block multiple epidermal growth factor receptor family members (e.g., afatinib [BIBW 29921 and PF-00299804) and/or vascular endothelial growth factor receptor pathways (e.g., BMS-690514 and XL647). In addition, drugs that block parallel signaling pathways or signaling molecules downstream of the epidermal growth factor receptor, such as the insulin-like growth factor-1 receptor and the mammalian target of rapamycin, are undergoing clinical evaluation. As drug resistance appears to be pleomorphic, combinations of drugs or drugs with multiple targets may be more effective in circumventing resistance. Published by Elsevier Ltd. C1 [Giaccone, Giuseppe; Wang, Yisong] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), NCI, Ctr Canc Res, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) FX Financial support for medical and editorial assistance was provided by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The author meets criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), was fully responsible for all content and editorial decisions, and was involved in all stages of manuscript development. The author received no compensation related to the development of the manuscript. NR 96 TC 53 Z9 59 U1 0 U2 17 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0305-7372 EI 1532-1967 J9 CANCER TREAT REV JI Cancer Treat. Rev. PD OCT PY 2011 VL 37 IS 6 BP 456 EP 464 DI 10.1016/j.ctrv.2011.01.003 PG 9 WC Oncology SC Oncology GA 822QQ UT WOS:000295065100007 PM 21367530 ER PT J AU Yan, L Wei, X Tang, QZ Feng, JH Zhang, Y Liu, C Bian, ZY Zhang, LF Chen, MY Bai, X Wang, AB Fassett, J Chen, YJ He, YW Yang, QL Liu, PP Li, HL AF Yan, Ling Wei, Xiang Tang, Qi-Zhu Feng, Jinghua Zhang, Yan Liu, Chen Bian, Zhou-Yan Zhang, Lian-Feng Chen, Manyin Bai, Xue Wang, Ai-Bing Fassett, John Chen, Yingjie He, You-Wen Yang, Qinglin Liu, Peter P. Li, Hongliang TI Cardiac-specific mindin overexpression attenuates cardiac hypertrophy via blocking AKT/GSK3 beta and TGF-beta 1-Smad signalling SO CARDIOVASCULAR RESEARCH LA English DT Article DE Mindin; Hypertrophy; Remodelling; Signal transduction; AKT ID PATTERN-RECOGNITION MOLECULE; MATRIX PROTEIN MINDIN; CHRONIC PRESSURE-OVERLOAD; F-SPONDIN; INTEGRIN LIGAND; FAILURE; MECHANISMS; PATHWAYS; CELLS; IDENTIFICATION AB Aims Mindin is a secreted extracellular matrix protein, an integrin ligand, and an angiogenesis inhibitor, other examples of which are all key players in the progression of cardiac hypertrophy. However, its function during cardiac hypertrophy remains unclear. This study was aimed to identify the effect of mindin on cardiac hypertrophy and the underlying mechanisms. Methods and results A significant down-regulation of mindin expression was observed in human failing hearts. To further investigate the role of mindin in cardiac hypertrophy, we used cultured neonatal rat cardiomyocytes with gain and loss of mindin function and cardiac-specific Mindin-overexpressing transgenic (TG) mice. In cultured cardiomyocytes, mindin negatively regulated angiotensin II (Ang II)-mediated hypertrophic growth, as detected by [(3)H]-Leucine incorporation, cardiac myocyte area, and hypertrophic marker protein levels. Cardiac hypertrophy in vivo was produced by aortic banding (AB) or Ang II infusion in TG mice and their wild-type controls. The extent of cardiac hypertrophy was evaluated by echocardiography as well as by pathological and molecular analyses of heart samples. Mindin overexpression in the heart markedly attenuated cardiac hypertrophy, fibrosis, and left ventricular dysfunction in mice in response to AB or Ang II. Further analysis of the signalling events in vitro and in vivo indicated that these beneficial effects of mindin were associated with the interruption of AKT/glycogen synthase kinase 3 beta (GSK3 beta) and transforming growth factor (TGF)-beta 1-Smad signalling. Conclusion The present study demonstrates for the first time that mindin serves as a novel mediator that protects against cardiac hypertrophy and the transition to heart failure by blocking AKT/GSK3 beta and TGF-beta 1-Smad signalling. C1 [Liu, Peter P.] Toronto Gen Hosp, Dept Cardiol, Toronto, ON M5G 2C4, Canada. [Yan, Ling; Tang, Qi-Zhu; Feng, Jinghua; Zhang, Yan; Bian, Zhou-Yan; Bai, Xue; Li, Hongliang] Wuhan Univ, Renmin Hosp, Dept Cardiol, Wuhan 430060, Peoples R China. [Yan, Ling; Tang, Qi-Zhu; Feng, Jinghua; Zhang, Yan; Bian, Zhou-Yan; Bai, Xue; Li, Hongliang] Wuhan Univ, Cardiovasc Res Inst, Wuhan 430060, Peoples R China. [Wei, Xiang] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Thorac & Cardiac Surg, Wuhan 430030, Peoples R China. [Liu, Chen] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Cardiol, Guangzhou 510275, Guangdong, Peoples R China. [Zhang, Lian-Feng] Minist Hlth, Key Lab Human Dis Comparat Med, Beijing, Peoples R China. [Chen, Manyin] Univ Toronto, Univ Hlth Network, Richard Lewar Ctr Excellence, Div Cardiol Heart & Stroke, Toronto, ON M5S 3E2, Canada. [Wang, Ai-Bing] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Fassett, John; Chen, Yingjie] Univ Minnesota, Div Cardiovasc, Minneapolis, MN 55455 USA. [He, You-Wen] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. [Yang, Qinglin] Univ Alabama, Dept Nutr Sci, Birmingham, AL 35294 USA. RP Liu, PP (reprint author), Toronto Gen Hosp, Dept Cardiol, Toronto, ON M5G 2C4, Canada. EM peter.liu@utoronto.ca; lihl@whu.edu.cn OI Fassett, John/0000-0003-4591-6875 FU National Natural Science Foundation of China [30900524, 30972954, 81000036, 81000095]; Support Program for Disciplinary Leaders in Wuhan [200951830561]; Fundamental Research Funds for the Central Universities [3081013]; National Basic Research Program of China [2011CB503902] FX This work was supported by the National Natural Science Foundation of China (30900524, 30972954, 81000036, and 81000095), the Support Program for Disciplinary Leaders in Wuhan (200951830561), the Fundamental Research Funds for the Central Universities (3081013), and the National Basic Research Program of China (2011CB503902). NR 39 TC 30 Z9 30 U1 3 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD OCT 1 PY 2011 VL 92 IS 1 BP 85 EP 94 DI 10.1093/cvr/cvr159 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 821IT UT WOS:000294969000013 PM 21632881 ER PT J AU Ssekitoleko, R Jacob, ST Banura, P Pinkerton, R Meya, DB Reynolds, SJ Kenya-Mugisha, N Mayanja-Kizza, H Muhindo, R Bhagani, S Scheld, WM Moore, CC AF Ssekitoleko, Richard Jacob, Shevin T. Banura, Patrick Pinkerton, Relana Meya, David B. Reynolds, Steven J. Kenya-Mugisha, Nathan Mayanja-Kizza, Harriet Muhindo, Rose Bhagani, Sanjay Scheld, W. Michael Moore, Christopher C. TI Hypoglycemia at admission is associated with inhospital mortality in Ugandan patients with severe sepsis SO CRITICAL CARE MEDICINE LA English DT Article DE Africa; hypoglycemia; mortality; outcomes; severe sepsis; Uganda ID CRITICALLY-ILL PATIENTS; GLUCOSE VARIABILITY; CARE; MALARIA; POPULATION; MANAGEMENT; ACCURACY; OUTCOMES; ILLNESS; AFRICA AB Objective: Dysglycemia during sepsis is associated with poor outcomes in resource-rich settings. In resource-limited settings, hypoglycemia is often diagnosed clinically without the benefit of laboratory support. We studied the utility of point-of-care glucose monitoring to predict mortality in severely septic patients in Uganda. Design: Prospective observational study. Setting: One national and two regional referral hospitals in Uganda. Patients: We enrolled 532 patients with sepsis at three hospitals in Uganda. The analysis included 418 patients from the three sites with inhospital mortality data, a documented admission blood glucose concentration, and evidence of organ dysfunction at admission (systolic blood pressure <= 100 mm Hg, lactate >4 mmol/L, platelet number <100,000/mu L, or altered mental status). Interventions: None. Measurements and Main Results: We evaluated the association between admission point-of-care blood glucose concentration and inhospital mortality. We also assessed the accuracy of altered mental status as a predictor of hypoglycemia. Euglycemia occurred in 33.5% (140 of 418) of patients, whereas 16.3% (68 of 418) of patients were hypoglycemic and 50.2% (210 of 418) were hyperglycemic. Univariate Cox regression analyses comparing inhospital mortality among hypoglycemic (35.3% [24 of 68], hazard ratio 2.0, 95% confidence interval 1.2-3.6, p = .013) and hyperglycemic (29.5% [62 of 210], hazard ratio 1.5, 95% confidence interval 0.96-2.4, p = .08) patients to euglycemic (19.3% [27 of 140]) patients showed statistically significantly higher rates of inhospital mortality for patients with hypoglycemia. Hypoglycemia (adjusted hazard ratio 1.9, 95% confidence interval 1.1-3.3, p = .03) remained significantly and independently associated with inhospital mortality in the multivariate model. The sensitivity and specificity of altered mental status for hypoglycemia were 25% and 86%, respectively. Conclusion: Hypoglycemia is an independent risk factor for inhospital mortality in patients with severe sepsis and cannot be adequately assessed by clinical examination. Correction of hypoglycemia may improve outcomes of critically ill patients in resource-limited settings. (Crit Care Med 2011; 39:2271-2276) C1 [Pinkerton, Relana; Scheld, W. Michael; Moore, Christopher C.] Univ Virginia, Charlottesville, VA 22903 USA. [Ssekitoleko, Richard; Muhindo, Rose] Mbarara Univ Sci & Technol, Dept Med, Mbarara, Uganda. [Jacob, Shevin T.] Univ Washington, Seattle, WA 98195 USA. [Banura, Patrick] Masaka Reg Referral Hosp, Masaka, Uganda. [Meya, David B.; Mayanja-Kizza, Harriet] Makerere Univ, Sch Med, Coll Hlth Sci, Kampala, Uganda. [Reynolds, Steven J.] NIAID, NIH, Bethesda, MD 20892 USA. [Reynolds, Steven J.] Johns Hopkins Sch Med, Baltimore, MD USA. [Kenya-Mugisha, Nathan] Minist Hlth, Kampala, Uganda. [Bhagani, Sanjay] Royal Free Hosp, London NW3 2QG, England. RP Moore, CC (reprint author), Univ Virginia, Charlottesville, VA 22903 USA. EM ccm5u@virginia.edu OI Meya, David/0000-0002-4138-240X; Mayanja-Kizza, Harriet/0000-0002-9297-6208 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Pfizer FX Supported, in part, by the Rakai Health Sciences Program through the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Funding for the study was also provided by the Pfizer Initiative in International Health at the University of Virginia. This initiative was conceived to fund global infectious disease research and exchange programs between postdoctoral fellows and students from the University of Virginia and several international partners to conduct research on global health issues. The major purpose of this program is to foster and enhance bidirectional research training. An independent board at the University of Virginia determines which research proposals are funded. Pfizer provides funds to promote the initiative but has no role in the planning or execution of research protocols, including the study described in this article. Pfizer also had no role in the analysis and interpretation of the data for this study. NR 29 TC 12 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD OCT PY 2011 VL 39 IS 10 BP 2271 EP 2276 DI 10.1097/CCM.0b013e3182227bd2 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA 821EU UT WOS:000294958500009 PM 21666451 ER PT J AU Shaikh, AR Vinokur, AD Yaroch, AL Williams, GC Resnicow, K AF Shaikh, Abdul R. Vinokur, Amiram D. Yaroch, Amy L. Williams, Geoffrey C. Resnicow, Ken TI Direct and Mediated Effects of Two Theoretically Based Interventions to Increase Consumption of Fruits and Vegetables in the Healthy Body Healthy Spirit Trial SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE African Americans; fruit and vegetable consumption; mediation analysis; interaction effects; latent variable structural equation modeling ID SELF-DETERMINATION THEORY; RANDOMIZED CONTROLLED-TRIAL; OF-THE-LITERATURE; PHYSICAL-ACTIVITY; PSYCHOSOCIAL PREDICTORS; SUPPORTING AUTONOMY; TOBACCO CESSATION; NUTRITION; ADULTS; PREVENTION AB This study tested the effects of two theory-based interventions to increase fruit and vegetable intake. Hypothesized intervention mediators included self-efficacy (SE), social support (SS), autonomous motivation (AM), and controlled motivation (CM). At baseline, 1,021 African American adults were recruited from 16 churches randomized to one comparison and two intervention groups: Group 1 (standard educational materials), Group 2 (culturally targeted materials), and Group 3 (culturally targeted materials and telephone-based motivational interviewing). A well-fitted model based on structural equation modeling-chi(2)(df = 541, N = 353, 325) = 864.28, p < .001, normed fit index = .96, nonnormed fit index = .98, comparative fit index = .98, root mean square error of approximation = .042-demonstrated that AM was both a significant mediator and moderator. In the subgroup with low baseline AM, AM mediated 17% of the effect of the Group 3 intervention on fruit and vegetable intake. Conversely, SS, SE, and CM were not significant mediators. Implications related to theory and intervention development are discussed. C1 [Shaikh, Abdul R.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Resnicow, Ken] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Yaroch, Amy L.] Ctr Human Nutr, Omaha, NE USA. [Williams, Geoffrey C.] Univ Rochester, New York, NY USA. RP Shaikh, AR (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM shaikhab@mail.nih.gov RI Reis, Aline/G-9573-2012 NR 43 TC 14 Z9 14 U1 0 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD OCT PY 2011 VL 38 IS 5 BP 492 EP 501 DI 10.1177/1090198110384468 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 822EJ UT WOS:000295026400008 PM 21596903 ER PT J AU Jackson, LW Howards, PP Wactawski-Wende, J Schisterman, EF AF Jackson, L. W. Howards, P. P. Wactawski-Wende, J. Schisterman, E. F. TI The association between cadmium, lead and mercury blood levels and reproductive hormones among healthy, premenopausal women SO HUMAN REPRODUCTION LA English DT Article DE cadmium; lead; mercury; estradiol; menstrual cycle ID NUTRITION EXAMINATION SURVEY; OVARIAN GRANULOSA-CELLS; 3RD NATIONAL-HEALTH; BREAST-CANCER CELLS; MENSTRUAL-CYCLE; CIGARETTE-SMOKING; OCCUPATIONAL-EXPOSURE; HEAVY-METALS; FOLLICULAR-FLUID; DETECTION LIMITS AB BACKGROUND: Cadmium, lead and mercury have been identified in human follicular fluid and ovarian tissue, and have been associated with adverse reproductive outcomes in epidemiologic studies; however, few studies have examined the relationship between blood metal levels and reproductive hormones. METHODS: Among 252 premenopausal women aged 18-44 years, we examined the association between blood metal levels (cadmium, lead and mercury), cycle length, and reproductive hormones [FSH, LH, estradiol (E(2)) and progesterone] measured at clinically relevant time points in the menstrual cycle. The association between metal levels (continuous) and hormone levels was assessed using linear regression with hormone levels (natural) log transformed and the results interpreted as the percentage difference in hormone level per unit increase in metal level. RESULTS: Median (interquartile range) cadmium, lead and mercury levels were 0.30 mu g/l (0.19, 0.43), 0.87 mu g/dl (0.68, 1.20) and 1.10 mu g/l (0.58, 2.10), respectively. Each 1 mu g/l increase in cadmium levels was associated with a 21% [95% confidence interval (CI): -2.9, 49.9] increase in early follicular phase E(2) levels after adjusting for age, race/ethnicity, lead and mercury. This association decreased when restricted to never smokers (10%; 95% CI: -19.5, 51.3). Cadmium was also associated with a non-significant 9% (95% CI: -0.2, 19.9), or 2.7 day, increase in cycle length among never smokers. No associations were observed between lead or mercury and the outcomes in adjusted analyses. CONCLUSIONS: Further evaluation of the association between cadmium, E(2) and cycle length is warranted, taking into consideration cigarette smoke and its multiple components. C1 [Jackson, L. W.] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Howards, P. P.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Wactawski-Wende, J.] SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Dept Social & Prevent Med, Buffalo, NY 14214 USA. [Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. RP Jackson, LW (reprint author), Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. EM leila.jackson@case.edu OI Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. None of the authors have competing financial interests related to this work. NR 59 TC 15 Z9 15 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD OCT PY 2011 VL 26 IS 10 BP 2887 EP 2895 DI 10.1093/humrep/der250 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 821IX UT WOS:000294969500036 PM 21778284 ER PT J AU Sarkar, A Hayes, BM Dulebohn, DP Rosa, PA AF Sarkar, Amit Hayes, Beth M. Dulebohn, Daniel P. Rosa, Patricia A. TI Regulation of the Virulence Determinant OspC by bbd18 on Linear Plasmid lp17 of Borrelia burgdorferi SO JOURNAL OF BACTERIOLOGY LA English DT Article ID LYME-DISEASE SPIROCHETE; OUTER-SURFACE PROTEIN; TICK INFECTIOUS CYCLE; GENE-EXPRESSION; MAMMALIAN INFECTION; CIRCULAR PLASMID; IMMUNE-RESPONSE; HOST; RPOS; EVASION AB Persistent infection of a mammalian host by Borrelia burgdorferi, the spirochete that causes Lyme disease, requires specific downregulation of an immunogenic outer surface protein, OspC. Although OspC is an essential virulence factor needed by the spirochete to establish infection in the mammal, it represents a potent target for the host acquired immune response, and constitutive expression of OspC results in spirochete clearance. In this study, we demonstrate that a factor encoded on a linear plasmid of B. burgdorferi, lp17, can negatively regulate ospC transcription from the endogenous gene on the circular plasmid cp26 and from an ospC promoter-lacZ fusion on a shuttle vector. Furthermore, we have identified bbd18 as the gene on lp17 that is responsible for this effect. These data identify a novel component of ospC regulation and provide the basis for determining the molecular mechanisms of ospC repression in vivo. C1 [Sarkar, Amit; Hayes, Beth M.; Dulebohn, Daniel P.; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Sarkar, A (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM sarkara@niaid.nih.gov FU NIAID, NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. NR 60 TC 11 Z9 11 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2011 VL 193 IS 19 BP 5365 EP 5373 DI 10.1128/JB.01496-10 PG 9 WC Microbiology SC Microbiology GA 819LE UT WOS:000294826200035 PM 21784941 ER PT J AU Bogdanove, AJ Koebnik, R Lu, H Furutani, A Angiuoli, SV Patil, PB Van Sluys, MA Ryan, RP Meyer, DF Han, SW Aparna, G Rajaram, M Delcher, AL Phillippy, AM Puiu, D Schatz, MC Shumway, M Sommer, DD Trapnell, C Benahmed, F Dimitrov, G Madupu, R Radune, D Sullivan, S Jha, G Ishihara, H Lee, SW Pandey, A Sharma, V Sriariyanun, M Szurek, B Vera-Cruz, CM Dorman, KS Ronald, PC Verdier, V Dow, JM Sonti, RV Tsuge, S Brendel, VP Rabinowicz, PD Leach, JE White, FF Salzberg, SL AF Bogdanove, Adam J. Koebnik, Ralf Lu, Hong Furutani, Ayako Angiuoli, Samuel V. Patil, Prabhu B. Van Sluys, Marie-Anne Ryan, Robert P. Meyer, Damien F. Han, Sang-Wook Aparna, Gudlur Rajaram, Misha Delcher, Arthur L. Phillippy, Adam M. Puiu, Daniela Schatz, Michael C. Shumway, Martin Sommer, Daniel D. Trapnell, Cole Benahmed, Faiza Dimitrov, George Madupu, Ramana Radune, Diana Sullivan, Steven Jha, Gopaljee Ishihara, Hiromichi Lee, Sang-Won Pandey, Alok Sharma, Vikas Sriariyanun, Malinee Szurek, Boris Vera-Cruz, Casiana M. Dorman, Karin S. Ronald, Pamela C. Verdier, Valerie Dow, J. Maxwell Sonti, Ramesh V. Tsuge, Seiji Brendel, Volker P. Rabinowicz, Pablo D. Leach, Jan E. White, Frank F. Salzberg, Steven L. TI Two New Complete Genome Sequences Offer Insight into Host and Tissue Specificity of Plant Pathogenic Xanthomonas spp. SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ORYZAE PV.-ORYZAE; 2-COMPONENT SIGNAL-TRANSDUCTION; CAMPESTRIS PATHOVAR CAMPESTRIS; GYP DOMAIN PROTEIN; OUTER-MEMBRANE; III EFFECTORS; RESISTANCE GENE; DI-GMP; HYPERSENSITIVE RESPONSE; ARABIDOPSIS-THALIANA AB Xanthomonas is a large genus of bacteria that collectively cause disease on more than 300 plant species. The broad host range of the genus contrasts with stringent host and tissue specificity for individual species and pathovars. Whole-genome sequences of Xanthomonas campestris pv. raphani strain 756C and X. oryzae pv. oryzicola strain BLS256, pathogens that infect the mesophyll tissue of the leading models for plant biology, Arabidopsis thaliana and rice, respectively, were determined and provided insight into the genetic determinants of host and tissue specificity. Comparisons were made with genomes of closely related strains that infect the vascular tissue of the same hosts and across a larger collection of complete Xanthomonas genomes. The results suggest a model in which complex sets of adaptations at the level of gene content account for host specificity and subtler adaptations at the level of amino acid or noncoding regulatory nucleotide sequence determine tissue specificity. C1 [Bogdanove, Adam J.; Meyer, Damien F.; Trapnell, Cole] Iowa State Univ, Dept Plant Pathol, 351 Bessey Hall, Ames, IA 50011 USA. [Koebnik, Ralf; Szurek, Boris; Verdier, Valerie] Inst Rech Dev, UMR RPB IRD CIRAD UM2, F-34394 Montpellier 5, France. [Lu, Hong; Brendel, Volker P.] Iowa State Univ, Dept Genet Cell & Dev Biol, Ames, IA 50011 USA. [Furutani, Ayako] Natl Inst Agrobiol Sci, Dept Genet Resources, Tsukuba, Ibaraki 3058602, Japan. [Furutani, Ayako] Ibaraki Univ, Ctr Gene Res, Ami, Ibaraki 3000393, Japan. [Angiuoli, Samuel V.; Delcher, Arthur L.; Phillippy, Adam M.; Puiu, Daniela; Schatz, Michael C.; Sommer, Daniel D.; Salzberg, Steven L.] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Patil, Prabhu B.; Sharma, Vikas] CSIR, Inst Microbial Technol, Chandigarh 160036, India. [Van Sluys, Marie-Anne; Ishihara, Hiromichi; Leach, Jan E.] Colorado State Univ, Dept Bioagr Sci & Pest Management, Ft Collins, CO 80523 USA. [Van Sluys, Marie-Anne] IB USP, Dept Bot, Sao Paulo, Brazil. [Ryan, Robert P.; Dow, J. Maxwell] Univ Coll Cork, BioSci Inst, BIOMERIT Res Ctr, Cork, Ireland. [Meyer, Damien F.] INRA, CIRAD, Control Emerging & Exot Anim Dis, Prise Deau 97170, Petit Bourg, Guadeloupe. [Han, Sang-Wook; Lee, Sang-Won; Sriariyanun, Malinee; Ronald, Pamela C.] Univ Calif Davis, Dept Plant Pathol, Davis, CA 95616 USA. [Aparna, Gudlur; Jha, Gopaljee; Pandey, Alok; Sonti, Ramesh V.] CSIR, Ctr Cellular & Mol Biol, Hyderabad, Andhra Pradesh, India. [Aparna, Gudlur] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [Rajaram, Misha; Dorman, Karin S.; Brendel, Volker P.] Iowa State Univ, Dept Stat, Ames, IA 50011 USA. [Rajaram, Misha] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Phillippy, Adam M.] Natl Biodef Anal & Countermeasures Ctr, Frederick, MD 21702 USA. [Schatz, Michael C.] Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, Cold Spring Harbor, NY 11724 USA. [Shumway, Martin] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Trapnell, Cole] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Benahmed, Faiza; Dimitrov, George; Madupu, Ramana; Radune, Diana; Sullivan, Steven; Rabinowicz, Pablo D.] Inst Genom Res, Rockville, MD 20850 USA. [Benahmed, Faiza] US FDA, Div Food & Anim Microbiol, Res Off, Ctr Vet Med, Laurel, MD 20708 USA. [Sullivan, Steven] NYU, Ctr Genom & Syst Biol, New York, NY 10003 USA. [Jha, Gopaljee] CSIR, Inst Himalayan Bioresouce Technol, Palampur, Himachal Prades, India. [Ishihara, Hiromichi] Okayama Univ, Grad Sch Nat Sci & Technol, Dept Chem Mat, Okayama 7008530, Japan. [Lee, Sang-Won] Kyung Hee Univ, Dept Plant Mol Syst Biotechnol, Yongin 446701, South Korea. [Lee, Sang-Won] Kyung Hee Univ, Crop Biotech Inst, Yongin 446701, South Korea. [Vera-Cruz, Casiana M.] Int Rice Res Inst, Plant Breeding Genet & Biotechnol Div, Manila, Philippines. [Tsuge, Seiji] Kyoto Prefectural Univ, Plant Pathol Lab, Sakyo Ku, Kyoto 6068522, Japan. [Delcher, Arthur L.; Rabinowicz, Pablo D.] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Rabinowicz, Pablo D.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [White, Frank F.] Kansas State Univ, Dept Plant Pathol, Manhattan, KS 66506 USA. [Salzberg, Steven L.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. RP Bogdanove, AJ (reprint author), Iowa State Univ, Dept Plant Pathol, 351 Bessey Hall, Ames, IA 50011 USA. EM ajbog@iastate.edu RI Salzberg, Steven/F-6162-2011; Van Sluys, Marie-Anne/A-8483-2012; MEYER, Damien/G-2607-2013; IB/USP, Botanica/Q-7627-2016; 2, INCT/G-6506-2013; Bioetanol, Inct/I-1068-2013; Angiuoli, Samuel/H-7340-2014; Lu, Hong/F-2744-2015; Gudlur, Aparna/J-9646-2015; Sriariyanun, Malinee/B-6767-2016; Verdier, Valerie/K-1004-2016; Koebnik, Ralf/J-5627-2014 OI Jha, Gopaljee/0000-0002-3965-3135; Angiuoli, Samuel/0000-0001-9525-4350; Ryan, Rober/0000-0002-7353-0913; Dorman, Karin/0000-0003-3650-0018; Salzberg, Steven/0000-0002-8859-7432; Van Sluys, Marie-Anne/0000-0002-6506-2734; MEYER, Damien/0000-0003-2735-176X; IB/USP, Botanica/0000-0002-4192-3747; Lu, Hong/0000-0002-4026-4292; Gudlur, Aparna/0000-0001-8753-183X; Sriariyanun, Malinee/0000-0002-3088-9256; Verdier, Valerie/0000-0001-5425-9454; Koebnik, Ralf/0000-0002-4419-0542 FU USDA-NSF [20043560015022] FX This work was supported by the USDA-NSF Microbial Genome Sequencing Program (award CSREES 20043560015022). NR 109 TC 85 Z9 94 U1 5 U2 37 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2011 VL 193 IS 19 BP 5450 EP 5464 DI 10.1128/JB.05262-11 PG 15 WC Microbiology SC Microbiology GA 819LE UT WOS:000294826200044 PM 21784931 ER PT J AU Ehret, G Munroe, PB Rice, K Bochud, M Johnson, A Chasman, D Vernon-Smith, A Psaty, B Abecasis, G Charavarti, A Elliott, P van Diujn, C Cheh, CN Levy, D Caulfield, M Johnson, T AF Ehret, G. Munroe, P. B. Rice, K. Bochud, M. Johnson, A. Chasman, D. Vernon-Smith, A. Psaty, B. Abecasis, G. Charavarti, A. Elliott, P. van Diujn, C. Cheh, Newton C. Levy, D. Caulfield, M. Johnson, T. TI Sixteen novel loci influence blood pressure and cardiovascular risk SO JOURNAL OF HUMAN HYPERTENSION LA English DT Meeting Abstract C1 [Ehret, G.] Univ Geneva, Geneva, Switzerland. [Munroe, P. B.; Caulfield, M.; Johnson, T.] Barts & London Queen Marys Sch Med & Dent, William Harvey Res Inst, London, England. [Rice, K.; Psaty, B.] Univ Washington, Seattle, WA 98195 USA. [Bochud, M.] Univ Lausanne, Lausanne, Switzerland. [Johnson, A.; van Diujn, C.; Cheh, Newton C.; Levy, D.] NIH, Bethesda, MD 20892 USA. [Chasman, D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Vernon-Smith, A.] Univ Iceland, Rekjavik, Iceland. [Abecasis, G.] Univ Michigan, Ann Arbor, MI 48109 USA. [Elliott, P.] Univ London Imperial Coll Sci Technol & Med, London, England. [Charavarti, A.] Johns Hopkins, Baltimore, MD USA. RI Abecasis, Goncalo/B-7840-2010; Rice, Kenneth/A-4150-2013; Bochud, Murielle/A-3981-2010 OI Rice, Kenneth/0000-0001-5779-4495; Bochud, Murielle/0000-0002-5727-0218 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9240 J9 J HUM HYPERTENS JI J. Hum. Hypertens. PD OCT PY 2011 VL 25 IS 10 BP 635 EP 636 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 820FT UT WOS:000294891700032 ER PT J AU Cullinane, AR Vilboux, T O'Brien, K Curry, JA Maynard, DM Carlson-Donohoe, H Ciccone, C Markello, TC Gunay-Aygun, M Huizing, M Gahl, WA AF Cullinane, Andrew R. Vilboux, Thierry O'Brien, Kevin Curry, James A. Maynard, Dawn M. Carlson-Donohoe, Hannah Ciccone, Carla Markello, Thomas C. Gunay-Aygun, Meral Huizing, Marjan Gahl, William A. CA NISC Comparative Sequencing TI Homozygosity Mapping and Whole-Exome Sequencing to Detect SLC45A2 and G6PC3 Mutations in a Single Patient with Oculocutaneous Albinism and Neutropenia SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID HERMANSKY-PUDLAK-SYNDROME; SEVERE CONGENITAL NEUTROPENIA; PROTEIN IGRP; GENE; TYROSINASE; FORM; MELANOCYTES; TRAFFICKING; BIOGENESIS; EXPRESSION AB We evaluated a 32-year-old woman whose oculocutaneous albinism (OCA), bleeding diathesis, neutropenia, and history of recurrent infections prompted consideration of the diagnosis of Hermansky Pudlak syndrome type 2. This was ruled out because of the presence of platelet delta-granules and absence of AP3B1 mutations. As parental consanguinity suggested an autosomal recessive mode of inheritance, we employed homozygosity mapping, followed by whole-exome sequencing, to identify two candidate disease-causing genes, SLC45A2 and G6PC3. Conventional dideoxy sequencing confirmed pathogenic mutations in SLC45A2, associated with OCA type 4 (OCA-4), and G6PC3, associated with neutropenia. The substantial reduction of SLC45A2 protein in the patient's melanocytes caused the mislocalization of tyrosinase from melanosomes to the plasma membrane and also led to the incorporation of tyrosinase into exosomes and secretion into the culture medium, explaining the hypopigmentation in OCA-4. Our patient's G6PC3 mRNA expression level was also reduced, leading to increased apoptosis of her fibroblasts under endoplasmic reticulum stress. To our knowledge, this report describes the first North American patient with OCA-4, the first culture of human OCA-4 melanocytes, and the use of homozygosity mapping, followed by whole-exome sequencing, to identify disease-causing mutations in multiple genes in a single affected individual. C1 [Cullinane, Andrew R.; Vilboux, Thierry; Curry, James A.; Maynard, Dawn M.; Carlson-Donohoe, Hannah; Ciccone, Carla; Markello, Thomas C.; Huizing, Marjan; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [O'Brien, Kevin; Gunay-Aygun, Meral; Gahl, William A.] NIH, Intramural Off Rare Dis Res, Off Director, Bethesda, MD 20892 USA. [NISC Comparative Sequencing] NHGRI, Natl Inst Hlth Intramural Sequencing Ctr NISC, NIH, Bethesda, MD 20892 USA. RP Cullinane, AR (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM andrew.cullinane@nih.gov FU National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA FX We thank S Anderson, R Hess, R Fischer, and H Dorward for their help with the study. This study was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. NR 39 TC 38 Z9 40 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2011 VL 131 IS 10 BP 2017 EP 2025 DI 10.1038/jid.2011.157 PG 9 WC Dermatology SC Dermatology GA 822RV UT WOS:000295068200010 PM 21677667 ER PT J AU Le Corre, V Martin, L Brampton, C Bollt, O Dean, M Veenstra, T De Paepe, A Le Saux, O AF Le Corre, Y. Martin, L. Brampton, C. Bollt, O. Dean, M. Veenstra, T. De Paepe, A. Le Saux, O. TI The lymphatic vasculature determines the extent and localization of ectopic calcification in pseudoxanthoma elasticum SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Congress of the French-Speaking-Society-for-Dermatological-Research CY JUN 23-24, 2011 CL Besancon, FRANCE SP Soc Investigat Dermatol C1 [Le Corre, Y.; Brampton, C.; Bollt, O.] Univ Hawaii, John A Burns Sch Med, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. [Le Corre, Y.; Martin, L.] Angers Univ Hosp, Univ Angers, Dept Dermatol, Angers 9, France. [Le Corre, Y.; Martin, L.] Univ Angers, Angers Sch Med, UMR CNRSINSERM Integrated Neurovasc Bio 6214 771, Angers 1, France. [Dean, M.; Veenstra, T.] NCI, Cancer & Inflammat Program, Frederick, MD 21701 USA. [De Paepe, A.] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2011 VL 131 IS 10 BP 2151 EP 2151 PG 1 WC Dermatology SC Dermatology GA 822RV UT WOS:000295068200076 ER PT J AU Chaiworapongsa, T Romero, R Savasan, ZA Kusanovic, JP Ogge, G Soto, E Dong, Z Tarca, A Gaurav, B Hassan, SS AF Chaiworapongsa, Tinnakorn Romero, Roberto Savasan, Zeynep Alpay Kusanovic, Juan Pedro Ogge, Giovanna Soto, Eleazar Dong, Zhong Tarca, Adi Gaurav, Bhatti Hassan, Sonia S. TI Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE automated assay; IUGR; Placental growth factor (PlGF); preterm labor; soluble endoglin (sEng); soluble vascular endothelial growth factor receptor-1 (sVEGFR-1); soluble vascular endothelial growth factor receptor-2 (sVEGFR-2); angiogenesis; sflt-1 ID ENDOTHELIAL GROWTH-FACTOR; FOR-GESTATIONAL-AGE; PREGNANCY-INDUCED HYPERTENSION; LOW-DOSE ASPIRIN; CIRCULATING ANTIANGIOGENIC FACTORS; FACTOR RECEPTOR-1 CONCENTRATION; ADVERSE PERINATAL OUTCOMES; PROTEIN-CREATININE RATIO; UNEXPLAINED FETAL-DEATH; INNATE-IMMUNE-SYSTEM AB Objective: To determine whether maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and -2 could identify patients at risk for developing preeclampsia (PE) requiring preterm delivery. Study design: Patients presenting with the diagnosis "rule out PE" to the obstetrical triage area of our hospital at <37 weeks of gestation (n = 87) were included in this study. Delivery outcomes were used to classify patients into four groups: I) patients without PE or those with gestational hypertension (GHTN) or chronic hypertension (CHTN) who subsequently developed PE at term (n = 19); II): mild PE who delivered at term (n = 15); III): mild disease (mild PE, GHTN, CHTN) who subsequently developed severe PE requiring preterm delivery (n = 26); and IV): diagnosis of severe PE (n = 27). Plasma concentrations of PlGF, sEng, sVEGFR-1 and -2 were determined at the time of presentation by ELISA. Reference ranges for analytes were constructed by quantile regression in our laboratory (n = 180; 1046 samples). Comparisons among groups were performed using multiples of the median (MoM) and parametric statistics after log transformation. Receiver operating characteristic curves, logistic regression and survival analysis were employed for analysis. Results: The mean MoM plasma concentration of PlGF/sVEGFR-1, PlGF/sEng, PlGF, sVEGFR-1 and -2, and sEng in Group III was significantly different from Group II (all p<0.05). A plasma concentration of PlGF/sVEGFR-1 <= 0.05 MoM or PlGF/sEng <= 0.07 MoM had the highest likelihood ratio of a positive test (8.3, 95% CI 2.8-25 and 8.6, 95% CI 2.9-25, respectively), while that of PlGF <= 0.396 MoM had the lowest likelihood ratio of a negative test (0.08, 95% CI 0.03-0.25). The association between low plasma concentrations of PlGF/sVEGFR-1 (= 0.05 MoM) as well as that of PlGF/sEng (= 0.07 MoM) and the development of severe PE remained significant after adjusting for gestational age at presentation, average systolic and diastolic blood pressure, and a history of chronic hypertension [ adjusted odds ratio (OR) = 27 (95% CI 6.4-109) and adjusted OR 30 (95% CI 6.9-126), respectively]. Among patients who presented < 34 weeks gestation (n = 59), a plasma concentration of PlGF/sVEGFR-1 < 0.033 MoM identified patients who delivered within 2 weeks because of PE with a sensitivity of 93% (25/27) and a specificity of 78% (25/32). This cut-off was associated with a shorter interval-to-delivery due to PE [ hazard ratio = 6 (95% CI 2.5-14.6)]. Conclusions: Plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in the obstetrical triage area. These observations support the value of these biomarkers in the clinical setting for the identification of the patient at risk for disease progression requiring preterm delivery. C1 [Chaiworapongsa, Tinnakorn; Romero, Roberto; Savasan, Zeynep Alpay; Ogge, Giovanna; Soto, Eleazar; Dong, Zhong; Tarca, Adi; Gaurav, Bhatti; Hassan, Sonia S.] Wayne State Univ, NICHD NIH DHHS, Perinatol Res Branch, Bethesda, MD USA. [Chaiworapongsa, Tinnakorn; Romero, Roberto; Savasan, Zeynep Alpay; Ogge, Giovanna; Soto, Eleazar; Dong, Zhong; Tarca, Adi; Gaurav, Bhatti; Hassan, Sonia S.] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, Detroit, MI 48201 USA. [Chaiworapongsa, Tinnakorn; Savasan, Zeynep Alpay; Soto, Eleazar; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kusanovic, Juan Pedro] Hosp Dr Sotero del Rio, Ctr Perinatal Res, Santiago, Chile. [Kusanovic, Juan Pedro] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Santiago, Chile. [Tarca, Adi; Gaurav, Bhatti] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. RP Chaiworapongsa, T (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM tchaiwor@med.wayne.edu; prbchiefstaff@med.wayne.edu RI Ogge, Giovanna/G-6109-2011 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 173 TC 68 Z9 70 U1 0 U2 11 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD OCT PY 2011 VL 24 IS 10 BP 1187 EP 1207 DI 10.3109/14767058.2011.589932 PG 21 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 822JH UT WOS:000295040500001 PM 21827221 ER PT J AU Milne, RL Lorenzo-Bermejo, J Burwinkel, B Malats, N Arias, JI Zamora, MP Benitez, J Humphreys, MK Garcia-Closas, M Chanock, SJ Lissowska, J Sherman, ME Mannermaa, A Kataja, V Kosma, VM Nevanlinna, H Heikkinen, T Aittomaki, K Blomqvist, C Anton-Culver, H Ziogas, A Devilee, P van Asperen, CJ Tollenaar, RAEM Seynaeve, C Hall, P Czene, K Liu, JJ Irwanto, AK Kang, D Yoo, KY Noh, DY Couch, FJ Olson, JE Wang, XS Fredericksen, Z Nordestgaard, BG Bojesen, SE Flyger, H Margolin, S Lindblom, A Fasching, PA Schulz-Wendtland, R Ekici, AB Beckmann, MW Wang-Gohrke, S Shen, CY Yu, JC Hsu, HM Wu, PE Giles, GG Severi, G Baglietto, L English, DR Cox, A Brock, I Elliott, G Reed, MWR Beesley, J Chen, XQ Fletcher, O Gibson, L Silva, ID Peto, J Frank, B Heil, J Meindl, A Chang-Claude, J Hein, R Vrieling, A Flesch-Janys, D Southey, MC Smith, L Apicella, C Hopper, JL Dunning, AM Pooley, KA Pharoah, PDP Hamann, U Pesch, B Ko, YD Easton, DF Chenevix-Trench, G AF Milne, Roger L. Lorenzo-Bermejo, Justo Burwinkel, Barbara Malats, Nuria Ignacio Arias, Jose Pilar Zamora, M. Benitez, Javier Humphreys, Manjeet K. Garcia-Closas, Montserrat Chanock, Stephen J. Lissowska, Jolanta Sherman, Mark E. Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Nevanlinna, Heli Heikkinen, Tuomas Aittomaki, Kristiina Blomqvist, Carl Anton-Culver, Hoda Ziogas, Argyrios Devilee, Peter van Asperen, Christie J. Tollenaar, Rob A. E. M. Seynaeve, Caroline Hall, Per Czene, Kamila Liu, Jianjun Irwanto, Astrid K. Kang, Daehee Yoo, Keun-Young Noh, Dong-Young Couch, Fergus J. Olson, Janet E. Wang, Xianshu Fredericksen, Zachary Nordestgaard, Borge G. Bojesen, Stig E. Flyger, Henrik Margolin, Sara Lindblom, Annika Fasching, Peter A. Schulz-Wendtland, Ruediger Ekici, Arif B. Beckmann, Matthias W. Wang-Gohrke, Shan Shen, Chen-Yang Yu, Jyh-Cherng Hsu, Huan-Ming Wu, Pei-Ei Giles, Graham G. Severi, Gianluca Baglietto, Laura English, Dallas R. Cox, Angela Brock, Ian Elliott, Graeme Reed, Malcolm W. R. Beesley, Jonathan Chen, Xiaoqing Fletcher, Olivia Gibson, Lorna Silva, Isabel dos Santos Peto, Julian Frank, Bernd Heil, Joerg Meindl, Alfons Chang-Claude, Jenny Hein, Rebecca Vrieling, Alina Flesch-Janys, Dieter Southey, Melissa C. Smith, Letitia Apicella, Carmel Hopper, John L. Dunning, Alison M. Pooley, Karen A. Pharoah, Paul D. P. Hamann, Ute Pesch, Beate Ko, Yon-Dschun Easton, Douglas F. Chenevix-Trench, Georgia CA KConFab Investigators AOCS Grp GENICA Network TI 7q21-rs6964587 and breast cancer risk: an extended case-control study by the Breast Cancer Association Consortium SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID GENE; SUSCEPTIBILITY; VARIANTS; ESTROGEN; WOMEN; ATM AB Background Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case-control studies. Methods The authors genotyped 14 843 invasive case patients and 19 852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression. Results For white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p=0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33 376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p=0.001). The OR was greater at younger ages (p trend=0.01). Conclusion This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance. C1 [Milne, Roger L.; Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Human Canc Genet Program, Madrid 28039, Spain. [Lorenzo-Bermejo, Justo] Univ Heidelberg Hosp, Inst Med Biometry & Informat, Heidelberg, Germany. [Lorenzo-Bermejo, Justo] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany. [Burwinkel, Barbara; Frank, Bernd] DKFZ, Mol Epidemiol Grp, Heidelberg, Germany. [Burwinkel, Barbara; Heil, Joerg] Univ Heidelberg Hosp, Dept Obstet & Gynecol, Heidelberg, Germany. [Ignacio Arias, Jose] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain. [Pilar Zamora, M.] Univ Hosp La Paz, Med Oncol Serv, Madrid, Spain. [Benitez, Javier] CNIO, Human Canc Genet Program, Human Genet Grp, Madrid, Spain. [Humphreys, Manjeet K.; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Garcia-Closas, Montserrat; Chanock, Stephen J.; Sherman, Mark E.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Garcia-Closas, Montserrat; Fletcher, Olivia] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Garcia-Closas, Montserrat] Inst Canc Res, Epidemiol Sect, London SW3 6JB, England. [Garcia-Closas, Montserrat] Inst Canc Res, Genet Sect, London SW3 6JB, England. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Mannermaa, Arto; Kosma, Veli-Matti] Univ Eastern Finland, Sch Med, Inst Clin Med Pathol & Forens Med, Bioctr Kuopio, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti] Kuopio Univ Hosp, Dept Clin Pathol, SF-70210 Kuopio, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Dept Oncol, SF-70210 Kuopio, Finland. [Kataja, Vesa] Univ Eastern Finland, Sch Med, Inst Clin Med, Kuopio, Finland. [Nevanlinna, Heli; Heikkinen, Tuomas] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Devilee, Peter] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [van Asperen, Christie J.] Leiden Univ, Dept Clin Genet, Med Ctr, Leiden, Netherlands. [Tollenaar, Rob A. E. M.] Leiden Univ, Dept Surg, Med Ctr, Leiden, Netherlands. [Seynaeve, Caroline] Erasmus MC Daniel den Hoed Canc Ctr, Rotterdam Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Hall, Per; Czene, Kamila] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Liu, Jianjun; Irwanto, Astrid K.] Genome Inst Singapore, Human Genet Lab, Singapore, Singapore. [Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Couch, Fergus J.; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Olson, Janet E.; Fredericksen, Zachary] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Nordestgaard, Borge G.; Bojesen, Stig E.] Univ Copenhagen, Herlev Univ Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. [Nordestgaard, Borge G.; Bojesen, Stig E.] Univ Copenhagen, Herlev Univ Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Flyger, Henrik] Univ Copenhagen, Herlev Univ Hosp, Dept Breast Surg HF, Copenhagen, Denmark. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Fasching, Peter A.; Beckmann, Matthias W.] Univ Hosp Erlangen, Dept Gynecol & Obstet, Univ Breast Ctr, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA. [Schulz-Wendtland, Ruediger] Univ Hosp Erlangen, Inst Diagnost Radiol, Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, D-8520 Erlangen, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Shen, Chen-Yang; Wu, Pei-Ei] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Shen, Chen-Yang; Wu, Pei-Ei] Taiwan Biobank, Taipei, Taiwan. [Yu, Jyh-Cherng; Hsu, Huan-Ming] Triserv Gen Hosp, Dept Surg, Taipei, Taiwan. [Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [English, Dallas R.; Apicella, Carmel; Hopper, John L.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Cox, Angela; Brock, Ian; Elliott, Graeme] Univ Sheffield, Sch Med, Inst Canc Studies, Sheffield, S Yorkshire, England. [Reed, Malcolm W. R.] Univ Sheffield, Sch Med, Acad Unit Surg Oncol, Sheffield, S Yorkshire, England. [Beesley, Jonathan; Chen, Xiaoqing; Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [KConFab Investigators; AOCS Grp] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Gibson, Lorna; Silva, Isabel dos Santos; Peto, Julian] London Sch Hyg & Trop Med, London WC1, England. [Frank, Bernd] DKFZ, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Meindl, Alfons] Tech Univ Munich, Dept Obstet & Gynaecol, Munich, Germany. [Chang-Claude, Jenny; Hein, Rebecca; Vrieling, Alina] DKFZ, Div Canc Epidemiol, Heidelberg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Dept Canc Epidemiol, Clin Canc Registry, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Southey, Melissa C.; Smith, Letitia] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Dunning, Alison M.; Pooley, Karen A.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pesch, Beate] German Social Accid Insurance IPA, Inst Prevent & Occupat Med, Bochum, Germany. [Ko, Yon-Dschun] Johanniter Krankenhaus, Evangel Kliniken Bonn gGmbH, Dept Internal Med, Bonn, Germany. Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-7000 Stuttgart, Germany. Univ Tubingen, Tubingen, Germany. [GENICA Network] Univ Bonn, Inst Pathol, D-5300 Bonn, Germany. RP Milne, RL (reprint author), Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Human Canc Genet Program, Calle Melchor Fernandez Almagro 3, Madrid 28039, Spain. EM rmilne@cnio.es RI Vrieling, Alina/A-2725-2016; Noh, Dong-Young/G-5531-2011; Bowtell, David/H-1007-2016; Shen, CY/F-6271-2010; Yoo, Keun-Young/J-5548-2012; Ekici, Arif/C-3971-2013; Smith, Letitia /J-9035-2014; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; OI Bowtell, David/0000-0001-9089-7525; Czene, Kamila/0000-0002-3233-5695; Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Nevanlinna, Heli/0000-0002-0916-2976; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099; English, Dallas/0000-0001-7828-8188 FU Cancer Research UK [10118, 10124, A10119, A10124, C1287/A10118, C1287/A12014, C490/A10124]; Intramural NIH HHS; NCI NIH HHS [R01 CA102740, CA-95-011, CA102740-01A2, CA116201, CA122340, CA128978, CA58860, CA69398, CA69417, CA69446, CA69467, CA69631, CA69638, CA92044, K01 CA077068, K07 CA092044, K22 CA095011, P50 CA116201, R01 CA058860, R01 CA122340, R01 CA128978, U01 CA069398, U01 CA069417, U01 CA069446, U01 CA069467, U01 CA069631, U01 CA069638]; NIA NIH HHS [R01 AG031067]; NIAID NIH HHS [P01 AI056320] NR 20 TC 2 Z9 2 U1 0 U2 3 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD OCT PY 2011 VL 48 IS 10 BP 698 EP 702 DI 10.1136/jmedgenet-2011-100303 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 822FZ UT WOS:000295030700007 PM 21931171 ER PT J AU Ramalingam, SS Davies, AM Longmate, J Edelman, MJ Lara, PN Vokes, EE Villalona-Calero, M Gitlitz, B Reckamp, K Salgia, R Wright, JJ Belani, CP Gandara, DR AF Ramalingam, Suresh S. Davies, Angela M. Longmate, Jeffrey Edelman, Martin J. Lara, Primo N., Jr. Vokes, Everett E. Villalona-Calero, Miguel Gitlitz, Barbara Reckamp, Karen Salgia, Ravi Wright, John J. Belani, Chandra P. Gandara, David R. TI Bortezomib for Patients with Advanced-Stage Bronchioloalveolar Carcinoma A California Cancer Consortium Phase II Study (NCI 7003) SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Bortezomib; Proteasome inhibition; BAC; Bronchioloalveolar carcinoma; NSCLC ID CELL LUNG-CANCER; SOUTHWEST-ONCOLOGY-GROUP; INHIBITOR BORTEZOMIB; SOLID TUMORS; TRIAL; ADENOCARCINOMA; COMBINATION; ERLOTINIB; PACLITAXEL; FEATURES AB Background: Bronchioloalveolar carcinoma (BAC), a subtype of non-small cell lung cancer, is a difficult disease to treat with low response rates with cytotoxic chemotherapy. Bortezomib, a proteasome inhibitor, has demonstrated objective responses in patients with BAC in early-phase clinical trials. We conducted a phase II study of bortezomib in patients with advanced-stage BAC. Methods: Patients with advanced BAC, adenocarcinoma with BAC features or BAC with adenocarcinoma features, and less than two prior regimens were eligible. Prior epidermal growth factor receptor (EGFR) inhibitor therapy was allowed. Bortezomib was administered intravenously at 1.6 mg/m(2) on days 1 and 8 of every 21-day cycle until disease progression or unacceptable toxicity. The primary end point was response rate. The Simon two-stage design was used. Results: Forty-two patients were enrolled, and the study was halted early for slow accrual. Patient characteristics were female 55%, median age 68 years, and Eastern Cooperative Oncology Group performance status of 0 and 1 in 31 and 11 patients, respectively. Twenty-six (62%) patients had received prior therapy with an EGFR inhibitor. A median of four cycles of therapy were administered. Objective responses were noted in 5%, whereas 57% had disease stabilization. The median progression-free survival and overall survival were 5.5 and 13.6 months, respectively. Grade 3 diarrhea and fatigue were noted in three and five patients, respectively. Conclusions: Bortezomib is tolerated well and is associated with modest anticancer activity in patients with advanced BAC, including patients who progressed on EGFR inhibitor therapy. C1 [Ramalingam, Suresh S.] Emory Univ, Dept Hematol & Med Oncol, Winship Canc Inst, Atlanta, GA 30322 USA. [Davies, Angela M.; Lara, Primo N., Jr.; Gandara, David R.] Univ Calif Davis, Div Hematol Oncol, Dept Internal Med, Sch Med, Sacramento, CA 95817 USA. [Davies, Angela M.; Lara, Primo N., Jr.; Gandara, David R.] UC Davis Canc Ctr, Sacramento, CA USA. [Longmate, Jeffrey; Reckamp, Karen] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Edelman, Martin J.] Univ Maryland, Med Ctr, Dept Med, Baltimore, MD 21201 USA. [Vokes, Everett E.; Salgia, Ravi] Univ Chicago, Med Ctr, Dept Med, Chicago, IL 60637 USA. [Villalona-Calero, Miguel] Ohio State Comprehens Canc Ctr, Div Med Oncol, Columbus, OH USA. [Gitlitz, Barbara] Univ So Calif, Dept Med, Norris Canc Ctr, Los Angeles, CA USA. [Wright, John J.] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. [Belani, Chandra P.] Penn State Canc Inst, Hershey Med Ctr, Dept Med, Hershey, PA USA. RP Ramalingam, SS (reprint author), Emory Univ, Dept Hematol & Med Oncol, Winship Canc Inst, 1365 Clifton Rd NE,Room C-3090, Atlanta, GA 30322 USA. EM suresh.ramalingam@emory.edu OI Belani, Chandra/0000-0001-5049-5329; Longmate, Jeffrey/0000-0002-0869-7928; Reckamp, Karen/0000-0002-9213-0325 FU Millennium Pharmaceuticals; NCI [NO1-CM-62209, NO1-CM-62201, NO1-CM-62208, NO1-CM-62207] FX Dr. Lara has served as a consultant and received research funding from Millennium Pharmaceuticals. The other authors have no conflicts of interest.; Supported by NCI NO1-CM-62209 (California Cancer Consortium), NO1-CM-62201 (University of Chicago Consortium), NO1-CM-62208 (Southeast Phase 2 Consortium), and NO1-CM-62207 (Ohio State University). NR 24 TC 9 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2011 VL 6 IS 10 BP 1741 EP 1745 DI 10.1097/JTO.0b013e318225924c PG 5 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 821FV UT WOS:000294961200018 PM 21716143 ER PT J AU Mackey, DC Manini, TM Schoeller, DA Koster, A Glynn, NW Goodpaster, BH Satterfield, S Newman, AB Harris, TB Cummings, SR AF Mackey, Dawn C. Manini, Todd M. Schoeller, Dale A. Koster, Annemarie Glynn, Nancy W. Goodpaster, Bret H. Satterfield, Suzanne Newman, Anne B. Harris, Tamara B. Cummings, Steven R. CA Hlth Aging Body Composition Study TI Validation of an Armband to Measure Daily Energy Expenditure in Older Adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Accelerometer; Activity monitor; Physical activity; Aged; DLW ID EXERCISE; MORTALITY; ACCURACY; VALIDITY; MONITORS AB Background. Objective methods to measure daily energy expenditure in studies of aging are needed. We sought to determine the accuracy of total energy expenditure (TEE) and activity energy expenditure (AEE) estimates from the SenseWear Pro armband (SWA) using software versions 6.1 (SWA 6.1) and 5.1 (SWA 5.1) relative to criterion methods in free-living older adults. Methods. Participants (n = 19, mean age 82.0 years) wore a SWA for a mean +/- SD 12.5 +/- 1.1 days, including while sleeping. During this same period, criterion values for TEE were assessed with doubly labeled water and for resting metabolic rate (RMR) with indirect calorimetry. AEE was calculated as 0.9 TEE - RMR. Results. For TEE, there was no difference in mean +/- SD values from doubly labeled water (2,040 +/- 472 kcal/day) versus SWA 6.1 (2,012 +/- 497 kcal/day, p = .593) or SWA 5.1 (2,066 +/- 474 kcal/day, p = .606); individual values were highly correlated between methods (SWA 6.1 r = .893, p < .001; SWA 5.1 r = .901, p < .001) and demonstrated strong agreement (SWA 6.1 intraclass correlation coefficient = .896; SWA 5.1 intraclass correlation coefficient = .904). For AEE, mean values from SWA 6.1 (427 +/- 304 kcal/day) were lower by 26.8% than criterion values (583 +/- 242 kcal/day, p = .003), and mean values from SWA 5.1 (475 +/- 299 kcal/day) were lower by 18.5% than criterion values (p = .021); however, individual values were highly correlated between methods (SWA 6.1 r = .760, p < .001; SWA 5.1 r = .786, p < .001) and demonstrated moderate agreement (SWA 6.1 intraclass correlation coefficient = .645; SWA 5.1 intraclass correlation coefficient = .720). Bland-Altman plots identified no systematic bias for TEE or AEE. Conclusions. Acceptable levels of agreement were observed between SWA and criterion measurements of TEE and AEE in older adults. C1 [Mackey, Dawn C.; Cummings, Steven R.] Calif Pacific Med Ctr, San Francisco, CA 94107 USA. [Manini, Todd M.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. [Schoeller, Dale A.] Univ Wisconsin Madison, Dept Nutr Sci, Madison, WI 53715 USA. [Koster, Annemarie; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Koster, Annemarie] Maastricht Univ, Sch Publ Hlth & Primary Care CAPHRI, Maastricht, Netherlands. [Glynn, Nancy W.; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Goodpaster, Bret H.] Univ Pittsburgh, Med Ctr, Div Endocrinol & Metab, Pittsburgh, PA 15260 USA. [Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. RP Mackey, DC (reprint author), Calif Pacific Med Ctr, 185 Berry St,Suite 5700, San Francisco, CA 94107 USA. EM dmackey@sfcc-cpmc.net RI Koster, Annemarie/E-7438-2010; Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Glynn, Nancy/0000-0003-2265-0162 FU National Institutes of Health, National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] FX National Institutes of Health, National Institute on Aging (contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106), and Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 15 TC 56 Z9 58 U1 1 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2011 VL 66 IS 10 BP 1108 EP 1113 DI 10.1093/gerona/glr101 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 821IW UT WOS:000294969400009 PM 21734231 ER PT J AU Thorpe, RJ Koster, A Kritchevsky, SB Newman, AB Harris, T Ayonayon, HN Perry, S Rooks, RN Simonsick, EM AF Thorpe, Roland J., Jr. Koster, Annemarie Kritchevsky, Stephen B. Newman, Anne B. Harris, Tamara Ayonayon, Hilsa N. Perry, Sara Rooks, Ronica N. Simonsick, Eleanor M. CA Hlth Aging Body Composition Study TI Race, Socioeconomic Resources, and Late-Life Mobility and Decline: Findings From the Health, Aging, and Body Composition Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Race disparities; Functional limitations; SES; Disability ID LOWER-EXTREMITY FUNCTION; OLDER-ADULTS; CUMULATIVE DISADVANTAGE; LONGITUDINAL ANALYSIS; AFRICAN-AMERICANS; FUNCTIONAL STATUS; PHYSICAL FUNCTION; WOMENS HEALTH; ACTIVE LIFE; DISABILITY AB Background. This study examines the relationship between race and mobility over 5 years in initially well-functioning older adults and evaluates how a broad set of socioeconomic status indicators affect this relationship. Methods. Data were from 2,969 black and white participants aged 70-79 from the Health, Aging, and Body Composition study. Mobility parameters included self-reported capacity to walk a quarter mile and climb 10 steps and usual gait speed. Incident mobility limitation was defined as reported difficulty walking a quarter mile or climbing 10 steps at two consecutive semiannual assessments. Gait speed decline was defined as a 4% reduction in speed per year. Results. At baseline, even though all participants were free of mobility limitation, blacks had slower walking speed than their white counterparts, which was not explained by poverty, education, reading level, or income adequacy. After 5 years, accounting for age, site, and baseline mobility, blacks were more likely to develop mobility limitation than whites. Adjusting for prevalent conditions at baseline eliminated this difference in women; controlling for education eliminated this difference in men. No differences in gait speed decline were identified. Conclusions. Higher rates of mobility loss observed in older blacks relative to older whites appear to be a function of both poorer initial mobility status and existing health conditions particularly for women. Education may also play a role especially for men. C1 [Thorpe, Roland J., Jr.] Johns Hopkins Bloomberg Sch Publ Hlth, Hopkins Ctr Hlth Dispar Solut, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. [Koster, Annemarie] Univ Maastricht, Fac Hlth Med & Life Sci, Maastricht, Netherlands. [Koster, Annemarie; Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sect Gerontol & Geriatr Med, Sticht Ctr Aging, Winston Salem, NC USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Perry, Sara] Tulane Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Rooks, Ronica N.] Univ Colorado Denver, Dept Hlth & Behav Sci, Denver, CO 80202 USA. [Simonsick, Eleanor M.] Johns Hopkins Sch Med, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Thorpe, RJ (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Hopkins Ctr Hlth Dispar Solut, Dept Hlth Policy & Management, 624 N Broadway Ste 441, Baltimore, MD 21205 USA. EM rthorpe@jhsph.edu RI Koster, Annemarie/E-7438-2010; Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institutes of Health, National Institute on Aging; National Center for Minority Health and Health Disparities [P60MD000214-01] FX This study was supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Research conducted by the first author was supported by a grant from the National Center for Minority Health and Health Disparities (P60MD000214-01). NR 59 TC 27 Z9 28 U1 4 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2011 VL 66 IS 10 BP 1114 EP 1123 DI 10.1093/gerona/glr102 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 821IW UT WOS:000294969400010 PM 21743093 ER PT J AU McLain, AC Ghosh, SK AF McLain, Alexander C. Ghosh, Sujit K. TI Nonparametric estimation of the conditional mean residual life function with censored data SO LIFETIME DATA ANALYSIS LA English DT Article DE Covariates; Local averaging; Mean residual life; Right censoring; Smoothing ID KAPLAN-MEIER ESTIMATE; EXPECTANCY REGRESSION; SMOOTH ESTIMATION; SURVIVAL-DATA; MODEL AB The conditional mean residual life (MRL) function is the expected remaining lifetime of a system given survival past a particular time point and the values of a set of predictor variables. This function is a valuable tool in reliability and actuarial studies when the right tail of the distribution is of interest, and can be more informative than the survivor function. In this paper, we identify theoretical limitations of some semi-parametric conditional MRL models, and propose two nonparametric methods of estimating the conditional MRL function. Asymptotic properties such as consistency and normality of our proposed estimators are established. We investigate via simulation study the empirical properties of the proposed estimators, including bootstrap pointwise confidence intervals. Using Monte Carlo simulations we compare the proposed nonparametric estimators to two popular semi-parametric methods of analysis, for varying types of data. The proposed estimators are demonstrated on the Veteran's Administration lung cancer trial. C1 [McLain, Alexander C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Ghosh, Sujit K.] N Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA. RP McLain, AC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. EM mclaina@mail.nih.gov OI McLain, Alexander/0000-0002-5475-0670; Ghosh, Sujit/0000-0001-8351-408X FU National Institute of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We would like to acknowledge the help of an associate editor and three referees whose insightful comments improved the overall quality of this manuscript. Furthermore, we would like to acknowledge Professor Yogendra Chaubey and Professor Tom Gerig for help on earlier versions of this manuscript. The research of the first author was supported in part by the Intramural Research Program of the National Institute of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 29 TC 2 Z9 2 U1 3 U2 15 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1380-7870 EI 1572-9249 J9 LIFETIME DATA ANAL JI Lifetime Data Anal. PD OCT PY 2011 VL 17 IS 4 BP 514 EP 532 DI 10.1007/s10985-011-9197-x PG 19 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA 821GW UT WOS:000294964000003 PM 21598091 ER PT J AU Challiss, RAJ Wess, J AF Challiss, R. A. John Wess, Juergen TI RECEPTORS GPCR-G protein preassembly? SO NATURE CHEMICAL BIOLOGY LA English DT News Item ID COUPLED RECEPTORS; LIVING CELLS; COMPLEXES C1 [Challiss, R. A. John] Univ Leicester, Dept Cell Physiol & Pharmacol, Coll Med Biol Sci & Psychol, Leicester LE1 9HN, Leics, England. [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. RP Challiss, RAJ (reprint author), Univ Leicester, Dept Cell Physiol & Pharmacol, Coll Med Biol Sci & Psychol, Leicester LE1 9HN, Leics, England. EM jc36@leicester.ac.uk; jwess@helix.nih.gov OI Challiss, John/0000-0001-5506-2848 NR 10 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD OCT PY 2011 VL 7 IS 10 BP 657 EP 658 DI 10.1038/nchembio.665 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 822EQ UT WOS:000295027100003 PM 21931312 ER PT J AU Komatsu, H Ohara, A Sasaki, K Abe, H Hattori, H Hall, FS Uhl, GR Sora, I AF Komatsu, Hiroshi Ohara, Arihisa Sasaki, Kazumasu Abe, Hiromi Hattori, Hisaki Hall, F. Scott Uhl, George R. Sora, Ichiro TI Decreased response to social defeat stress in mu-opioid-receptor knockout mice SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Chronic social defeat stress; mu-opioid-receptor knockout; Behavior; Hippocampus; Brain-derived neurotrophic factor ID MESSENGER-RNA; NEUROENDOCRINE RESPONSES; ANXIETY; DEPRESSION; EXPRESSION; DISORDERS; BRAIN; POLYMORPHISM; ANALGESIA; BEHAVIOR AB Substantial evidence exists that opioid systems are involved in stress response and that changes in opioid systems in response to stressors affect both reward and analgesia. Reportedly, mice suffering chronic social defeat stress subsequently show aversion to social contact with unfamiliar mice. To further examine the role of opioid systems in stress response, the behavioral and neurochemical effects of chronic social defeat stress (psychosocial stress) were evaluated in mu-opioid-receptor knockout (MOR-KO) mice. Aversion to social contact was induced by chronic social defeat stress in wild-type mice but was reduced in MOR-KO mice. Moreover, basal expression of brain-derived neurotrophic factor (BDNF) mRNA in MOR-KO mice hippocampi was significantly lower than in wild-type mice. Psychosocial stress significantly decreased BDNF mRNA expression in wild-type mice but did not affect BDNF expression in MOR-KO mice; no difference in basal levels of plasma corticosterone was observed. These results suggest that the mu-opioid receptor is involved in the behavioral sequelae of psychosocial stress and consequent regulation of BDNF expression in the hippocampus, and may play an important role in psychiatric disorders for which stress is an important predisposing or precipitating factor, such as depression, posttraumatic stress disorder, and social anxiety disorder. (C) 2011 Elsevier Inc. All rights reserved. C1 [Komatsu, Hiroshi; Ohara, Arihisa; Sasaki, Kazumasu; Abe, Hiromi; Hattori, Hisaki; Sora, Ichiro] Tohoku Univ, Dept Biol Psychiat, Grad Sch Med, Sendai, Miyagi 9808574, Japan. [Hall, F. Scott; Uhl, George R.] Natl Inst Drug Abuse, Mol Neurobiol Branch, Intramural Res Program, NIH DHHS, Baltimore, MD 21224 USA. RP Sora, I (reprint author), Tohoku Univ, Dept Biol Psychiat, Grad Sch Med, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan. EM hkomatsu1019@gmail.com; Arissaohara@hotmail.com; k-sasaki@med.tohoku.ac.jp; hiromiab@hotmail.com; hisakichin@hotmail.com; shall@intra.nida.noh.gov; guhl@intra.nida.nih.gov; sora@med.tohoku.ac.jp RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Ministry of Health, Labor and Welfare of Japan; Ministry of Education, Culture, Sports, Science and Technology of Japan [17022007, 18023007]; National Institute on Drug Abuse (NIH/DHHS, USA) FX The authors thank Harumi Hata, Tomomi Nakano, Dr. Hideaki Kobayashi, Dr. Yohtaro Numachi, Dr. Motoyasu Yamashita, and Dr. Fumiaki Ito for technical assistance and scientific advice. This study was supported by a Grant-in-Aid for Health and Labor Science Research (Research on Pharmaceutical and Medical Safety) from the Ministry of Health, Labor and Welfare of Japan; by Grants-in-Aid for Scientific Research on Priority Areas System Study on Higher Order Brain Functions and Research on Pathomechanisms of Brain Disorders from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Nos. 17022007, 18023007); and by the Intramural Research Program of the National Institute on Drug Abuse (NIH/DHHS, USA). NR 46 TC 20 Z9 21 U1 0 U2 6 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 OCT PY 2011 VL 99 IS 4 BP 676 EP 682 DI 10.1016/j.pbb.2011.06.008 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 820BI UT WOS:000294880100022 PM 21703297 ER PT J AU Miao, CL Chen, SG Ding, JZ Liu, KA Li, DB Macedo, R Lai, SH Vogel-Claussen, J Brown, ER Lima, JAC Bluemke, DA AF Miao, Cuilian Chen, Shaoguang Ding, Jingzhong Liu, Kiang Li, Debiao Macedo, Robson Lai, Shenghan Vogel-Claussen, Jens Brown, Elizabeth R. Lima, Joao A. C. Bluemke, David A. TI The Association of Pericardial Fat with Coronary Artery Plaque Index at MR Imaging: The Multi-Ethnic Study of Atherosclerosis (MESA) SO RADIOLOGY LA English DT Article ID EPICARDIAL ADIPOSE-TISSUE; VESSEL WALL; IN-VIVO; CAROTID ATHEROSCLEROSIS; RISK-FACTOR; RHO-KINASE; DISEASE; OBESITY; LESIONS; CALCIFICATION AB Purpose: To determine the relationship of pericardial fat, which secretes proinflammatory markers that have been implicated in coronary atherosclerosis, with atherosclerotic plaque in an asymptomatic population-based cohort. Materials and Methods: In this institutional review board-approved study, all participants supplied written informed consent. One hundred eighty-three participants (89 women, 94 men; mean age, 61 years 6 9 [standard deviation]) from the community-based Multi-Ethnic Study of Atherosclerosis (MESA) were included. The coronary artery eccentricity (ratio of maximal to minimal coronary artery wall thickness) was determined by using magnetic resonance (MR) imaging and served as an index of plaque burden. The pericardial fat volume was determined by using computed tomography. Linear regression coefficient analysis was used to correlate pericardial fat volume with coronary artery wall thickness and plaque eccentricity. Results: Pericardial fat volume correlated significantly with degree of plaque eccentricity (P < .05) in both men and women. After adjustments for body mass index (BMI) and waist circumference, traditional risk factors, C-reactive protein level, and coronary artery calcium content, the relationship between pericardial fat and plaque eccentricity remained significant in men (P < .01) but not in women. BMI and waist circumference correlated with degree of plaque eccentricity in the univariate model (P < .05) but not after adjustment for pericardial fat volume or traditional risk factors. Conclusion: Pericardial fat volume, rather than BMI and waist circumference, was more strongly related to plaque eccentricity as a measure of coronary atherosclerotic plaque burden. The results support the proposed role of pericardial fat in association with atherosclerosis. C1 [Macedo, Robson; Vogel-Claussen, Jens; Lima, Joao A. C.; Bluemke, David A.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Miao, Cuilian] Northwestern Univ, Sch Med, Dept Radiol, Chicago, IL 60611 USA. [Liu, Kiang] Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Chen, Shaoguang; Lai, Shenghan] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Ding, Jingzhong] Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Li, Debiao] Cedars Sinai Med Ctr, Biomed Imaging Res Inst, Los Angeles, CA 90048 USA. [Brown, Elizabeth R.] Univ Washington, Collaborat Hlth Studies Coordinating Ctr Biostat, Seattle, WA 98195 USA. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. EM bluemke@nih.gov RI Brown, Elizabeth/A-8984-2008; Li, Debiao/B-7622-2009; OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute; National Institutes of Health [R01 HL78909, N01-HC-95159, N01-HC-95169] FX This research was supported by the National Heart, Lung, and Blood Institute and the National Institutes of Health (grant R01 HL78909 and contracts N01-HC-95159 through N01-HC-95169). NR 29 TC 20 Z9 21 U1 0 U2 0 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 OCT PY 2011 VL 261 IS 1 BP 109 EP 115 DI 10.1148/radiol.11110346 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 822IW UT WOS:000295039000012 PM 21846753 ER PT J AU Zanotti-Fregonara, P Hindie, E AF Zanotti-Fregonara, Paolo Hindie, Elif TI Radiation Risk from Airport X-ray Backscatter Scanners: Should We Fear the Microsievert? SO RADIOLOGY LA English DT Letter C1 [Zanotti-Fregonara, Paolo] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Hindie, Elif] St Louis Hosp, Dept Nucl Med, Paris, France. RP Zanotti-Fregonara, P (reprint author), NIMH, Mol Imaging Branch, NIH, 31 Ctr Dr,Bldg 10,Room B1D43,MSC 1026, Bethesda, MD 20892 USA. EM zanottifregonp@mail.nih.gov FU Intramural NIH HHS NR 10 TC 0 Z9 0 U1 0 U2 8 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 OCT PY 2011 VL 261 IS 1 BP 330 EP 331 DI 10.1148/radiol.11110983 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 822IW UT WOS:000295039000045 PM 21931148 ER PT J AU Haseman, JK Allen, DG Lipscomb, EA Truax, JF Stokes, WS AF Haseman, Joseph K. Allen, David G. Lipscomb, Elizabeth A. Truax, James F. Stokes, William S. TI Using fewer animals to identify chemical eye hazards: Revised criteria necessary to maintain equivalent hazard classification SO REGULATORY TOXICOLOGY AND PHARMACOLOGY LA English DT Article DE CPSC; Eye irritant; FHSA; Hazard classification; Hazard labeling; Ocular safety testing ID STATISTICAL-ANALYSIS; UNITED-STATES; NUMBER; RABBITS; INJURY AB U.S. Federal Hazardous Substances Act (FHSA) regulations specify eye safety testing procedures and hazard classification criteria for substances regulated by the U.S. Consumer Product Safety Commission (CPSC). Current regulations require up to three sequential 6-animal tests. Testing consistent with the Organisation for Economic Co-operation and Development (OECD) test guideline for eye irritation/corrosion, which specifies 3 animals, can also be submitted to US agencies. However, current FHSA regulations do not provide criteria to classify results from 3-animal tests. An analysis was conducted to determine criteria using results from 3-animal tests that would provide equivalent labeling to FHSA regulations. The frequency that FHSA requirements identify substances as ocular irritants was compared with the frequency that a criterion of either >= 1/3 or >= 2/3 positive animals would identify these substances. A database of rabbit eye tests was also used to estimate over- and underprediction rates for each criterion. In each instance, a criterion of >= 1/3 positive animals more closely matched the expected outcome based on FHSA requirements, while a criterion of >= 2/3 positive animals identified far fewer irritants. Using a classification criterion of >= 1/3 positive animals provided equivalent or greater eye hazard labeling as current FHSA requirements, while using 50-83% fewer animals. Published by Elsevier Inc. C1 [Haseman, Joseph K.] JK Haseman Consulting, Raleigh, NC 27614 USA. [Allen, David G.; Lipscomb, Elizabeth A.; Truax, James F.] Integrated Lab Syst Inc, Res Triangle Pk, NC 27709 USA. [Stokes, William S.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Interagcy Ctr Evaluat Alternat Toxicol Methods, Res Triangle Pk, NC USA. RP Stokes, WS (reprint author), 530 Davis Dr,POB 12233,K2-16, Res Triangle Pk, NC 27709 USA. EM stokes@niehs.nih.gov FU NIEHS [N01-ES 35504] FX This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. ILS staff are supported by NIEHS contract N01-ES 35504. NR 12 TC 3 Z9 3 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0273-2300 J9 REGUL TOXICOL PHARM JI Regul. Toxicol. Pharmacol. PD OCT PY 2011 VL 61 IS 1 BP 98 EP 104 DI 10.1016/j.yrtph.2011.06.006 PG 7 WC Medicine, Legal; Pharmacology & Pharmacy; Toxicology SC Legal Medicine; Pharmacology & Pharmacy; Toxicology GA 820WO UT WOS:000294937000012 PM 21745525 ER PT J AU Madina, BR Kuppan, G Vashisht, AA Liang, YH Downey, KM Wohlschlegel, JA Ji, XH Sze, SH Sacchettini, JC Read, LK Cruz-Reyes, J AF Madina, Bhaskara Reddy Kuppan, Gokulan Vashisht, Ajay A. Liang, Yu-He Downey, Kurtis M. Wohlschlegel, James A. Ji, Xinhua Sze, Sing-Hoi Sacchettini, James C. Read, Laurie K. Cruz-Reyes, Jorge TI Guide RNA biogenesis involves a novel RNase III family endoribonuclease in Trypanosoma brucei SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE guide RNA processing; RNase III endonuclease; mitochondria; RNA editing; Trypanosoma brucei ID DIRECTED ENDONUCLEASE CLEAVAGE; INDUCIBLE EXPRESSION SYSTEM; LIFE-CYCLE STAGES; MESSENGER-RNA; EDITING ENDONUCLEASE; MASS-SPECTROMETRY; RIBONUCLEASE-III; BINDING COMPLEX; GENE-EXPRESSION; MRB1 COMPLEX AB The mitochondrial genome of kinetoplastids, including species of Trypanosoma and Leishmania, is an unprecedented DNA structure of catenated maxicircles and minicircles. Maxicircles represent the typical mitochondrial genome encoding components of the respiratory complexes and ribosomes. However, most mRNA sequences are cryptic, and their maturation requires a unique U insertion/deletion RNA editing. Minicircles encode hundreds of small guide RNAs (gRNAs) that partially anneal with unedited mRNAs and direct the extensive editing. Trypanosoma brucei gRNAs and mRNAs are transcribed as polycistronic precursors, which undergo processing preceding editing; however, the relevant nucleases are unknown. We report the identification and functional characterization of a close homolog of editing endonucleases, mRPN1 (mitochondrial RNA precursor-processing endonuclease 1), which is involved in gRNA biogenesis. Recombinant mRPN1 is a dimeric dsRNA-dependent endonuclease that requires Mg(2+), a critical catalytic carboxylate, and generates 2-nucleotide 39 overhangs. The cleavage specificity of mRPN1 is reminiscent of bacterial RNase III and thus is fundamentally distinct from editing endonucleases, which target a single scissile bond just 5' of short duplexes. An inducible knockdown of mRPN1 in T. brucei results in loss of gRNA and accumulation of precursor transcripts (pre-gRNAs), consistent with a role of mRPN1 in processing. mRPN1 stably associates with three proteins previously identified in relatively large complexes that do not contain mRPN1, and have been linked with multiple aspects of mitochondrial RNA metabolism. One protein, TbRGG2, directly binds mRPN1 and is thought to modulate gRNA utilization by editing complexes. The proposed participation of mRPN1 in processing of polycistronic RNA and its specific protein interactions in gRNA expression are discussed. C1 [Madina, Bhaskara Reddy; Kuppan, Gokulan; Sze, Sing-Hoi; Sacchettini, James C.; Cruz-Reyes, Jorge] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. [Vashisht, Ajay A.; Wohlschlegel, James A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. [Liang, Yu-He; Ji, Xinhua] NCI, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Downey, Kurtis M.; Read, Laurie K.] SUNY Buffalo, Dept Microbiol & Immunol, Buffalo, NY 14214 USA. [Sze, Sing-Hoi] Texas A&M Univ, Dept Comp Sci & Engn, College Stn, TX 77843 USA. RP Cruz-Reyes, J (reprint author), Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. EM cruzrey@tamu.edu RI Ji, Xinhua/C-9664-2012; LIANG, YUHE/B-6704-2012 OI Ji, Xinhua/0000-0001-6942-1514; FU National Institutes of Health [GM067130, AI081529, GM089778]; Jonsson Cancer Center at UCLA; NIH, National Cancer Institute, Center for Cancer Research FX We thank Damian Terry and Vikas Kumar in our laboratory for careful comments and discussion on the manuscript. Ricardo Zavala provided technical assistance with the preparation of plasmids. Craig Kaplan in our department provided detailed advice and access to equipment for real-time PCR. Ken Stuart and Paul Michels kindly provided monoclonal antibodies against core subunits of editing complexes and anti-serum against enolase, respectively. This work was supported by grants from the National Institutes of Health to J.C.-R. (GM067130, AI081529) and J.A.W. (GM089778) and by funding from the Jonsson Cancer Center at UCLA to J.A.W. and from the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research to X.J. NR 61 TC 21 Z9 21 U1 0 U2 2 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 OCT PY 2011 VL 17 IS 10 BP 1821 EP 1830 DI 10.1261/rna.2815911 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 821UP UT WOS:000295000200006 PM 21810935 ER PT J AU Lamichhane, TN Blewett, NH Maraia, RJ AF Lamichhane, Tek N. Blewett, Nathan H. Maraia, Richard J. TI Plasticity and diversity of tRNA anticodon determinants of substrate recognition by eukaryotic A37 isopentenyltransferases SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE codon; anticodon loop; tRNA modification; tRNA(Trp); wobble base; i(6)A; (isopentenyl)adenosine ID TRANSFER-RIBONUCLEIC-ACID; SERINE TRANSFER-RNA; ESCHERICHIA-COLI; SCHIZOSACCHAROMYCES-POMBE; NUCLEOTIDE-SEQUENCE; YEAST; DIMETHYLALLYLTRANSFERASE; TRANSLATION; ISOPENTENYLADENOSINE; MITOCHONDRIAL AB The N(6)-(isopentenyl) adenosine (i(6)A) modification of some tRNAs at position A37 is found in all kingdoms and facilitates codon-specific mRNA decoding, but occurs in different subsets of tRNAs in different species. Here we examine yeasts' tRNA isopentenyltransferases (i.e., dimethylallyltransferase, DMATase, members of the Delta(2)-isopentenylpyrophosphate transferase, IPPT superfamily) encoded by tit1(+) in Schizosaccharomyces pombe and MOD5 in Saccharomyces cerevisiae, whose homologs are Escherichia coli miaA, the human tumor suppressor TRIT1, and the Caenorhabditis elegans life-span gene product GRO-1. A major determinant of miaA activity is known to be the single-stranded tRNA sequence, A36A37A38, in a stem-loop. tRNA(CCA)(Trp) from either yeast is a Tit1p substrate, but neither is a Mod5p substrate despite the presence of A36A37A38. We show that Tit1p accommodates a broader range of substrates than Mod5p. tRNA(CCA)(Trp) is distinct from Mod5p substrates, which we sort into two classes based on the presence of G at position 34 and other elements. A single substitution of C34 to G converts tRNA(CCA)(Trp) to a Mod5p substrate in vitro and in vivo, consistent with amino acid contacts to G34 in existing Mod5p-tRNA(GCA)(Cys) crystal structures. Mutation of Mod5p in its G34 recognition loop region debilitates it differentially for its G34 (class I) substrates. Multiple alignments reveal that the G34 recognition loop sequence of Mod5p differs significantly from Tit1p, which more resembles human TRIT1 and other DMATases. We show that TRIT1 can also modify tRNA(CCA)(Trp) consistent with broad recognition similar to Tit1p. This study illustrates previously unappreciated molecular plasticity and biological diversity of the tRNA-isopentenyltransferase system of eukaryotes. C1 [Lamichhane, Tek N.; Blewett, Nathan H.; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Maraia, Richard J.] US PHS, Washington, DC 20201 USA. RP Maraia, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM maraiar@mail.nih.gov FU NICHD, NIH FX We thank V. Cherkasova for insight, assistance, and comments; M. Bayfield, D. Hatfield, M. Ibba, and D. Soll for critical comments; Amanda Crawford for reagents and assistance; and Anita Hopper (Ohio State University, Columbus) for anti-i6A antibody and the MOD5 and mod5-Delta strains. This work was supported by the Intramural Research Program of the NICHD, NIH. NR 40 TC 16 Z9 17 U1 0 U2 4 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 OCT PY 2011 VL 17 IS 10 BP 1846 EP 1857 DI 10.1261/rna.2628611 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 821UP UT WOS:000295000200008 PM 21873461 ER PT J AU Schiffman, M Gage, JC Clarke, MA AF Schiffman, Mark Gage, Julia C. Clarke, Megan A. TI Accepting the Universal Truths of Cervical Human Papillomavirus Epidemiology in Pursuit of the Remaining Mysteries SO SEXUALLY TRANSMITTED DISEASES LA English DT Editorial Material ID MULTICENTRIC CASE-CONTROL; COLLABORATIVE REANALYSIS; INDIVIDUAL DATA; CANCER; WOMEN; WORLDWIDE; CONTRACEPTIVES; PREVALENCE; CARCINOMA; SMOKING C1 [Schiffman, Mark; Gage, Julia C.; Clarke, Megan A.] NCI, Clin Genet Branch, DCEG, NIH, Bethesda, MD 20892 USA. RP Schiffman, M (reprint author), NCI, Clin Genet Branch, DCEG, NIH, Room 7012, Bethesda, MD 20892 USA. NR 15 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD OCT PY 2011 VL 38 IS 10 BP 907 EP 908 DI 10.1097/OLQ.0b013e318224a63f PG 2 WC Infectious Diseases SC Infectious Diseases GA 821RS UT WOS:000294992700005 PM 21934561 ER PT J AU Coseo, SE Porras, C Dodd, LE Hildesheim, A Rodriguez, AC Schiffman, M Herrero, R Wacholder, S Gonzalez, P Sherman, ME Jimenez, S Solomon, D Bougelet, C van Doorn, LJ Quint, W Safaeian, M AF Coseo, Sarah E. Porras, Carolina Dodd, Lori E. Hildesheim, Allan Cecilia Rodriguez, Ana Schiffman, Mark Herrero, Rolando Wacholder, Sholom Gonzalez, Paula Sherman, Mark E. Jimenez, Silvia Solomon, Diane Bougelet, Catherine van Doorn, Leen-Jan Quint, Wim Safaeian, Mahboobeh CA Costa Rica HPV Vaccine Trial CVT G TI Evaluation of the Polyclonal ELISA HPV Serology Assay as a Biomarker for Human Papillomavirus Exposure SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID INVASIVE CERVICAL-CANCER; COSTA-RICA; YOUNG-WOMEN; CHLAMYDIA-TRACHOMATIS; INFECTION; VACCINE; RISK; DNA; LESIONS; METAANALYSIS AB Background: Seropositivity to human papillomavirus (HPV)16 and 18 antibodies is used as a measure of cumulative HPV exposure and as a stratifier of HPV exposure for vaccine efficacy analyses. Overall performance of these assays, as a measure of HPV exposure, has not been evaluated. Methods: Using data from the enrollment phase of the HPV16/18 vaccine trial in Costa Rica, we evaluated the performance of the polyclonal enzyme-linked immunosorbent assay (ELISA) HPV16 and 18 serological assays as a measure of HPV exposure. Biologic (e. g., HPV infection at the cervix) and behavioral characteristics (e. g., lifetime number of sexual partners) with known associations with current and past HPV infection were used to define cases and controls (HPV exposed vs. not exposed). Prevaccination serum was measured for antibodies against HPV16 and 18 by ELISA; cervical samples were tested for HPV DNA using PCR SPF10/LiPA25. ELISA results were analyzed using receiver-operator characteristic curves; performance was evaluated at the manufacturer set cut point (HPV16 = 8, HPV18 = 7) and at cut points chosen to optimize sensitivity and specificity (HPV16 = 34, HPV18 = 60). Results: Defining cases as type-specific HPV DNA positive with high-grade abnormal cytology (i.e., combined molecular and microscopic markers of infection), HPV16-ELISA gave sensitivity that was lower at the optimal cut point than the manufacturer cut point (62.2 compared with 75.7, respectively; P = 0.44). However, specificity was higher (85.3 compared with 70.4, respectively; P < 0.0001). Similarly, HPV18-ELISA gave sensitivity that was lower at the optimal cut point than the manufacturer cut point (34.5 compared with 51.7, respectively; P = 0.40), with higher specificities (94.9 compared with 72.6, respectively; P < 0.0001). Conclusions: Modifying cut points did not improve the low sensitivity. The low sensitivity of this assay does not support its use for risk stratification or clinical settings. C1 [Coseo, Sarah E.; Hildesheim, Allan; Schiffman, Mark; Wacholder, Sholom; Sherman, Mark E.; Safaeian, Mahboobeh] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Porras, Carolina; Cecilia Rodriguez, Ana; Herrero, Rolando; Gonzalez, Paula; Jimenez, Silvia] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, Liberia, Costa Rica. [Dodd, Lori E.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Solomon, Diane] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Bougelet, Catherine] GlaxoSmithKline Biol, Rixensart, Belgium. [van Doorn, Leen-Jan; Quint, Wim] DDL Diagnost Lab, Voorburg, Netherlands. RP Safaeian, M (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS,EPS, 6120 Execut Blvd,Room 7086, Rockville, MD 20852 USA. EM safaeianm@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NCI [N01-CP-11005]; NIH Office of Research on Women's Health; Ministry of Health of Costa Rica; NIH [R25 CA098566] FX Supported by NCI (N01-CP-11005) with support from the NIH Office of Research on Women's Health and conducted in agreement with the Ministry of Health of Costa Rica. S. E. C. is supported in part by training grant NIH R25 CA098566. NR 22 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD OCT PY 2011 VL 38 IS 10 BP 976 EP 982 DI 10.1097/OLQ.0b013e31822545c0 PG 7 WC Infectious Diseases SC Infectious Diseases GA 821RS UT WOS:000294992700020 PM 21934576 ER PT J AU Barnes, AJ Scheidweiler, KB Kolbrich-Spargo, EA Gorelick, DA Goodwin, RS Huestis, MA AF Barnes, Allan J. Scheidweiler, Karl B. Kolbrich-Spargo, Erin A. Gorelick, David A. Goodwin, Robert S. Huestis, Marilyn A. TI MDMA and Metabolite Disposition in Expectorated Oral Fluid After Controlled Oral MDMA Administration SO THERAPEUTIC DRUG MONITORING LA English DT Article DE oral fluid; saliva; alternative matrix; MDMA; DRUID ID ECSTASY MDMA; DRUGS; 3,4-METHYLENEDIOXYMETHAMPHETAMINE; PHARMACOKINETICS; HUMANS; SALIVA; ABUSE; PLASMA; METHAMPHETAMINE; PHARMACOLOGY AB Introduction: The use of 3,4-methylenedioxymethamphetamine (MDMA) is increasing, enhancing the need for its detection in clinical, workplace, pain management, and driving under the influence of drugs testing programs. Oral fluid is an important alternative matrix for drug testing, but little is known about MDMA detection windows in oral fluid. Aims: The aim was to characterize MDMA and metabolite disposition in expectorated oral fluid after controlled MDMA administration. Methods: Placebo, low (1.0 mg/kg), and high (1.6 mg/kg) oral MDMA doses were given double-blind in random order in separate sessions to 29 healthy adults with histories of MDMA use. One thousand two hundred eighty-six expectorated oral fluid specimens collected up to 7 days after dosing were analyzed for MDMA, 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 4-hydroxy-3-methoxyamphetamine (HMA) by gas chromatography mass spectrometry. The limits of quantification were 5 ng/mL for MDMA and MDA and 10 ng/mL for HMA and HMMA. Results: MDMA was the primary analyte detected, with concentrations up to 12,000 ng/mL in 872 specimens (67.8%). MDA was quantified in 656 specimens (51.0%) at concentrations,403 ng/mL and was never present without concurrent MDMA. HMA and HMMA were not detected. Of the specimens, 59.8%, 58.6%, and 54.9% were found to be MDMA positive at the Talloires (20 ng/mL), Driving under the Influence of Drugs, Alcohol, and Medicines (25 ng/mL) and proposed US Substance Abuse and Mental Health Services Administration (50 ng/mL) confirmation cutoffs, respectively. MDMA was first observed in oral fluid 0.25-1.25 hours after dosing; MDA was initially detected at 0.5-1.75 hours. In general, the windows of detection for MDMA and MDA were 47 and 29 hours, respectively, although a few specimens were positive up to 71 and 47 hours. Conclusions: Oral fluid monitoring efficiently detects single, recreational 70-150 mg of MDMA use for 1-2 days. These controlled administration data provide a scientific basis for interpreting MDMA oral fluid test results. C1 [Huestis, Marilyn A.] Natl Inst Drug Abuse, IRP, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, IRP, NIH, 251 Bayview Blvd,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000468-05, ZIA DA000468-06, Z01 DA000468-04, ZIA DA000468-07] NR 28 TC 7 Z9 8 U1 2 U2 13 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 OCT PY 2011 VL 33 IS 5 BP 602 EP 608 DI 10.1097/FTD.0b013e3182281975 PG 7 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 822XE UT WOS:000295083000005 PM 21860342 ER PT J AU Scheidweiler, KB Marrone, GF Shakleya, DM Singleton, EG Heishman, SJ Huestis, MA AF Scheidweiler, Karl B. Marrone, Gina F. Shakleya, Diaa M. Singleton, Edward G. Heishman, Stephen J. Huestis, Marilyn A. TI Oral Fluid Nicotine Markers to Assess Smoking Status and Recency of Use SO THERAPEUTIC DRUG MONITORING LA English DT Article DE nicotine; metabolite; oral fluid; liquid chromatography; mass spectrometry ID SERUM COTININE LEVELS; SALIVARY COTININE; DISPOSITION KINETICS; CIGARETTE-SMOKING; SMOKERS; METABOLISM; PHARMACOKINETICS; DETERMINANTS; VALIDATION; NONSMOKERS AB Introduction: Oral fluid collection is noninvasive and easily observed making it an attractive matrix for objectively determining smoking status. Despite large intersubject variability, cotinine oral fluid concentrations correlate with cigarettes smoked per day (CPD). Few studies, however, assessed nicotine markers in oral fluid other than cotinine; other markers might improve smoking status assessment and/or time of last cigarette. Materials and Methods: Smoking histories and oral fluid specimens were collected from nontreatment-seeking light (1-10 CPD) and heavy smokers (greater than 10 CPD) and from environmentally exposed and nonexposed nonsmokers who provided written informed consent for this Institutional Review Board-approved study. Nicotine, cotinine, hydroxycotinine (OH-cotinine), and norcotinine oral fluid concentrations were quantified by liquid chromatography tandem mass spectrometry. Results: Comparison of 1, 3, and 10 ng/mL oral fluid liquid chromatography tandem mass spectrometry cutoffs demonstrated that 10-ng/mL cutoffs performed optimally for cotinine, OH-cotinine, nicotine, and norcotinine identifying 98%, 97%, 88%, and 15% of self-reported smokers; 1% nonsmokers had greater than 10 ng/mL cotinine. No self-reported nonsmoker had greater than 10 ng/mL OH-cotinine, nicotine, or norcotinine. Norcotinine was only identified in smokers' oral fluid. Oral fluid nicotine, cotinine, and nicotine/cotinine ratios were correlated with time of last smoking (r = -0.53, -0.23, and -0.51; P < 0.05) and CPD (r = 0.35, 0.26, and 0.33; P < 0.01), respectively. Discussion and Conclusion: OH-cotinine performed slightly better than cotinine for distinguishing smokers from nonsmokers and should be considered as an additional oral fluid smoking indicator. Further research is required to determine if oral fluid norcotinine is a marker for distinguishing light and heavy smokers. Moderate correlations suggest nicotine, cotinine, and nicotine/cotinine ratios may be useful for determining smoking recency in "spot samples'' collected during nicotine cessation treatment. C1 [Scheidweiler, Karl B.; Shakleya, Diaa M.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Chem & Drug Metab Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Marrone, Gina F.; Heishman, Stephen J.] Natl Inst Drug Abuse, Nicotine Psychopharmacol Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Singleton, Edward G.] Stevenson Univ, Stevenson, MD USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Chem & Drug Metab Sect, NIDA Intramural Res Program, NIH,Biomed Res Ctr, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov OI Singleton, Edward G./0000-0003-3442-877X FU National Institutes of Health, National Institute on Drug Abuse FX This research was supported by funds from the National Institutes of Health, Intramural Research Program, National Institute on Drug Abuse. NR 33 TC 7 Z9 7 U1 0 U2 5 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 OCT PY 2011 VL 33 IS 5 BP 609 EP 618 DI 10.1097/FTD.0b013e318228ba39 PG 10 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 822XE UT WOS:000295083000006 PM 21860341 ER PT J AU Concheiro, M Jones, HE Johnson, RE Choo, R Huestis, MA AF Concheiro, Marta Jones, Hendree E. Johnson, Rolley E. Choo, Robin Huestis, Marilyn A. TI Preliminary Buprenorphine Sublingual Tablet Pharmacokinetic Data in Plasma, Oral Fluid, and Sweat During Treatment of Opioid-Dependent Pregnant Women SO THERAPEUTIC DRUG MONITORING LA English DT Article DE buprenorphine; pharmacokinetics; pregnancy; plasma; oral fluid ID NEONATAL OUTCOMES; METHADONE; LIQUID; NORBUPRENORPHINE; CHROMATOGRAPHY; METABOLISM; TRIALS AB Background: Buprenorphine is currently under investigation as a pharmacotherapy to treat pregnant women for opioid dependence. This research evaluates buprenorphine (BUP), norbuprenophine (NBUP), buprenorphine-glucuronide (BUP-Gluc), and norbuprenorphine-glucuronide (NBUP-Gluc) pharmacokinetics after high-dose (14-20 mg) BUP sublingual tablet administration in three opioid-dependent pregnant women. Methods: Oral fluid and sweat specimens were collected in addition to plasma specimens for 24 hours during gestation weeks 28 or 29 and 34, and 2 months after delivery. Time to maximum concentration was not affected by pregnancy; however, BUP and NBUP maximum concentration and area under the curve at 0 to 24 hours tended to be lower during pregnancy compared with postpartum levels. Results: Statistically significant but weak positive correlations were found for BUP plasma and OF concentrations and BUP/NBUP ratios in plasma and oral fluid. Statistically significant negative correlations were observed for times of specimen collection and BUP and NBUP oral fluid/plasma ratios. BUP-Gluc and NBUP-Gluc were detected in only 5% of oral fluid specimens. In sweat, BUP and NBUP were detected in only four of 25 (12 or 24 hours) specimens in low concentrations (less than 2.4 ng/patch). Conclusion: These preliminary data describe BUP and metabolite pharmacokinetics in pregnant women and suggest that, like methadone, upward dose adjustments may be needed with advancing gestation. C1 [Huestis, Marilyn A.] Natl Inst Drug Abuse, NIH, BRC, IRP, Baltimore, MD 21224 USA. [Concheiro, Marta] Univ Santiago de Compostela, Inst Ciencias Forenses, Serv Toxicol Forense, Santiago De Compostela, Spain. [Jones, Hendree E.; Johnson, Rolley E.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Johnson, Rolley E.] Reckitt Benckiser Pharmaceut Inc, Richmond, VA USA. [Choo, Robin] Univ Pittsburgh, Dept Biol, Titusville, PA USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, NIH, BRC, IRP, 251 Bayview Blvd,Suite 200,Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health; National Institute on Drug Abuse [RO1 DA12220] FX This research was funded by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health and by National Institute on Drug Abuse grant RO1 DA12220. NR 37 TC 15 Z9 15 U1 0 U2 3 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 OCT PY 2011 VL 33 IS 5 BP 619 EP 626 DI 10.1097/FTD.0b013e318228bb2a PG 8 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 822XE UT WOS:000295083000007 PM 21860340 ER PT J AU Ren, XF Hurley, JH AF Ren, Xuefeng Hurley, James H. TI Proline-Rich Regions and Motifs in Trafficking: From ESCRT Interaction to Viral Exploitation SO TRAFFIC LA English DT Review DE ALG-2; ALIX; CEP55; cytokinesis; endosome; protein structure; TSG101; UEV domain; virus budding; WW domain ID ALG-2-INTERACTING PROTEIN-X; TSG101 UEV DOMAIN; UBIQUITIN-LIGASE; STRUCTURAL BASIS; SORTING COMPLEX; ADAPTER PROTEINS; PEPTIDE COMPLEX; HIV-1 RELEASE; ALIX; MACHINERY AB Most membrane-enveloped viruses bud from infected cells by hijacking the host ESCRT machinery. The ESCRTs are recruited to the budding sites by viral proteins that contain short proline (Pro)-rich motifs (PRMs) known as late domains. The late domains probably evolved by co-opting host PRMs involved in the normal functions of ESCRTs in endosomal sorting and cytokinesis. The solution and crystal structures of PRMs bound to their interaction partners explain the conserved roles of Pro and other residues that predominate in these sequences. PRMs are often grouped together in much larger Prorich regions (PRRs) of as many as 150 residues. The PRR of the ESCRT-associated protein, ALIX, autoregulates its conformation and activity. The robustness of different viral budding and host pathways to impairments in Pro-based interactions varies considerably. The known biology of PRM recognition in the ESCRT pathway seems, in principle, compatible with antiviral development, given our increasingly nuanced understanding of the relative weakness and robustness of the host and viral processes. C1 [Ren, Xuefeng; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov FU NIH, NIDDK; Office of the Director, NIH; Intramural AIDS Research Fellowship FX This work was supported by the Intramural Program of the NIH, NIDDK and the Intramural AIDS Targeted Anti-viral Program of the Office of the Director, NIH (J. H. H.), and an Intramural AIDS Research Fellowship to X. R. NR 74 TC 26 Z9 26 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-9219 EI 1600-0854 J9 TRAFFIC JI Traffic PD OCT PY 2011 VL 12 IS 10 BP 1282 EP 1290 DI 10.1111/j.1600-0854.2011.01208.x PG 9 WC Cell Biology SC Cell Biology GA 822MR UT WOS:000295052500002 PM 21518163 ER PT J AU Ng, OT Munshaw, S Lamers, SL Chew, KK Lin, L Redd, AD Manucci, J Quinn, TC Ray, SC Chua, A Leo, YS Laeyendecker, O AF Oon Tek Ng Munshaw, Supriya Lamers, Susanna L. Chew, Kuan Kiat Lin, Li Redd, Andrew D. Manucci, Jordyn Quinn, Thomas C. Ray, Stuart C. Chua, Arlene Leo, Yee Sin Laeyendecker, Oliver TI Molecular Epidemiology of HIV Type 1 in Singapore and Identification of Novel CRF01_AE/B Recombinant Forms SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID INJECTING DRUG-USERS; THAILAND; TRANSMISSION; CRF15-01B AB To investigate HIV-1 molecular epidemiology in Singapore, we sequenced portions of three regions of the HIV-1 genome (protease HXB2: 2163 to 2620, gp120 HXB2: 6904 to 7628, and gp41 HXB2: 7817 to 8264) from 212 plasma samples collected between February 2008 and August 2009. From these samples, 109 (51.4%) generated interpretable data in all regions. Sixty-one (56.0%) were identified as CRF01_AE, 26 (23.9%) as subtype B and 14 (12.8%) as possible novel recombinant forms. The main novel recombinant pattern, detected in 13 sequences, had subtype B in protease and gp41 and CRF01_AE in gp120. There was intermixing of subtypes within transmission risk groups. However, 85% of subjects infected with the novel recombinant forms self-identified as men who have sex with men or bisexuals compared with only 41% of individuals infected with CRF01_AE and 62% infected with subtype B (p = 0.001). C1 [Oon Tek Ng; Munshaw, Supriya; Quinn, Thomas C.; Ray, Stuart C.; Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. [Oon Tek Ng; Chew, Kuan Kiat; Lin, Li; Chua, Arlene; Leo, Yee Sin] Tan Tock Seng Hosp, Dept Infect Dis, Singapore, Singapore. [Lamers, Susanna L.] BioInfoExperts, Thibodaux, LA USA. [Redd, Andrew D.; Manucci, Jordyn; Quinn, Thomas C.; Laeyendecker, Oliver] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. RP Ng, OT (reprint author), Johns Hopkins Univ, Sch Med, Rangos Bldg,Room 527,855 N Wolfe St, Baltimore, MD 21205 USA. EM oong@jhsph.edu RI Ray, Stuart/B-7527-2008; Laeyendecker, Oliver/B-9331-2009; OI Ray, Stuart/0000-0002-1051-7260; Laeyendecker, Oliver/0000-0002-6429-4760; Chua, Arlene/0000-0001-6428-9083 FU Singapore National Medical Research Training Fellowship FX A Singapore National Medical Research Training Fellowship grant provided salary support for O.T. Ng. We acknowledge the physicians, staff, and patients of the outpatient service at the Communicable Disease Centre, Singapore who made this study possible. Additional support was provided by the Division of Intramural Research, NIAID, NIH. The sequences analyzed in this study have been deposited in GenBank under accession numbers HQ538893 to HQ539411. Clinical chart review was conducted mainly by Dr. Ohnma Papa Seinn. NR 15 TC 10 Z9 10 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2011 VL 27 IS 10 BP 1135 EP 1137 DI 10.1089/aid.2010.0364 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 832GD UT WOS:000295790500366 PM 21235306 ER PT J AU Mandelblatt, JS Cronin, KA Berry, DA Chang, YJ de Koning, HJ Lee, SJ Plevritis, SK Schechter, CB Stout, NK van Ravesteyn, NT Zelen, M Feuer, EJ AF Mandelblatt, Jeanne S. Cronin, Kathleen A. Berry, Donald A. Chang, Yaojen de Koning, Harry J. Lee, Sandra J. Plevritis, Sylvia K. Schechter, Clyde B. Stout, Natasha K. van Ravesteyn, Nicolien T. Zelen, Marvin Feuer, Eric J. TI Modeling the impact of population screening on breast cancer mortality in the United States SO BREAST LA English DT Article DE Mammography; Screening; Modeling ID SERVICES TASK-FORCE; UPPER AGE LIMIT; RANDOMIZED-TRIALS; OLDER WOMEN; FOLLOW-UP; MAMMOGRAPHY; RECOMMENDATIONS; CHEMOTHERAPY; BENCHMARKS; SURVIVAL AB Objective: Optimal US screening strategies remain controversial. We use six simulation models to evaluate screening outcomes under varying strategies. Methods: The models incorporate common data on incidence, mammography characteristics, and treatment effects. We evaluate varying initiation and cessation ages applied annually or biennially and calculate mammograms, mortality reduction (vs. no screening), false-positives, unnecessary biopsies and over-diagnosis. Results: The lifetime risk of breast cancer death starting at age 40 is 3% and is reduced by screening. Screening biennially maintains 81% (range 67% to 99%) of annual screening benefits with fewer false-positives. Biennial screening from 50-74 reduces the probability of breast cancer death from 3% to 2.3%. Screening annually from 40 to 84 only lowers mortality an additional one-half of one percent to 1.8% but requires substantially more mammograms and yields more false-positives and over-diagnosed cases. Conclusion: Decisions about screening strategy depend on preferences for benefits vs. potential harms and resource considerations. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Mandelblatt, Jeanne S.; Chang, Yaojen] Lombardi Comprehens Canc Ctr, Canc Control Program, Washington, DC 20007 USA. [Mandelblatt, Jeanne S.; Chang, Yaojen] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Mandelblatt, Jeanne S.; Chang, Yaojen] Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. [Cronin, Kathleen A.; Feuer, Eric J.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [de Koning, Harry J.; van Ravesteyn, Nicolien T.] Erasmus MC, Dept Publ Hlth, NL-3015 GE Rotterdam, Netherlands. [Lee, Sandra J.; Zelen, Marvin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lee, Sandra J.; Zelen, Marvin] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Plevritis, Sylvia K.] Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA. [Schechter, Clyde B.] Albert Einstein Coll Med, Dept Family & Social Med, Bronx, NY 10461 USA. [Schechter, Clyde B.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Stout, Natasha K.] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02215 USA. [Stout, Natasha K.] Harvard Pilgrim Hlth Care, Boston, MA 02215 USA. RP Mandelblatt, JS (reprint author), Lombardi Comprehens Canc Ctr, Canc Control Program, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM mandelbj@georgetown.edu FU NCI [RC2CA148577, U01CA086076]; BCSC [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040] FX This work was done under contracts from the Agency for Healthcare Research and Quality (AHRQ) and NCI and grants from the NCI. The NCI provided some data and technical assistance and AHRQ reviewed the manuscript. Model results are the sole responsibility of the investigators.; By NCI cooperative agreement U01 CA152958-01 and NCI Grants RC2CA148577 and U01CA086076. Data collection in the BCSC was supported by NCI-funded BCSC cooperative agreements (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, and U01CA70040) and several U.S. state public health departments and cancer registries. CISNET data management and Web site support were provided by Cornerstone Systems Northwest (NCI contract HHSN261200800002C). NR 37 TC 9 Z9 9 U1 0 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD OCT PY 2011 VL 20 SU 3 BP S75 EP S81 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 037CA UT WOS:000311077400013 PM 22015298 ER PT J AU Martin, SE Wu, ZH Gehlhaus, K Jones, TL Zhang, YW Guha, R Miyamoto, S Pommier, Y Caplen, NJ AF Martin, S. E. Wu, Z. -H. Gehlhaus, K. Jones, T. L. Zhang, Y. -W. Guha, R. Miyamoto, S. Pommier, Y. Caplen, N. J. TI RNAi Screening Identifies TAK1 as a Potential Target for the Enhanced Efficacy of Topoisomerase Inhibitors SO CURRENT CANCER DRUG TARGETS LA English DT Review DE RNAi; siRNA; Screen; Camptothecin; TAK1; MAP3K7; TAB2; TRAF6 ID NF-KAPPA-B; GLIOBLASTOMA CELL-LINES; DNA-DAMAGE RESPONSE; BREAST-CANCER; I INHIBITORS; CAMPTOTHECIN RESISTANCE; MICROARRAY ANALYSIS; PANCREATIC-CANCER; ANTICANCER DRUG; PARP INHIBITOR AB In an effort to develop strategies that improve the efficacy of existing anticancer agents, we have conducted a siRNA-based RNAi screen to identify genes that, when targeted by siRNA, improve the activity of the topoisomerase I (Top1) poison camptothecin (CPT). Screening was conducted using a set of siRNAs corresponding to over 400 apoptosis-related genes in MDA-MB-231 breast cancer cells. During the course of these studies, we identified the silencing of MAP3K7 as a significant enhancer of CPT activity. Follow-up analysis of caspase activity and caspase-dependent phosphorylation of histone H2AX demonstrated that the silencing of MAP3K7 enhanced CPT-associated apoptosis. Silencing MAP3K7 also sensitized cells to additional compounds, including CPT clinical analogs. This activity was not restricted to MDA-MB-231 cells, as the silencing of MAP3K7 also sensitized the breast cancer cell line MDA-MB-468 and HCT-116 colon cancer cells. However, MAP3K7 silencing did not affect compound activity in the comparatively normal mammary epithelial cell line MCF10A, as well as some additional tumorigenic lines. MAP3K7 encodes the TAK1 kinase, an enzyme that is central to the regulation of many processes associated with the growth of cancer cells (e. g. NF-kappa B, JNK, and p38 signaling). An analysis of TAK1 signaling pathway members revealed that the silencing of TAB2 also sensitizes MDA-MB-231 and HCT-116 cells towards CPT. These findings may offer avenues towards lowering the effective doses of Top1 inhibitors in cancer cells and, in doing so, broaden their application. C1 [Martin, S. E.; Gehlhaus, K.; Jones, T. L.; Caplen, N. J.] NCI, Gene Silencing Sect, Genet Branch, CCR,NIH, Bethesda, MD 20892 USA. [Wu, Z. -H.; Miyamoto, S.] Univ Wisconsin, Dept Pharmacol, Madison, WI 53706 USA. [Zhang, Y. -W.; Pommier, Y.] NCI, Mol Pharmacol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Martin, S. E.; Guha, R.] NHGRI, Trans NIH RNAi Initiat, NIH Ctr Translat Therapeut, NIH, Bethesda, MD 20892 USA. RP Caplen, NJ (reprint author), NCI, Gene Silencing Sect, Genet Branch, CCR,NIH, Bldg 37,Rm 6128, Bethesda, MD 20892 USA. EM ncaplen@mail.nih.gov RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 FU (Center for Cancer Research, NCI) of the NIH FX This research was supported by the Intramural Research Program (Center for Cancer Research, NCI) of the NIH. Qiagen Inc. supplied some of the RNAi reagents used in this study to the NCI as part of a Collaborative Research Agreement. We thank Konrad Huppi, Mark Mackiewicz, and Brady Wahlberg GSS, GB, CCR, NCI, NIH for useful discussion. We also thank Phillip Lorenzi (MD Anderson), Stanley Lipkowitz (LCMB, CCR, NCI), Marc Ferrer and Craig Thomas (NCGC, NIH) and Kathleen Veety for their insightful comments, and thank Bill Reinhold and John Weinstein (LMP, CCR, NCI) for MDA-MB-231 cells. NR 59 TC 25 Z9 25 U1 1 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0096 J9 CURR CANCER DRUG TAR JI Curr. Cancer Drug Targets PD OCT PY 2011 VL 11 IS 8 BP 976 EP 986 PG 11 WC Oncology SC Oncology GA 864MP UT WOS:000298244600007 PM 21834757 ER PT J AU Broadbent, AJ Subbarao, K AF Broadbent, Andrew J. Subbarao, Kanta TI Influenza virus vaccines: lessons from the 2009 H1N1 pandemic SO CURRENT OPINION IN VIROLOGY LA English DT Article ID CHILDREN AGED 6; RANDOMIZED CONTROLLED-TRIAL; CROSS-REACTIVE IMMUNITY; A H1N1; MF59-ADJUVANTED VACCINE; UNITED-STATES; SPLIT-VIRION; B VIRUSES; IMMUNOGENICITY; INFECTION AB Reflecting on the 2009 H1N1 pandemic, we summarize lessons regarding influenza vaccines that can be applied in the future. The two major challenges to vaccination during the 2009 H1N1 pandemic were timing and availability of vaccine. Vaccines were, however, well-tolerated and immunogenic, with inactivated vaccines containing 15 mu g of HA generally inducing antibody titers >= 1:40 in adults within 2 weeks of the administration of a single dose. Moreover, the use of oil-in-water adjuvants in Europe permitted dose-reduction, with vaccines containing as little as 3.75 or 7.5 mu g HA being immunogenic. Case-control studies demonstrated that monovalent 2009 H1N1 vaccines were effective in preventing infection with the 2009 H1N1 virus, but preliminary data suggest that it is important for individuals to be re-immunized annually. C1 [Broadbent, Andrew J.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov OI Broadbent, Andrew/0000-0002-4716-1835 FU Intramural NIH HHS [Z99 AI999999] NR 59 TC 22 Z9 22 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD OCT PY 2011 VL 1 IS 4 BP 254 EP 262 DI 10.1016/j.coviro.2011.08.002 PG 9 WC Virology SC Virology GA 051FS UT WOS:000312112200006 PM 22125588 ER PT J AU Ernst, M Daniele, T Frantz, K AF Ernst, Monique Daniele, Teresa Frantz, Kyle TI New perspectives on adolescent motivated behavior: Attention and conditioning SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Review DE Adolescent; Goal-directed attention; Stimulus-driven; Appetitive conditioning; Saccadic eye movement; Development AB Adolescence is a critical transition period, during which fundamental changes prepare the adolescent for becoming an adult. Heuristic models of the neurobiology of adolescent behavior have emerged, promoting the central role of reward and motivation, coupled with cognitive immaturities. Here, we bring focus to two basic sets of processes, attention and conditioning, which are essential for adaptive behavior. Using the dual-attention model developed by Corbetta and Shulman (2002), which identifies a stimulus-driven and a goal-driven attention network, we propose a balance that favors stimulus-driven attention over goal-driven attention in youth. Regarding conditioning, we hypothesize that stronger associations tend to be made between environmental cues and appetitive stimuli, and weaker associations with aversive stimuli, in youth relative to adults. An attention system geared to prioritize stimulus-driven attention, together with more powerful associative learning with appetitive incentives, contribute to shape patterns of adolescent motivated behavior. This proposed bias in attention and conditioning function could facilitate the impulsive, novelty-seeking and risk-taking behavior that is typical of many adolescents. Published by Elsevier Ltd. C1 [Ernst, Monique; Daniele, Teresa] NIMH, NIH, US Dept HHS, Emot Dev & Affect Neurosci Branch, Bethesda, MD 20892 USA. [Frantz, Kyle] Georgia State Univ, Inst Neurosci, Atlanta, GA 30303 USA. [Frantz, Kyle] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. RP Ernst, M (reprint author), NIMH, NIH, US Dept HHS, Emot Dev & Affect Neurosci Branch, 15K North Dr, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health FX This work was supported in part by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. NR 130 TC 25 Z9 26 U1 4 U2 23 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD OCT PY 2011 VL 1 IS 4 SI SI BP 377 EP 389 DI 10.1016/j.dcn.2011.07.013 PG 13 WC Neurosciences SC Neurosciences & Neurology GA V28AL UT WOS:000208653600003 PM 21977221 ER PT J AU Bjork, JM Smith, AR Chen, G Hommer, DW AF Bjork, James M. Smith, Ashley R. Chen, Gang Hommer, Daniel W. TI Psychosocial problems and recruitment of incentive neurocircuitry: Exploring individual differences in healthy adolescents SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE Reward; Impulsivity; Adolescence; Ventral striatum; Instrumental behavior AB Maturational differences in brain responsiveness to rewards have been implicated in the increased rates of injury and death in adolescents from behavior-related causes. However, much of this morbidity is related to drug intoxication or other externalizing behaviors, and may be concentrated in a subset of adolescents who are at psychosocial or neurobiological risk. To examine whether individual differences in psychosocial and behavioral symptomatology relate to activation of motivational neurocircuitry, we scanned 26 psychiatrically healthy adolescents using fMRI as they performed a monetary incentive delay task. Overall Problem Density on the Drug Use Screening Inventory (DUSI-OPD) correlated positively with activation of ventral mesofrontal cortex (mFC) during anticipation of responding for rewards (vs responding for no incentive). In addition, DUSI-OPD correlated positively with right ventral striatum recruitment during anticipation of responding to win rewards (vs responding for no incentive or to avoid losses of identical magnitudes). Finally, a psychophysiological interaction (PPI) analysis indicated that increased connectivity between nucleus accumbens and portions of anterior cingulate and mFC as a function of reward prospects also correlated with DUSI-OPD. These findings extend previous reports demonstrating that in adolescents, individual differences in reactivity of motivational neurocircuitry relate to different facets of impulsivity or externalizing behaviors. (C) Published by Elsevier Ltd. C1 [Bjork, James M.] NIDA, Div Clin Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. [Smith, Ashley R.; Hommer, Daniel W.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Chen, Gang] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. RP Bjork, JM (reprint author), NIDA, Div Clin Neurosci & Behav Res, NIH, 6001 Execut Blvd,Room 3172, Bethesda, MD 20892 USA. EM jbjork@mail.nih.gov OI Bjork, James/0000-0003-0593-3291 FU NIAAA FX This research was funded by NIAAA intramural research funding. NR 49 TC 19 Z9 20 U1 2 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD OCT PY 2011 VL 1 IS 4 SI SI BP 570 EP 577 DI 10.1016/j.dcn.2011.07.005 PG 8 WC Neurosciences SC Neurosciences & Neurology GA V28AL UT WOS:000208653600018 PM 21927631 ER PT J AU Ukegbu, UJ Castillo, DC Knight, MG Ricks, M Miller, BV Onumah, BM Sumner, AE AF Ukegbu, Ugochi J. Castillo, Darleen C. Knight, Michael G. Ricks, Madia Miller, Bernard V., III Onumah, Barbara M. Sumner, Anne E. TI Metabolic Syndrome Does Not Detect Metabolic Risk in African Men Living in the US SO DIABETES CARE LA English DT Article ID INSULIN-RESISTANCE; AMERICANS; HEALTH AB OBJECTIVE-Metabolic risk and metabolic syndrome (MetSyn) prevalence were compared in Africans who immigrated to the U.S. and African Americans. If MetSyn were an effective predictor of cardiometabolic risk, then the group with a worse metabolic risk profile would have a higher rate of MetSyn. RESEARCH DESIGN AND METHODS-Cross-sectional analyses were performed on 95 men (39 Africans, 56 African Americans, age 38 +/- 6 years [mean +/- SDI). Glucose tolerance was determined by oral glucose tolerance test, visceral adipose tissue (VAT) was determined by computerized tomography, and MetSyn was determined by the presence of three of Five factors: central obesity, hypertriglyceridemia, low levels of HDL cholesterol, hypertension, and fasting hyperglycemia. RESULTS-MetSyn prevalence was similar in Africans and African Americans (10 vs. 13%, P = 0.74), but hypertension, glycemia (fasting and 2-h glucose), and VAT were higher in Africans. CONCLUSIONS-African immigrants have a worse metabolic profile than African Americans but a similar prevalence of MetSyn. Therefore, MetSyn may underpredict metabolic risk in Africans. C1 [Ukegbu, Ugochi J.; Castillo, Darleen C.; Knight, Michael G.; Ricks, Madia; Miller, Bernard V., III; Sumner, Anne E.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. [Onumah, Barbara M.] Washington Hosp Ctr, Div Endocrinol, Washington, DC 20010 USA. RP Sumner, AE (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. EM annes@intra.niddk.nih.gov OI Knight, Michael G/0000-0002-4113-9936 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health (NIH); Pfizer Inc. FX All of the investigators of this study were supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases. M.G.K. received support through the Clinical Research Training Program, a public-private partnership supported jointly by the National Institutes of Health (NIH) and Pfizer Inc. (via a grant to the Foundation for NIH from Pfizer Inc.). No other potential conflicts of interest relevant to this article were reported. NR 15 TC 18 Z9 18 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2011 VL 34 IS 10 BP 2297 EP 2299 DI 10.2337/dc11-1055 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 910AG UT WOS:000301609000030 PM 21873563 ER PT J AU Mathe, D Gulyas, B Szigeti, K Horvath, I Donohue, SR Agoston, D Palkovits, M Ledent, C Pike, VW Halldin, C Freund, TF AF Mathe, D. Gulyas, B. Szigeti, K. Horvath, I. Donohue, S. R. Agoston, D. Palkovits, M. Ledent, C. Pike, V. W. Halldin, C. Freund, T. F. TI Imaging the CB1 Receptor Radioligand [125I]SD7015 in Mouse Brain using In-vivo SPECT and Ex-vivo Autoradiography SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Meeting Abstract C1 [Mathe, D.] CROmed Translat Imaging Ctr, Budapest, Hungary. [Gulyas, B.; Agoston, D.; Halldin, C.] Karolinska Inst, Stockholm, Sweden. [Szigeti, K.; Horvath, I.] Semmelweis Univ, Dept Biophys & Radiat Biol, H-1085 Budapest, Hungary. [Donohue, S. R.; Pike, V. W.] NIMH, NIH, Bethesda, MD 20892 USA. [Palkovits, M.] Semmelweis Univ, Dept Anat, H-1085 Budapest, Hungary. [Ledent, C.] Univ Libre Brussels, IRIBHM, Brussels, Belgium. [Freund, T. F.] Inst Expt Med HAS, Budapest, Hungary. RI Palkovits, Miklos/F-2707-2013 NR 1 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD OCT PY 2011 VL 38 SU 2 BP S147 EP S148 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V27NH UT WOS:000208619400200 ER PT J AU Chowell, G Viboud, C Simonsen, L Miller, MA AF Chowell, Gerardo Viboud, Cecile Simonsen, Lone Miller, Mark A. TI Measuring the benefits of school closure interventions to mitigate influenza SO EXPERT REVIEW OF RESPIRATORY MEDICINE LA English DT Editorial Material DE influenza; mathematical model; reproduction number; school closure interventions; transmission rate ID PUBLIC-HEALTH; TRANSMISSION; IMPACT C1 [Chowell, Gerardo; Viboud, Cecile; Simonsen, Lone; Miller, Mark A.] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ USA. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC USA. RP Chowell, G (reprint author), NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM gchowell@asu.edu RI Chowell, Gerardo/F-5038-2012; OI Chowell, Gerardo/0000-0003-2194-2251; Simonsen, Lone/0000-0003-1535-8526 NR 20 TC 2 Z9 2 U1 0 U2 1 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-6348 J9 EXPERT REV RESP MED JI Expert Rev. Respir. Med. PD OCT PY 2011 VL 5 IS 5 BP 597 EP 599 DI 10.1586/ERS.11.60 PG 3 WC Respiratory System SC Respiratory System GA 056RH UT WOS:000312508300002 PM 21955228 ER PT J AU Merrick, BA Dhungana, S Williams, JG Aloor, JJ Peddada, S Tomer, KB Fessler, MB AF Merrick, B. Alex Dhungana, Suraj Williams, Jason G. Aloor, Jim J. Peddada, Shyamal Tomer, Kenneth B. Fessler, Michael B. TI Proteomic Profiling of S-acylated Macrophage Proteins Identifies a Role for Palmitoylation in Mitochondrial Targeting of Phospholipid Scramblase 3 SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID ORDER-RESTRICTED INFERENCE; PLASMA-MEMBRANE; LIPID RAFTS; GENE; ELECTROPHORESIS; ACTIVATION; EXPRESSION; FAMILY; SUBSTRATE; RECEPTOR AB S-Palmitoylation, the reversible post-translational acylation of specific cysteine residues with the fatty acid palmitate, promotes the membrane tethering and subcellular localization of proteins in several biological pathways. Although inhibiting palmitoylation holds promise as a means for manipulating protein targeting, advances in the field have been hampered by limited understanding of palmitoylation enzymology and consensus motifs. In order to define the complement of S-acylated proteins in the macrophage, we treated RAW 264.7 macrophage membranes with hydroxylamine to cleave acyl thioesters, followed by biotinylation of newly exposed sulfhydryls and streptavidin-agarose affinity chromatography. Among proteins identified by LC-MS/MS, S-acylation status was established by spectral counting to assess enrichment under hydroxylamine versus mock treatment conditions. Of 1183 proteins identified in four independent experiments, 80 proteins were significant for S-acylation at false discovery rate = 0.05, and 101 significant at false discovery rate = 0.10. Candidate S-acylproteins were identified from several functional categories, including membrane trafficking, signaling, transporters, and receptors. Among these were 29 proteins previously biochemically confirmed as palmitoylated, 45 previously reported as putative S-acylproteins in proteomic screens, 24 not previously associated with palmitoylation, and three presumed false-positives. Nearly half of the candidates were previously identified by us in macrophage detergent-resistant membranes, suggesting that palmitoylation promotes lipid raft-localization of proteins in the macrophage. Among the candidate novel S-acylproteins was phospholipid scramblase 3 (Plscr3), a protein that regulates apoptosis through remodeling the mitochondrial membrane. Palmitoylation of Plscr3 was confirmed through H-3-palmitate labeling. Moreover, site-directed mutagenesis of a cluster of five cysteines (Cys159-161-163-164-166) abolished palmitoylation, caused Plscr3 mislocalization from mitochondrion to nucleus, and reduced macrophage apoptosis in response to etoposide, together suggesting a role for palmitoylation at this site for mitochondrial targeting and pro-apoptotic function of Plscr3. Taken together, we propose that manipulation of protein palmitoylation carries great potential for intervention in macrophage biology via reprogramming of protein localization. Molecular & Cellular Proteomics 10: 10.1074/mcp.M110.006007, 1-13, 2011. C1 [Merrick, B. Alex; Dhungana, Suraj; Aloor, Jim J.; Fessler, Michael B.] NIEHS, Biol Res Lab, NIH, Res Triangle Pk, NC 27709 USA. [Williams, Jason G.; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Peddada, Shyamal] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Fessler, MB (reprint author), NIEHS, Biol Res Lab, NIH, 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov RI Peddada, Shyamal/D-1278-2012; Tomer, Kenneth/E-8018-2013 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES102005, ES050171] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences Z01 ES102005 and ES050171. NR 40 TC 4 Z9 5 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2011 VL 10 IS 10 AR M110.006007 DI 10.1074/mcp.M110.006007 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 832BA UT WOS:000295773800009 PM 21785166 ER PT J AU Wuchty, S Siwo, GH Ferdig, MT AF Wuchty, Stefan Siwo, Geoffrey H. Ferdig, Michael T. TI Shared Molecular Strategies of the Malaria Parasite P. falciparum and the Human Virus HIV-1 SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; INTERACTION NETWORK; PLASMODIUM-FALCIPARUM; INTERACTION DATABASE; INTERACTION MAP; MASS-SPECTROMETRY; INTERACTOME; RESOURCE; COMPLEXES; INFECTION AB We augmented existing computationally predicted and experimentally determined interactions with evolutionarily conserved interactions between proteins of the malaria parasite, P. falciparum, and the human host. In a validation step, we found that conserved interacting host-parasite protein pairs were specifically expressed in host tissues where both the parasite and host proteins are known to be active. We compared host-parasite interactions with experimentally verified interactions between human host proteins and a very different pathogen, HIV-1. Both pathogens were found to use their protein repertoire in a combinatorial manner, providing a broad connection to host cellular processes. Specifically, the two biologically distinct pathogens predominately target central proteins to take control of a human host cell, effectively reaching into diversified cellular host cellular functions. Interacting signaling pathways and a small set of regulatory and signaling proteins were prime targets of both pathogens, suggesting remarkably similar patterns of host-pathogen interactions despite the vast biological differences of both pathogens. Such an identification of shared molecular strategies by the virus HIV-1 and the eukaryotic intracellular pathogen P. falciparum may allow us to illuminate new avenues of disease intervention. Molecular & Cellular Proteomics 10: 10.1074/mcp.M111.009035, 1-8, 2011. C1 [Wuchty, Stefan] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Siwo, Geoffrey H.; Ferdig, Michael T.] Univ Notre Dame, Dept Biol, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. RP Wuchty, S (reprint author), NIH, Natl Ctr Biotechnol Informat, Bldg 10, Bethesda, MD 20892 USA. EM wuchtys@ncbi.nlm.nih.gov RI Ferdig, Michael/C-6627-2016 FU NIH [AI055035, AI071121] FX This work was partly supported by NIH Grants AI055035 and AI071121 to MTF. NR 45 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2011 VL 10 IS 10 AR M111.009035 DI 10.1074/mcp.M111.009035 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 832BA UT WOS:000295773800007 PM 21586753 ER PT J AU Abrahamsson, S Dubinsky, A Angelini, D Oh, U Battistini, L Martin, R Mancardi, G Burt, R Muraro, P AF Abrahamsson, S. Dubinsky, A. Angelini, D. Oh, U. Battistini, L. Martin, R. Mancardi, G. Burt, R. Muraro, P. TI Immune reconstitution after haematopoietic stem cell transplantation depends on the specific immunosuppressive protocol SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 Univ London Imperial Coll Sci Technol & Med, London, England. Univ Iowa, Iowa City, IA USA. Fdn Santa Lucia, Rome, Italy. NIH, Bethesda, MD 20892 USA. Univ Med Ctr Eppendorf, Hamburg, Germany. Univ Genoa, Genoa, Italy. Northwestern Univ, Chicago, IL 60611 USA. OI Angelini, Daniela F./0000-0003-4552-9226 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA 125 BP S46 EP S47 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300077 ER PT J AU Bagnato, F Ikonomidou, V Tovar-Moll, F Agarwal, J Chiu, A Ehrmantraut, M Ohayon, J Talagala, L AF Bagnato, F. Ikonomidou, V. Tovar-Moll, F. Agarwal, J. Chiu, A. Ehrmantraut, M. Ohayon, J. Talagala, L. TI T1-hypointense neocortical lesions and their relation with disease progression in multiple sclerosis: a 3.0 Tesla imaging study SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 Vanderbilt Univ, Nashville, TN 37235 USA. Gerge Mason Univ, Fairfax, VA USA. DOr Inst Res & Educ, Rio De Janeiro, Brazil. NINDS, NIB, NIH, Bethesda, MD 20892 USA. NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P373 BP S151 EP S151 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300302 ER PT J AU Borges, I Shea, C Ohayon, J Bielekova, B Reich, D AF Borges, I. Shea, C. Ohayon, J. Bielekova, B. Reich, D. TI Daclizumab reduces the rate of brain atrophy in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 [Borges, I.; Shea, C.; Ohayon, J.; Bielekova, B.; Reich, D.] NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P540 BP S233 EP S234 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300469 ER PT J AU Cantor, F Ohayon, J Richert, N Reich, D Locust, D Wu, T Cortese, I Remaly, A Fenton, K Cutter, G McFarland, H Jacobson, S AF Cantor, F. Ohayon, J. Richert, N. Reich, D. Locust, D. Wu, T. Cortese, I. Remaly, A. Fenton, K. Cutter, G. McFarland, H. Jacobson, S. TI Vitamin D, sunlight and multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Univ Alabama Birmingham, Birmingham, AL USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P697 BP S307 EP S308 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137301063 ER PT J AU Cortese, I Zampieri, C Griffith, H Fenton, K Ohayon, J Vu, KP Damiano, D Reich, DS Bielekova, B AF Cortese, I. Zampieri, C. Griffith, H. Fenton, K. Ohayon, J. Vu, K. -P. Damiano, D. Reich, D. S. Bielekova, B. TI Cognitive-motor dual tasking in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 [Cortese, I.; Zampieri, C.; Griffith, H.; Fenton, K.; Ohayon, J.; Vu, K. -P.; Damiano, D.; Reich, D. S.; Bielekova, B.] NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P723 BP S320 EP S321 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137301089 ER PT J AU Cortese, I Ohayon, J Fenton, K Griffith, H Reich, DS Bielekova, B AF Cortese, I. Ohayon, J. Fenton, K. Griffith, H. Reich, D. S. Bielekova, B. TI Comparison of SDMT and PASAT in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 [Cortese, I.; Ohayon, J.; Fenton, K.; Griffith, H.; Reich, D. S.; Bielekova, B.] NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P241 BP S91 EP S91 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300170 ER PT J AU Gaitan, MI Maggi, P Wohler, J Sati, P Silva, AC Massacesi, L Jacobson, S Reich, DS AF Gaitan, M. I. Maggi, P. Wohler, J. Sati, P. Silva, A. C. Massacesi, L. Jacobson, S. Reich, D. S. TI 7T MRI reveals the perivascular distribution of lesions in an animal model of multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 [Gaitan, M. I.; Maggi, P.; Wohler, J.; Sati, P.; Silva, A. C.; Massacesi, L.; Jacobson, S.; Reich, D. S.] NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P843 BP S376 EP S376 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137301209 ER PT J AU Gaitan, MI Sati, P Inati, S Reich, DS AF Gaitan, M. I. Sati, P. Inati, S. Reich, D. S. TI Initial investigation of the blood-brain barrier in MS lesions at 7 Tesla SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 [Gaitan, M. I.; Sati, P.; Inati, S.; Reich, D. S.] NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA 71 BP S28 EP S29 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300042 ER PT J AU George, IC Shea, CD Shiee, N Gaitan, MI Evangelou, IE Reich, DS AF George, I. C. Shea, C. D. Shiee, N. Gaitan, M. I. Evangelou, I. E. Reich, D. S. TI Quantitative MRI at the time of and leading up to MS lesion appearance SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 NINDS, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P378 BP S153 EP S154 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300307 ER PT J AU Leibovitch, E Wohler, J Gaitan, M Maggi, P Motanic, K Harberts, E Silva, A Reich, D Jacobson, S AF Leibovitch, E. Wohler, J. Gaitan, M. Maggi, P. Motanic, K. Harberts, E. Silva, A. Reich, D. Jacobson, S. TI Effects of HHV-6A infection in the common marmoset SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 [Leibovitch, E.; Wohler, J.; Gaitan, M.; Maggi, P.; Motanic, K.; Harberts, E.; Silva, A.; Reich, D.; Jacobson, S.] NIH, Bethesda, MD 20892 USA. NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P745 BP S330 EP S330 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137301111 ER PT J AU Maggi, P Gaitan, MI Wohler, J Liu, J Senseney, J Shea, C Massacesi, L Jacobson, S Silva, A Reich, DS AF Maggi, P. Gaitan, M. I. Wohler, J. Liu, J. Senseney, J. Shea, C. Massacesi, L. Jacobson, S. Silva, A. Reich, D. S. TI Early blood-brain-barrier permeability changes in the normal-appearing white matter of a marmoset model of MS SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 NINDS, NIH, Bethesda, MD 20892 USA. Ctr Informat Technol, Bethesda, MD USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P266 BP S103 EP S103 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300195 ER PT J AU Newsome, S Syc, S Saidha, S Stankiewicz, A Ford, E Ratchford, J Chen, M Bazin, PL Balcer, L Frohman, E Reich, D Calabresi, P AF Newsome, S. Syc, S. Saidha, S. Stankiewicz, A. Ford, E. Ratchford, J. Chen, M. Bazin, P-L. Balcer, L. Frohman, E. Reich, D. Calabresi, P. TI Diffusion tensor imaging indices predict visual outcome after acute optic neuritis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 Johns Hopkins Sch Med, Baltimore, MD USA. Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany. Univ Penn, Philadelphia, PA USA. Univ Texas Southwestern, Dallas, TX USA. Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P837 BP S372 EP S373 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137301203 ER PT J AU Oh, J Chen, M Zackowski, K Newsome, S Smith, S Prince, J Calabresi, P Reich, D AF Oh, J. Chen, M. Zackowski, K. Newsome, S. Smith, S. Prince, J. Calabresi, P. Reich, D. TI Spinalcord atrophy correlates with quantitative measures of sensorimotor dysfunction in MS SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. Vanderbilt Univ, Nashville, TN 37235 USA. NIH, Bethesda, MD 20892 USA. NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P380 BP S154 EP S155 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300309 ER PT J AU Ratchford, J Seigo, M Farrell, S Shiee, N Eckstein, C Saidha, S Newsome, S Syc, S Stankiewicz, A Bazin, PL Pham, D Frohman, E Reich, D Calabresi, P AF Ratchford, J. Seigo, M. Farrell, S. Shiee, N. Eckstein, C. Saidha, S. Newsome, S. Syc, S. Stankiewicz, A. Bazin, P. -L. Pham, D. Frohman, E. Reich, D. Calabresi, P. TI Retinal nerve fibre layer thickness is associated with rate of brain atrophy SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany. Ctr Neurosci & Regenerat Med, Rockville, MD USA. Univ Texas Southwestern, Dallas, TX USA. NINDS, Bethesda, MD 20892 USA. NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA 41 BP S20 EP S21 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300026 ER PT J AU Sati, P George, IC Shea, CD Gaitan, MI Reich, DS AF Sati, P. George, I. C. Shea, C. D. Gaitan, M. I. Reich, D. S. TI FLAIR*: a new MRI contrast for visualising perivascular distribution of multiple sclerosis lesions SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 [Sati, P.; George, I. C.; Shea, C. D.; Gaitan, M. I.; Reich, D. S.] NINDS, NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA 91 BP S32 EP S32 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300048 ER PT J AU Shea, C Shiee, N Pham, D Reich, D AF Shea, C. Shiee, N. Pham, D. Reich, D. TI Automated MS lesion segmentation and longitudinal tracking via subtraction imaging SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. JHU, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P379 BP S154 EP S154 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300308 ER PT J AU Shinohara, RT Goldsmith, J Mateen, FJ Crainiceanu, C Reich, DS AF Shinohara, R. T. Goldsmith, J. Mateen, F. J. Crainiceanu, C. Reich, D. S. TI Predicting breakdown of the blood-brain barrier in multiple sclerosis without contrast agents SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. NINDS, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P166 BP S56 EP S57 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300095 ER PT J AU Syc, S Ratchford, J Shiee, N Seigo, M Stankiewicz, A Ford, E Durbin, M Oakley, J Meyer, S Pham, Z Frohman, E Reich, D Calabresi, P Saidha, S AF Syc, S. Ratchford, J. Shiee, N. Seigo, M. Stankiewicz, A. Ford, E. Durbin, M. Oakley, J. Meyer, S. Pham, Z. Frohman, E. Reich, D. Calabresi, P. Saidha, S. TI Cortical grey-matter atrophy correlates with retinal neuronal but not retinal axonal loss in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD 21218 USA. Carl Zeiss Meditec Inc, Dublin, CA USA. Henry M Jackson Fdn, Rockville, MD USA. Univ Texas Southwestern, Dallas, TX USA. NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA 39 BP S19 EP S19 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300024 ER PT J AU Virtanen, JO Wohler, J Fenton, K Cortese, I Reich, DS Jacobson, S AF Virtanen, J. O. Wohler, J. Fenton, K. Cortese, I. Reich, D. S. Jacobson, S. TI Oligoclonal antibody response in multiple sclerosis includes antibodies to herpesviruses SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 [Virtanen, J. O.; Wohler, J.; Fenton, K.; Cortese, I.; Reich, D. S.; Jacobson, S.] NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 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 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P340 BP S136 EP S136 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300269 ER PT J AU Chen, LY Eberlein, M Alsaaty, S Martinez-Anton, A Barb, J Munson, PJ Danner, RL Liu, Y Logun, C Shelhamer, JH Woszczek, G AF Chen, L. Y. Eberlein, M. Alsaaty, S. Martinez-Anton, A. Barb, J. Munson, P. J. Danner, R. L. Liu, Y. Logun, C. Shelhamer, J. H. Woszczek, G. TI Cooperative and redundant signaling of leukotriene B-4 and leukotriene D-4 in human monocytes SO ALLERGY LA English DT Article DE asthma; inflammation; leukotrienes; monocytes; receptors ID RECEPTOR BLT1; EXPRESSION; IMMUNE; NEUTROPHILS; MECHANISMS; MEDIATORS; RESPONSES; ACTIVATE; GENES; BLOOD AB Background: Leukotriene B-4 (LTB4) and cysteinyl leukotrienes (cysLTs) are important immune mediators, often found concomitantly at sites of inflammation. Although some of the leukotriene-mediated actions are distinctive (e. g., bronchial constriction for cysLTs), many activities such as leukocyte recruitment to tissues and amplification of inflammatory responses are shared by both classes of leukotrienes. Objective: We used human monocytes to characterize leukotriene-specific signaling, gene expression signatures, and functions and to identify interactions between LTB4- and cysLTs-induced pathways. Methods: Responsiveness to leukotrienes was assessed using oligonucleotide microarrays, real-time PCR, calcium mobilization, kinase activation, and chemotaxis assays. Results: Human monocytes were found to express mRNA for high-and low-affinity LTB4 receptors, BLT1 and BLT2, but signal predominantly through BLT1 in response to LTB4 stimulation as shown using selective agonists, inhibitors, and gene knock down experiments. LTB4 acting through BLT1 coupled to G-protein a inhibitory subunit activated calcium signaling, p44/42 mitogen-activated protein kinase, gene expression, and chemotaxis. Twenty-seven genes, including immediate early genes (IEG), transcription factors, cytokines, and membrane receptors were significantly up-regulated by LTB4. LTB4 and LTD4 had similar effects on signaling, gene expression, and chemotaxis indicating redundant cell activation pathways but costimulation with both lipid mediators was additive for many monocyte functions. Conclusion: Leukotriene B-4 and LTD4 display both redundant and cooperative effects on intracellular signaling, gene expression, and chemotaxis in human monocytes. These findings suggest that therapies targeting either leukotriene alone may be less effective than approaches directed at both. C1 [Chen, L. Y.; Eberlein, M.; Alsaaty, S.; Martinez-Anton, A.; Danner, R. L.; Liu, Y.; Logun, C.; Shelhamer, J. H.; Woszczek, G.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Barb, J.; Munson, P. J.] NIH, Div Computat Biosci, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Woszczek, G.] Kings Coll London, MRC, London WC2R 2LS, England. [Woszczek, G.] Kings Coll London, Asthma UK Ctr Allerg Mech Asthma, London WC2R 2LS, England. RP Shelhamer, JH (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Rm 2C145,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jshelhamer@cc.nih.gov; grzegorz.woszczek@kcl.ac.uk RI Woszczek, Grzegorz/H-5792-2012; Martinez Anton, Asuncion/A-5806-2017 OI Martinez Anton, Asuncion/0000-0001-9758-5911 FU Clinical Center, NIH FX This research was supported by the Intramural Research Program of the Clinical Center, NIH. NR 25 TC 3 Z9 3 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-4538 J9 ALLERGY JI Allergy PD OCT PY 2011 VL 66 IS 10 BP 1304 EP 1311 DI 10.1111/j.1398-9995.2011.02647.x PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 820IA UT WOS:000294897700005 PM 21605126 ER PT J AU Patton, KK Benjamin, EJ Kosheleva, A Curtis, LH Glymour, MM AF Patton, Kristen K. Benjamin, Emelia J. Kosheleva, Anna Curtis, Lesley H. Glymour, M. Maria TI Early-Life Antecedents of Atrial Fibrillation: Place of Birth and Atrial Fibrillation-Related Mortality SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Atrial Fibrillation; Geographic; Lifecourse Mortality; Residence ID CORONARY-HEART-DISEASE; CHILDHOOD SOCIOECONOMIC CIRCUMSTANCES; NATIONAL LONGITUDINAL MORTALITY; UNITED-STATES; STROKE BELT; RISK-FACTOR; AFRICAN-AMERICANS; RESIDENCE; ADULTHOOD; INCOME AB PURPOSE: Recent evidence suggests early-life factors correlate with atrial fibrillation (AF). We hypothesized that AF-related mortality, similar to stroke mortality, is elevated for individuals born in the southeastern United States. METHODS: We estimated 3-year (1999-2001) average AF-related mortality rates by using U.S. vital statistics for 55- to 89-year-old white (136,573 AF-related deaths) and black subjects (8,288 AF-related deaths). We estimated age- and sex-adjusted odds of AF-related (contributing cause) mortality associated with birth state, and birth within the U.S. stroke belt (SB), stratified by race. SB results were replicated with the use of 1989-1991 data. RESULTS: Among black subjects, four contiguous birth states were associated with statistically significant odds ratios >= 1.25 compared with the national average AF-related mortality. The four highest-risk birth states for blacks also predicted elevated AF-related mortality among white subjects, but patterns were attenuated. The odds ratio for AF-related mortality associated with SB birth was 1.19 (confidence interval 1.13-1.25) for black and 1.09 (CI 1.07-1.12) for white subjects when we adjusted for SB adult residence. CONCLUSIONS: Place of birth predicted AF-related mortality, after we adjusted for place of adult residence. The association of AF-related mortality and SB birth parallels that of other cardiovascular diseases and may likewise indicate an importance of early life factors in the development of AF. Ann Epidemiol 2011;21:732-738. (C) 2011 Elsevier Inc. All rights reserved. C1 [Patton, Kristen K.] Univ Washington, Med Ctr, Div Cardiol, Dept Med, Seattle, WA 98195 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Sch Publ Hlth, Dept Epidemiol,Dept Med,Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Sch Publ Hlth, Dept Epidemiol,Dept Med,Prevent Med Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Framingham, MA USA. [Benjamin, Emelia J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Kosheleva, Anna; Glymour, M. Maria] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Curtis, Lesley H.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. RP Patton, KK (reprint author), Univ Washington, Med Ctr, Div Cardiol, Dept Med, 1959 NE Pacific St,Box 356422, Seattle, WA 98195 USA. EM krpatton@u.washington.edu OI Benjamin, Emelia/0000-0003-4076-2336; Patton, Kristen K./0000-0002-9034-6966 FU Harvard Program on Global Demography and Aging; National Institute on Aging [R21AG03438501]; NIH [1R01AG027122-01A2]; Robert Wood Johnson Foundation Health and Society, at Columbia; Harvard Universities; MacArthur Foundation Network on Socioeconomic Status and Health; American Heart Association; Harvard School of Public Health; Harvard Center for Population and Development Studies; NIOSH [1R03OH009338-01, 1R03CA137666-01A1]; Program on Global Demography of Aging (Harvard School of Public Health); [1RC1 HL101056]; [IR01HL092577]; [1R01HL102214]; [1 R01 AG028321]; [N01-HC 25195] FX This study was supported with a pilot project grant from the Harvard Program on Global Demography and Aging, which is supported by the National Institute on Aging, and by National Institute on Aging grant R21AG03438501.; Dr. Glymour has received honoraria for lectures or educational activities not funded by industry and received research support from the NIH, the Robert Wood Johnson Foundation Health and Society Scholars Programs at Columbia and Harvard Universities, and the MacArthur Foundation Network on Socioeconomic Status and Health, the American Heart Association, the Harvard School of Public Health, and the Harvard Center for Population and Development Studies.; Ms. Kosheleva receives/has received research support as a programmer from the NIH (#1R01AG027122-01A2, NIOSH #1R03OH009338-01, and #1R03CA137666-01A1), the Program on Global Demography of Aging (Harvard School of Public Health), and from the MacArthur Foundation Network on Socioeconomic Status and Health.; Dr. Benjamin receives research support from 1RC1 HL101056; IR01HL092577; 1R01HL102214; 1 R01 AG028321; and N01-HC 25195. NR 40 TC 2 Z9 2 U1 0 U2 5 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 OCT PY 2011 VL 21 IS 10 BP 732 EP 738 DI 10.1016/j.annepidem.2011.06.003 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 820WJ UT WOS:000294936500003 PM 21798760 ER PT J AU George, SM Moore, SC Chow, WH Schatzkin, A Hollenbeck, AR Matthews, CE AF George, Stephanie M. Moore, Steven C. Chow, Wong-Ho Schatzkin, Arthur Hollenbeck, Albert R. Matthews, Charles E. TI A Prospective Analysis of Prolonged Sitting Time and Risk of Renal Cell Carcinoma Among 300,000 Older Adults SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Sedentary Lifestyle; Kidney Neoplasms; Cohort Studies ID PHYSICAL-ACTIVITY SCALE; NIH-AARP DIET; ELDERLY PASE; SEDENTARY BEHAVIOR; ENDOMETRIAL CANCER; HEALTH; VALIDITY; COHORT AB PURPOSE: Accumulating evidence suggests an etiologic role in renal cell carcinoma (RCC) for physical activity. However, it is unknown if prolonged sitting, which is thought to be distinct from too little moderate-vigorous physical activity, is an independent risk factor for RCC. The authors prospectively examined the relationship of prolonged sitting and risk of RCC among 289,512 women and men in the National Institutes of Health-AARP Diet and Health Study. METHODS: From 1996 through 2006, 1206 invasive RCC cancer cases were identified. Cox proportional hazards regression was used to estimate multivariate hazard ratios (HR) and 95% confidence intervals. RESULTS: After controlling for known risk factors for RCC, we did not find evidence of associations between RCC risk and time spent per day sitting while watching television or videos (HR(7+1hrs: <1 hr) = 0.96 (0.66, 1.38); p trend = 0.707) or total sitting time (HR(9+hrs: <3hrs) = 1.11 (0.87, 1.41); p trend = 0.765). CONCLUSIONS: Prolonged sitting time was not associated with RCC risk among men and women in this large cohort. Ann Epidemiol 2011;21:787-790. Published by Elsevier Inc. C1 [George, Stephanie M.; Moore, Steven C.; Chow, Wong-Ho; Schatzkin, Arthur; Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP George, SM (reprint author), NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, 6120 Execut Blvd,Suite 320, Bethesda, MD 20892 USA. EM materess@mail.nih.gov RI matthews, Charles/E-8073-2015; Moore, Steven/D-8760-2016 OI matthews, Charles/0000-0001-8037-3103; Moore, Steven/0000-0002-8169-1661 FU National Institutes of Health, National Cancer Institute; Florida Department of Health (FDOH) FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System (FCDC) under contract with the Florida Department of Health (FDOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the FCDC or FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. We are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. NR 18 TC 9 Z9 9 U1 0 U2 5 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 OCT PY 2011 VL 21 IS 10 BP 787 EP 790 DI 10.1016/j.annepidem.2011.04.012 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 820WJ UT WOS:000294936500010 PM 21737302 ER PT J AU Lovely, RS Yang, Q Massaro, JM Wang, J D'Agostino, RB O'Donnell, CJ Shannon, J Farrell, DH AF Lovely, Rehana S. Yang, Qiong Massaro, Joseph M. Wang, Jing D'Agostino, Ralph B., Sr. O'Donnell, Christopher J. Shannon, Jackilen Farrell, David H. TI Assessment of Genetic Determinants of the Association of gamma ' Fibrinogen in Relation to Cardiovascular Disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE coronary heart disease; epidemiology; fibrin; gene mutations; risk factors ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; ISCHEMIC-STROKE; SPLICE VARIANT; CHAIN; RISK; FIBRINOLYSIS; POPULATION; RATIO AB Objective-gamma ' fibrinogen is a newly emerging biomarker that is associated with cardiovascular disease (CVD). However, the genetic determinants of gamma ' fibrinogen levels are unknown. We therefore conducted a genome-wide association study on 3042 participants from the Framingham Heart Study Offspring Cohort. Methods and Results-A genome-wide association study with 2.5 million single-nucleotide polymorphisms (SNPs) was carried out for gamma ' fibrinogen levels from the cycle 7 examination. Fifty-four SNPs in or near the fibrinogen gene locus demonstrated genome-wide significance (P<5.0x10(-8)) for association with gamma ' fibrinogen levels. The top-signal SNP was rs7681423 (P=9.97x10(-110)) in the fibrinogen gene locus near FGG, which encodes the gamma chain. Conditional on the top SNP, the only other SNP that remained genome-wide significant was rs1049636. Associations between SNPs, gamma ' fibrinogen levels, and prevalent CVD events were examined using multiple logistic regression. gamma ' fibrinogen levels were associated with prevalent CVD (P=0.02), although the top 2 SNPs associated with gamma ' fibrinogen levels were not associated with CVD. These findings contrast those for total fibrinogen levels, which are associated with different genetic loci, particularly FGB, which encodes the B beta chain. Conclusion-gamma ' fibrinogen is associated with prevalent CVD and with SNPs exclusively in and near the fibrinogen gene locus. (Arterioscler Thromb Vasc Biol. 2011;31:2345-2352.) C1 [Farrell, David H.] Oregon Hlth & Sci Univ, Sch Med, Dept Med, Div Cardiovasc Med, Portland, OR 97239 USA. [Lovely, Rehana S.] Missouri State Univ, Dept Biomed Sci, Springfield, MO USA. [Yang, Qiong; Massaro, Joseph M.; Wang, Jing] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Shannon, Jackilen] Oregon Hlth & Sci Univ, Ctr Res Occupat & Environm Toxicol, Portland, OR 97239 USA. RP Farrell, DH (reprint author), Oregon Hlth & Sci Univ, Sch Med, Dept Med, Div Cardiovasc Med, MQ280,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM farrelld@ohsu.edu RI Yang, Qiong/G-5438-2014; OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Heart Association [0865486G]; National Heart, Lung, and Blood Institute; National Institutes of Health [R21-HL-75006, R21-HL-097298]; Office of Naval Research [N000140610411] FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195); American Heart Association Grant 0865486G (to R. S. L.); National Heart, Lung, and Blood Institute, National Institutes of Health, Grants R21-HL-75006 and R21-HL-097298 (to D. H. F.); and Office of Naval Research Grant N000140610411 (to D.H.F.). NR 30 TC 19 Z9 19 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD OCT PY 2011 VL 31 IS 10 BP 2345 EP U399 DI 10.1161/ATVBAHA.111.232710 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 819QK UT WOS:000294843700024 PM 21757653 ER PT J AU Wu, CO Tian, X Jiang, WH AF Wu, Colin O. Tian, Xin Jiang, Wenhua TI A shared parameter model for the estimation of longitudinal concomitant intervention effects SO BIOSTATISTICS LA English DT Article DE Change-point model; Concomitant intervention; Likelihood; Longitudinal study; Shared parameter model ID MYOCARDIAL-INFARCTION; ENHANCING RECOVERY; ENRICHD AB We investigate a change-point approach for modeling and estimating the regression effects caused by a concomitant intervention in a longitudinal study. Since a concomitant intervention is often introduced when a patient's health status exhibits undesirable trends, statistical models without properly incorporating the intervention and its starting time may lead to biased estimates of the intervention effects. We propose a shared parameter change-point model to evaluate the pre- and postintervention time trends of the response and develop a likelihood-based method for estimating the intervention effects and other parameters. Application and statistical properties of our method are demonstrated through a longitudinal clinical trial in depression and heart disease and a simulation study. C1 [Wu, Colin O.; Tian, Xin; Jiang, Wenhua] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Wu, CO (reprint author), NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. EM wuc@nhlbi.nih.gov FU National Heart, Lung and Blood Institute [N01-HC-55140, N01-HC-55141, N01-HC-55142, N01-HC-55143, N01-HC-55144, N01-HC-55145, N01-HC-55146, N01-HC-55147, N01-HC-55148] FX Financial support of the ENRICHD study was provided by contracts N01-HC-55140, N01-HC-55141, N01-HC-55142, N01-HC-55143, N01-HC-55144, N01-HC-55145, N01-HC-55146, N01-HC-55147, and N01-HC-55148 from the National Heart, Lung and Blood Institute. NR 13 TC 0 Z9 0 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 J9 BIOSTATISTICS JI Biostatistics PD OCT PY 2011 VL 12 IS 4 BP 737 EP 749 DI 10.1093/biostatistics/kxq084 PG 13 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 819DY UT WOS:000294806800011 PM 21262930 ER PT J AU Fiori, JL Sanghvi, M O'Connell, MP Krzysik-Walker, SM Moaddel, R Bernier, M AF Fiori, J. L. Sanghvi, M. O'Connell, M. P. Krzysik-Walker, S. M. Moaddel, R. Bernier, M. TI The cannabinoid receptor inverse agonist AM251 regulates the expression of the EGF receptor and its ligands via destabilization of oestrogen-related receptor alpha protein SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE cancer; cell cycle; cell invasion; colony formation; EGF receptor; inverse agonist; orphan nuclear hormone receptors; signal transduction ID GROWTH-FACTOR RECEPTOR; PHOSPHORYLATION-DEPENDENT SUMOYLATION; PROLIFERATOR-ACTIVATED RECEPTOR; CANCER-CELL-PROLIFERATION; HUMAN BREAST-CANCER; ERR-ALPHA; PANCREATIC-CANCER; PROSTATE-CANCER; GENE-EXPRESSION; TRANSCRIPTIONAL CONTROL AB BACKGROUND AND PURPOSE AM251 is an inverse agonist of the cannabinoid 1 receptor (CB1R) that can exert 'off-target' effects in vitro and in CB1R knock-out mice. AM251 is also potent at modulating tumour cell growth, suggesting that growth factor-mediated oncogenic signalling could be regulated by AM251. Since dysregulation of the EGF receptor has been associated with carcinogenesis, we examined AM251 regulation of EGF receptor (EGFR) expression and function. EXPERIMENTAL APPROACH The various biological functions of AM251 were measured in CB1R-negative human cancer cells. Pharmacological and genetic approaches were used to validate the data. KEY RESULTS The mRNA levels for EGFR and its associated ligands, including HB-EGF, were induced several fold in PANC-1 and HCT116 cells in response to AM251. This event was associated with enhanced expression of EGFR on the cell surface with concomitant increase in EGF-induced cellular responses in AM251-treated cells. Exposure to XCT790, a synthetic inverse agonist of the orphan nuclear oestrogen-related receptor alpha (ERR alpha), also induced EGFR and HB-EGF expression to the same extent as AM251, whereas pretreatment with the ERR alpha-selective agonist, biochanin A, blunted AM251 actions. AM251 promoted the degradation of ERR alpha protein without loss of the corresponding mRNA. Knock-down of ERR alpha by siRNA-based approach led to constitutive induction of EGFR and HB-EGF levels, and eliminated the biological responses of AM251 and XCT790. Finally, AM251 displaced diethylstilbestrol prebound to the ligand-binding domain of ERR alpha. CONCLUSIONS AND IMPLICATIONS AM251 up-regulates EGFR expression and signalling via a novel non-CB1R-mediated pathway involving destabilization of ERR alpha protein in selected cancer cell lines. C1 [Fiori, J. L.; Sanghvi, M.; Krzysik-Walker, S. M.; Moaddel, R.; Bernier, M.] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [O'Connell, M. P.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. RP Bernier, M (reprint author), NIA, Clin Invest Lab, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM bernierm@mail.nih.gov RI Sanghvi, Mitesh/C-6740-2013; OI Bernier, Michel/0000-0002-5948-368X FU NIH, NIA FX We thank Drs Robert P. Wersto for expert advice on flow cytometry analysis and Irving W. Wainer for critical reading of the manuscript. We would also like to thank Sutapa Kole for her technical assistance and Jade Scheers in the Research Resources Branch at the NIA for her technical assistance with the flow cytometry, which includes sample preparation, flow acquisition and cell cycle analysis. This research was supported entirely by the Intramural Research Program of the NIH, NIA. NR 73 TC 12 Z9 12 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD OCT PY 2011 VL 164 IS 3 SI SI BP 1026 EP 1040 DI 10.1111/j.1476-5381.2011.01384.x PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 820SP UT WOS:000294926000016 PM 21449913 ER PT J AU Knodler, LA Ibarra, JA Perez-Rueda, E Yip, CK Steele-Mortimer, O AF Knodler, Leigh A. Ibarra, J. Antonio Perez-Rueda, Ernesto Yip, Calvin K. Steele-Mortimer, Olivia TI Coiled-coil domains enhance the membrane association of Salmonella type III effectors SO CELLULAR MICROBIOLOGY LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; N-TERMINAL PLECKSTRIN; CELL PLASMA-MEMBRANE; SECRETION SYSTEMS; VIRULENCE FACTORS; ESCHERICHIA-COLI; TRANSLOCATED EFFECTORS; EPITHELIAL-CELLS; GENE-EXPRESSION; HOST-CELLS AB Coiled-coil domains in eukaryotic and prokaryotic proteins contribute to diverse structural and regulatory functions. Here we have used in silico analysis to predict which proteins in the proteome of the enteric pathogen, Salmonella enterica serovar Typhimurium, harbour coiled-coil domains. We found that coiled-coil domains are especially prevalent in virulence-associated proteins, including type III effectors. Using SopB as a model coiled-coil domain type III effector, we have investigated the role of this motif in various aspects of effector function including chaperone binding, secretion and translocation, protein stability, localization and biological activity. Compared with wild-type SopB, SopB coiled-coil mutants were unstable, both inside bacteria and after translocation into host cells. In addition, the putative coiled-coil domain was required for the efficient membrane association of SopB in host cells. Since many other Salmonella effectors were predicted to contain coiled-coil domains, we also investigated the role of this motif in their intracellular targeting in mammalian cells. Mutation of the predicted coiled-coil domains in PipB2, SseJ and SopD2 also eliminated their membrane localization in mammalian cells. These findings suggest that coiled-coil domains represent a common membrane-targeting determinant for Salmonella type III effectors. C1 [Knodler, Leigh A.; Ibarra, J. Antonio; Steele-Mortimer, Olivia] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Perez-Rueda, Ernesto] UNAM, Inst Biotecnol, Cuernavaca, Morelos, Mexico. [Yip, Calvin K.] Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V5Z 1M9, Canada. RP Knodler, LA (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM lknodler@niaid.nih.gov RI Perez-Rueda, Ernesto/F-8337-2013; OI Ernesto, Perez-Rueda/0000-0002-6879-0673 FU National Institute of Allergy and Infectious Diseases; DGAPA-UNAM [IN-217508] FX We kindly thank Victor Cid for helpful discussions, Jean Celli for critical reading of this manuscript, Seth Winfree for IT assistance, members of the Steele-Mortimer laboratory for helpful discussions, Gary Hettrick and Austin Athman for graphics assistance, and the Genomics Core Facility at Rocky Mountain Laboratories for DNA sequencing analysis. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. E.P.-R. was financed by a grant (IN-217508) from DGAPA-UNAM. NR 79 TC 16 Z9 16 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD OCT PY 2011 VL 13 IS 10 BP 1497 EP 1517 DI 10.1111/j.1462-5822.2011.01635.x PG 21 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 820SA UT WOS:000294924500006 PM 21679290 ER PT J AU Coleman, CM Scheremeta, BH Boyce, AT Mauck, RL Tuan, RS AF Coleman, Cynthia M. Scheremeta, Brooke H. Boyce, Amanda T. Mauck, Robert L. Tuan, Rocky S. TI Delayed Fracture Healing in Growth Differentiation Factor 5-deficient Mice: A Pilot Study SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID BRACHYDACTYLY TYPE-C; HUMAN GROWTH/DIFFERENTIATION FACTOR-5; STIMULATES OSTEOGENIC DIFFERENTIATION; RECOMBINANT HUMAN GROWTH; FACTOR-BETA SUPERFAMILY; MESENCHYMAL STEM-CELLS; PROTEIN-1 CDMP1 GENE; MARROW STROMAL CELLS; MORPHOGENETIC PROTEIN-1; EMBRYONIC-DEVELOPMENT AB Growth differentiation factor-5 (GDF-5) is a key regulator of skeletogenesis and bone repair and induces bone formation in spinal fusions and nonunion applications by enhancing chondrocytic and osteocytic differentiation and stimulating angiogenesis. Elucidating the contribution of GDF-5 to fracture repair may support its clinical application in complex fractures. We therefore asked whether the absence of GDF-5 during fracture repair impaired bone healing as assessed radiographically, histologically, and mechanically. In this pilot study, we performed tibial osteotomies on 10-week-old male mice, stabilized by intramedullary and extramedullary nailing. Healing was assessed radiographically and histologically on Days 1 (n = 1 wild-type; n = 5 bp [brachopodism]), 5 (n = 3 wild-type; n = 3 bp), 10 (n = 6 wild-type; n = 3 bp), 14 (n = 6 wild-type; n = 6 bp), 21 (n = 6 wild-type; n = 6 bp), 28 (n = 7 wild-type; n = 6 bp), and 56 (n = 6 wild-type; n = 6 bp) after fracture. After 10 (n = 7 wild-type; n = 7 bp contralateral and n = 3 bp fractured tibiae), 14 (n = 6 wild-type; n = 6 bp), 21 (n = 6 wild-type; n = 6 bp), 28 (n = 6 wild-type; n = 3 bp), and 56 (n = 8 wild-type; n = 6 bp) days, the callus cross-sectional area was calculated. We characterized the mechanical integrity of the healing fracture by yield stress and Young's modulus at 28 (n = 6 wild-type; n = 3 bp) and 56 (n = 8 wild-type; n = 6 bp) days postfracture. The absence of GDF-5 impaired cartilaginous matrix deposition in the callus and reduced callus cross-sectional area. After 56 days, the repaired bp fracture was mechanically comparable to that of controls. Although GDF-5 deficiency did not compromise long-term fracture healing, a delay in cartilage formation and remodeling supports roles for GDF-5 in the early phase of bone repair. Local delivery of GDF-5 to clinically difficult fractures may simulate cartilage formation in the callus and support subsequent remodeling. C1 [Tuan, Rocky S.] Univ Pittsburgh, Sch Med, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, Pittsburgh, PA 15219 USA. [Mauck, Robert L.] Univ Penn, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA. [Scheremeta, Brooke H.] Schneider Childrens Hosp, New Hyde Pk, NY USA. [Coleman, Cynthia M.] Natl Univ Ireland Galway, Regenerat Med Inst, Galway, County Galway, Ireland. [Coleman, Cynthia M.; Scheremeta, Brooke H.; Boyce, Amanda T.; Mauck, Robert L.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), Univ Pittsburgh, Sch Med, Ctr Cellular & Mol Engn, Dept Orthopaed Surg, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM rst13@pitt.edu FU National Institutes of Health [ZO1 AR41131] FX One or more of the authors (RT) received funding from National Institutes of Health grant ZO1 AR41131. NR 53 TC 3 Z9 4 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD OCT PY 2011 VL 469 IS 10 BP 2915 EP 2924 DI 10.1007/s11999-011-1912-0 PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 819KA UT WOS:000294822600028 PM 21590487 ER PT J AU Zelinka, T Musil, Z Duskova, J Burton, D Merino, MJ Milosevic, D Widimsky, J Pacak, K AF Zelinka, Tomas Musil, Zdenek Duskova, Jaroslava Burton, Deborah Merino, Maria J. Milosevic, Dragana Widimsky, Jiri, Jr. Pacak, Karel TI Metastatic pheochromocytoma: Does the size and age matter? SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE Epinephrine; malignant pheochromocytoma; norepinephrine ID GLAND SCALED SCORE; B GENE-MUTATIONS; MALIGNANT PHEOCHROMOCYTOMAS; EXTRAADRENAL PARAGANGLIOMA; ADRENAL PHEOCHROMOCYTOMAS; GERMLINE MUTATIONS; BENIGN; FEATURES; HYPERTENSION; RECURRENCE AB Background Pheochromocytomas are tumours arising from chromaffin tissue located in the adrenal medulla associated with typical symptoms and signs which may occasionally develop metastases, which are defined as the presence of tumour cells at sites where these cells are not found. This retrospective analysis was focused on clinical, genetic and histopathologic characteristics of primary metastatic versus primary benign pheochromocytomas. Materials and methods We identified 41 subjects with metastatic pheochromocytoma and 108 subjects with apparently benign pheochromocytoma. We assessed dimension and biochemical profile of the primary tumour, age at presentation and time to develop metastases. Results Subjects with metastatic pheochromocytoma presented at a significantly younger age (41 4 +/- 14 7 vs. 50 2 +/- 13 7 years; P < 0 001) with larger primary tumours (8 38 +/- 3 27 vs. 6 18 +/- 2 75 cm; P < 0 001) and secreted more frequently norepinephrine (95.1% vs. 83.3%; P = 0 046) compared to subjects with apparently benign pheochromocytomas. No significant differences were found in the incidence of genetic mutations in both groups of subjects (25.7% in the metastatic group and 14.7% in the benign group; P = 0 13). From available histopathologic markers of potential malignancy, only necrosis occurred more frequently in subjects with metastatic pheochromocytoma (27.6% vs. 0%; P < 0 001). The median time to develop metastases was 3 6 years with the longest interval 24 years. Conclusions In conclusion, regardless of a genetic background, the size of a primary pheochromocytoma and age of its first presentation are two independent risk factors associated with the development of metastatic disease. C1 [Zelinka, Tomas; Widimsky, Jiri, Jr.] Charles Univ Prague, Fac Med 1, Dept Endocrinol & Metab, Dept Med 3, Prague, Czech Republic. [Zelinka, Tomas; Musil, Zdenek; Duskova, Jaroslava; Widimsky, Jiri, Jr.] Gen Univ Hosp Prague, Prague, Czech Republic. [Musil, Zdenek] Charles Univ Prague, Fac Med 1, Inst Biol & Med Genet, Prague, Czech Republic. [Duskova, Jaroslava] Charles Univ Prague, Fac Med 1, Inst Pathol, Prague, Czech Republic. [Burton, Deborah] NCI, Dept Lab Med, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Surg Pathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Milosevic, Dragana] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod & Adult Endocrinol Program, NIH, Bethesda, MD USA. RP Pacak, K (reprint author), NICHD, Sect Med Neuroendocrinol, Reprod & Adult Endocrinol Program, NIH,CRC, Bldg 10,1 East,Room 1-3140,10 Ctr Dr,MSC-1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov RI Zelinka, Tomas/D-4276-2017 OI Zelinka, Tomas/0000-0003-3395-8373 FU NICHD/NIH; Czech Ministry of Education [0021620807, 0021620808] FX This research was supported by the Intramural Research Program of the NICHD/NIH and by Research projects of Czech Ministry of Education 0021620807 and 0021620808. NR 31 TC 17 Z9 19 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD OCT PY 2011 VL 41 IS 10 BP 1121 EP 1128 DI 10.1111/j.1365-2362.2011.02518.x PG 8 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 820NH UT WOS:000294912200011 PM 21692797 ER PT J AU Traore, M Coulibaly, T Meilleur, KG La Pean, A Sangare, M Landoure, G Mochel, F Karambe, M Guinto, CO Fischbeck, KH AF Traore, M. Coulibaly, T. Meilleur, K. G. La Pean, A. Sangare, M. Landoure, G. Mochel, F. Karambe, M. Guinto, C. O. Fischbeck, K. H. TI Clinical and genetic analysis of spinocerebellar ataxia in Mali SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE genetic and inherited disorders; Malians; spinocerebellar ataxia ID TYPE-2 SCA2 AB Background: Autosomal dominant cerebellar ataxia, currently denominated spinocerebellar ataxia (SCAs), represents a heterogeneous group of neurodegenerative disorders affecting the cerebellum and its connections. We describe the clinical and molecular findings in 16 patients originating from Malian families, who suffer from progressive cerebellar ataxia syndrome. Methods and results: Molecular analysis allows genetic profiles of SCA to be distinguished. In seven patients, SCA type 2 (CAG) mutation was expanded from 39 to 43 repeats. SCA type 7 (CAG) mutation was confirmed in six patients. Mutations were expanded from 49 to 59 repeats. In three patients, SCA type3 was diagnosed and CAG mutation was expanded to 73 repeats. Conclusions: Our data suggest that the most frequent types of SCA are SCA2 and SCA7. However, further studies are needed to confirm these preliminary results. C1 [Traore, M.; Coulibaly, T.; Karambe, M.; Guinto, C. O.] Point G Hosp, Dept Neurol, Bamako, Mali. [Meilleur, K. G.; La Pean, A.; Sangare, M.; Landoure, G.; Mochel, F.; Fischbeck, K. H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Traore, M (reprint author), Point G Hosp, Dept Neurol, BP 1805, Bamako, Mali. EM doyentraore@hotmail.com FU Neurogenetics Branch; National Institute of Neurological disorders and Stroke National Institute of Health, Bethesda FX The Author appreciates Dr Hilbert Pascale from IPG for critical help in Genetic testing. This work was supported in part by Kenneth Fischbeck from Neurogenetics Branch, National Institute of Neurological disorders and Stroke National Institute of Health, Bethesda. We also thank Melanie Giulias Sanogo for invaluable reading of the manuscript. NR 9 TC 7 Z9 8 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD OCT PY 2011 VL 18 IS 10 BP 1269 EP 1271 DI 10.1111/j.1468-1331.2011.03376.x PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 820QF UT WOS:000294919800020 PM 21418439 ER PT J AU Kennedy, BM Harsha, DW Bookman, EB Hill, YR Rankinen, T Rodarte, RQ Murla, CD AF Kennedy, Betty M. Harsha, David W. Bookman, Ebony B. Hill, Yolanda R. Rankinen, Tuomo Rodarte, Ruben Q. Murla, Connie D. TI Challenges to recruitment and retention of African Americans in the gene-environment trial of response to dietary interventions (GET READI) for heart health SO HEALTH EDUCATION RESEARCH LA English DT Article ID BREAST-OVARIAN CANCER; MAILING STRATEGIES; CLINICAL-TRIAL; ATTITUDES; KNOWLEDGE; WOMEN; PARTICIPATION; POPULATIONS; EXPERIENCE; SMOKERS AB In this paper, challenges to recruiting African Americans specifically for a dietary feeding trial are examined, learning experiences gained and suggestions to overcome these challenges in future trials are discussed. A total of 333 individuals were randomized in the trial and 234 (167 sibling pairs and 67 parents/siblings) completed the dietary intervention and required DNA blood sampling for genetic analysis. The trial used multiple strategies for recruitment. Hand distributed letters and flyers through mass distribution at various churches resulted in the largest number (n = 153, 46%) of African Americans in the trial. Word of mouth accounted for the second largest number (n = 120, 36%) and included prior study participants. These two recruitment sources represented 82% (n = 273) of the total number of individuals randomized in GET READI. The remaining 18% (n = 60) consisted of a combination of sources including printed message on check stubs, newspaper articles, radio and TV appearances, screening events and presentations. Though challenging, the recruitment efforts for GET READI produced a significant number of African American participants despite the inability to complete the trial as planned because of low recruitment yields. Nevertheless, the recruitment process produced substantial numbers that successfully completed all study requirements. C1 [Kennedy, Betty M.] Pennington Biomed Res Ctr, Adjunct Fac Populat Sci, Baton Rouge, LA 70808 USA. [Bookman, Ebony B.] NHGRI, Rockville Pikebethesda, MD 20892 USA. [Hill, Yolanda R.] Pennington Biomed Res Ctr, Outpatient Clin, Baton Rouge, LA 70808 USA. RP Kennedy, BM (reprint author), Pennington Biomed Res Ctr, Adjunct Fac Populat Sci, 6400 Perkins Rd,POB 80025, Baton Rouge, LA 70808 USA. EM bkennedy@lsba.com FU NHLBI NIH HHS [5 U01 HL072510] NR 34 TC 6 Z9 6 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 J9 HEALTH EDUC RES JI Health Educ. Res. PD OCT PY 2011 VL 26 IS 5 BP 923 EP 936 DI 10.1093/her/cyr061 PG 14 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 819FB UT WOS:000294809700014 PM 21865154 ER PT J AU Semnani, RT Mahapatra, L Moore, V Sanprasert, V Nutman, TB AF Semnani, Roshanak Tolouei Mahapatra, Lily Moore, Vanessa Sanprasert, Vivornpun Nutman, Thomas B. TI Functional and Phenotypic Characteristics of Alternative Activation Induced in Human Monocytes by Interleukin-4 or the Parasitic Nematode Brugia malayi SO INFECTION AND IMMUNITY LA English DT Article ID CD4(+) T-CELLS; SYNTHASE ARGINASE BALANCE; ANTIGEN-PRESENTING CELLS; NITRIC-OXIDE; DENDRITIC CELLS; LYMPHATIC FILARIASIS; HYDROGEN-PEROXIDE; HUMAN ALVEOLAR; CYTO-TOXICITY; IFN-GAMMA AB Human monocytes from patients with patent filarial infections are studded with filarial antigen and express markers associated with alternative activation of macrophages (M Phi). To explore the role of filaria-derived parasite antigen in differentiation of human monocytes, cells were exposed to microfilariae (mf) of Brugia malayi, and their phenotypic and functional characteristics were compared with those of monocytes exposed to factors known to generate either alternatively (interleukin-4 [IL-4]) or classically (macrophage colony-stimulating factor [MCSF]) activated M Phi. IL-4 upregulated mRNA expression of CCL13, CCL15, CCL17, CCL18, CCL22, CLEC10A, MRC1, CADH1, CD274, and CD273 associated with alternative activation of M Phi but not arginase 1. IL-4-cultured monocytes had a diminished ability to promote proliferation of both CD4(+) and CD8(+) T cells compared to that of unexposed monocytes. Similar to results with IL-4, exposure of monocytes to live mf induced upregulation of CCL15, CCL17, CCL18, CCL22, CD274, and CD273 and downregulation of Toll-like receptor 3 (TLR3), TLR5, and TLR7. In contrast to results with MCSF-cultured monocytes, exposure of monocytes to mf resulted in significant inhibition of the phagocytic ability of these cells to the same degree as that seen with IL-4. Our data suggest that short exposure of human monocytes to IL-4 induces a phenotypic characteristic of alternative activation and that secreted filarial products skew monocytes similarly. C1 [Semnani, Roshanak Tolouei; Mahapatra, Lily; Moore, Vanessa; Sanprasert, Vivornpun; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Semnani, RT (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr,Room B1-03, Bethesda, MD 20892 USA. EM rsemnani@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH FX This work was supported by the Intramural Research Program of the Division of Intramural Research, NIAID, NIH. NR 54 TC 19 Z9 20 U1 2 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2011 VL 79 IS 10 BP 3957 EP 3965 DI 10.1128/IAI.05191-11 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 821BY UT WOS:000294951000012 PM 21788379 ER PT J AU Sidique, N Kohli, A Shivakumar, B Migueles, S Subramanian, GM Naggie, S Polis, MA Masur, H Kottilil, S AF Sidique, Nadeera Kohli, Anita Shivakumar, Bhavana Migueles, Stephen Subramanian, G. Mani Naggie, Susanna Polis, Michael A. Masur, Henry Kottilil, Shyam TI HIV/HCV-Coinfected Natural Viral Suppressors Have Better Virologic Responses to PEG-IFN and Ribavirin Than ARV-Treated HIV/HCV Patients SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Letter ID HEPATITIS-C VIRUS; HIV C1 [Sidique, Nadeera; Kohli, Anita; Shivakumar, Bhavana; Migueles, Stephen; Polis, Michael A.; Kottilil, Shyam] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Naggie, Susanna] Duke Clin Res Inst, Durham, NC USA. [Masur, Henry] CC Natl Inst Hlth, Dept Crit Care Med, Bethesda, MD USA. [Subramanian, G. Mani] Human Genome Sci, Rockville, MD USA. RP Sidique, N (reprint author), NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. OI Polis, Michael/0000-0002-9151-2268 FU Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [K23 AI096913] NR 10 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2011 VL 58 IS 2 BP E38 EP E40 DI 10.1097/QAI.0b013e31822d463f PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 821AL UT WOS:000294947100005 PM 21921725 ER PT J AU Keller, JM Neely, HR Latoche, JR Noben-Trauth, K AF Keller, James M. Neely, Harold R. Latoche, Joseph R. Noben-Trauth, Konrad TI High-Frequency Sensorineural Hearing Loss and Its Underlying Genetics (Hfhl1 and Hfhl2) in NIH Swiss Mice SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE NIH Swiss; sensorineural hearing loss; quantitative trait locus analysis ID QUANTITATIVE TRAIT LOCI; INBRED STRAINS; MOUSE MODEL; INHERITANCE; SOFTWARE AB Studies using inbred strains of mice have been invaluable for identifying alleles that adversely affect hearing. However, the efficacy of those studies is limited by the phenotypes that these strains express and the alleles that they segregate. Here, by selectively breeding phenotypically and genetically heterogeneous NIH Swiss mice, we generated two lines-the all-frequency hearing loss (AFHL) line and the high-frequency hearing loss (HFHL) line-with differential hearing loss. The AFHL line exhibited characteristics typical of severe, early-onset, sensorineural hearing impairment. In contrast, the HFHL line expressed a novel early-onset, mildly progressive, and frequency-specific sensorineural hearing loss. By quantitative trait loci (QTLs) analyses in these two lines, we identified QTLs on chromosomes 7, 8, and 10 that significantly affected hearing function. The loci on chromosomes 7 and 8 (Hfhl1 and Hfhl2, respectively) are novel and appear to adversely affect only high frequencies (>= 30 kHz). Mice homozygous for NIH Swiss alleles at either Hfhl1 or Hfhl2 have 32-kHz auditory-evoked brain stem response thresholds that are 8-14 dB SPL higher than the corresponding heterozygotes. DNA sequence analyses suggest that both the Cdh23 (ahl) and Gipc3 (ahl5) variants contribute to the chromosome 10 QTL detected in the AFHL line. The frequency-specific hearing loss indicates that the Hfhl1 and Hfhl2 alleles may affect tonotopic development. In addition, dissecting the underlying complex genetics of high-frequency hearing loss may prove relevant in identifying less severe and common forms of hearing impairment in the human population. C1 [Keller, James M.; Neely, Harold R.; Latoche, Joseph R.; Noben-Trauth, Konrad] Natl Inst Deafness & Other Commun Disorders, Neurogenet Sect, Mol Biol Lab, NIH, Rockville, MD 20850 USA. RP Noben-Trauth, K (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurogenet Sect, Mol Biol Lab, NIH, 5 Res Court, Rockville, MD 20850 USA. EM nobentk@nidcd.nih.gov FU The Division of Intramural Research at NIDCD FX We thank M'Hamed Grati and Dennis Drayna for comments on the manuscript. The Division of Intramural Research at NIDCD supported the study. NR 27 TC 6 Z9 6 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 J9 JARO-J ASSOC RES OTO JI JARO PD OCT PY 2011 VL 12 IS 5 BP 617 EP 631 DI 10.1007/s10162-011-0270-7 PG 15 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 820MK UT WOS:000294909800007 PM 21594677 ER PT J AU Trifonov, EN Zhurkin, VB AF Trifonov, Edward N. Zhurkin, Victor B. TI Jon Widom, the Scientist In Memoriam SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Biographical-Item C1 [Trifonov, Edward N.] Univ Haifa, Inst Evolut, Genome Divers Ctr, IL-31905 Haifa, Israel. [Zhurkin, Victor B.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Trifonov, EN (reprint author), Univ Haifa, Inst Evolut, Genome Divers Ctr, IL-31905 Haifa, Israel. EM trifonov@research.haifa.ac.il; zhurkin@nih.gov NR 0 TC 0 Z9 0 U1 2 U2 2 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD OCT PY 2011 VL 29 IS 2 BP 257 EP 258 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 820CV UT WOS:000294884000003 ER PT J AU Alexandrescu, DT Ichim, TE Riordan, NH Marincola, FM Dasanu, CA AF Alexandrescu, Doru T. Ichim, Thomas E. Riordan, Neil H. Marincola, Francesco M. Dasanu, Constantin A. TI IFN-Conditioned Dendritic Cells for the Therapy of Melanoma: What Is Missing? SO JOURNAL OF IMMUNOTHERAPY LA English DT Letter ID METASTATIC MELANOMA; VACCINATION; BIOCHEMOTHERAPY; IMMUNOTHERAPY; TEMOZOLOMIDE C1 [Ichim, Thomas E.; Riordan, Neil H.] Medistem Inc, San Diego, CA USA. [Marincola, Francesco M.] NIH, Dept Transfus Med, IDIS, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, CHI, Bethesda, MD 20892 USA. [Dasanu, Constantin A.] St Francis Hosp & Med Ctr, Dept Hematol Oncol, Hartford, CT USA. FU Intramural NIH HHS [Z99 CL999999] NR 15 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD OCT PY 2011 VL 34 IS 8 BP 607 EP 609 DI 10.1097/CJI.0b013e31822b9ffc PG 4 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 821AH UT WOS:000294946700006 PM 22025902 ER PT J AU Allen, DL Hittel, DS McPherron, AC AF Allen, David L. Hittel, Dustin S. McPherron, Alexandra C. TI Expression and Function of Myostatin in Obesity, Diabetes, and Exercise Adaptation SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE GDF-8; ENDURANCE EXERCISE; RESISTANCE EXERCISE; METABOLISM ID SKELETAL-MUSCLE MASS; REGULATES GLUCOSE-UPTAKE; MESSENGER-RNA LEVELS; GENE-EXPRESSION; SIGNALING PATHWAYS; INSULIN-RESISTANCE; PROTEIN-SYNTHESIS; TRANSGENIC MICE; ADIPOSE-TISSUE; FAT MASS AB ALLEN, D. L., D. S. HITTEL, and A. C. MCPHERRON. Expression and Function of Myostatin in Obesity, Diabetes, and Exercise Adaptation. Med. Sci. Sports Exerc., Vol. 43, No. 10, pp. 1828-1835, 2011. Myostatin is a member of the transforming growth factor-beta/bone morphogenetic protein (TGF-beta/BMP) superfamily of secreted factors that functions as a potent inhibitor of skeletal muscle growth. Moreover, considerable evidence has accumulated that myostatin also regulates metabolism and that its inhibition can significantly attenuate the progression of obesity and diabetes. Although at least part of these effects on metabolism can be attributable to myostatin's influence over skeletal muscle growth and therefore on the total volume of metabolically active lean body mass, there is mounting evidence that myostatin affects the growth and metabolic state of other tissues, including the adipose and the liver. In addition, recent work has explored the role of myostatin in substrate mobilization, uptake, and/or utilization of muscle independent of its effects on body composition. Finally, the effects of both endurance and resistance exercise on myostatin expression, as well as the potential role of myostatin in the beneficial metabolic adaptations occurring in response to exercise, have also begun to be delineated in greater detail. The purpose of this review was to summarize the work to date on the expression and function of myostatin in obesity, diabetes, and exercise adaptation. C1 [Allen, David L.] Univ Colorado, Dept Integrat Physiol, Boulder, CO 80309 USA. [Hittel, Dustin S.] Univ Calgary, Fac Kinesiol, Calgary, AB T2N 1N4, Canada. [McPherron, Alexandra C.] NIDDK, NIH, Bethesda, MD USA. RP Allen, DL (reprint author), Univ Colorado, Dept Integrat Physiol, Boulder, CO 80309 USA. EM allendl@colorado.edu OI McPherron, Alexandra/0000-0002-5875-9154 FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health from the National Institute of Arthritis, Musculoskeletal Diseases, and Stroke; Natural Sciences and Engineering Research Council of Canada FX Part of this work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. D. L. A. was supported by an National Institutes of Health K01 grant from the National Institute of Arthritis, Musculoskeletal Diseases, and Stroke. D. S. H. was supported by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada. Under a licensing agreement between MetaMorphix, Inc. (MMI) and the Johns Hopkins University, A. C. M. is entitled to a share of royalty received by the university on sales of myostatin. A. C. M. and the university own MMI stock, which is subject to certain restrictions under university policy. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. NR 74 TC 47 Z9 52 U1 1 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD OCT PY 2011 VL 43 IS 10 BP 1828 EP 1835 DI 10.1249/MSS.0b013e3182178bb4 PG 8 WC Sport Sciences SC Sport Sciences GA 821DT UT WOS:000294955800003 PM 21364474 ER PT J AU Craig, DW Goor, RM Wang, ZY Paschall, J Ostell, J Feolo, M Sherry, ST Manolio, TA AF Craig, David W. Goor, Robert M. Wang, Zhenyuan Paschall, Justin Ostell, Jim Feolo, Michael Sherry, Stephen T. Manolio, Teri A. TI Assessing and managing risk when sharing aggregate genetic variant data SO NATURE REVIEWS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; POPULATION; LOCI; REPLICATION; EFFICIENT; PRIVACY; GWAS AB Access to genetic data across studies is an important aspect of identifying new genetic associations through genome-wide association studies (GWASs). Meta-analysis across multiple GWASs with combined cohort sizes of tens of thousands of individuals often uncovers many more genome-wide associated loci than the original individual studies; this emphasizes the importance of tools and mechanisms for data sharing. However, even sharing summary-level data, such as allele frequencies, inherently carries some degree of privacy risk to study participants. Here we discuss mechanisms and resources for sharing data from GWASs, particularly focusing on approaches for assessing and quantifying the privacy risks to participants that result from the sharing of summary-level data. C1 [Craig, David W.] TGen, Res Inst, Translat Genom, Phoenix, AZ 85004 USA. [Goor, Robert M.; Wang, Zhenyuan; Paschall, Justin; Ostell, Jim; Feolo, Michael; Sherry, Stephen T.] NCBI, Bethesda, MD 20892 USA. [Manolio, Teri A.] NHGRI, Bethesda, MD 20892 USA. RP Craig, DW (reprint author), TGen, Res Inst, Translat Genom, Phoenix, AZ 85004 USA. EM dcraig@tgen.org FU NIH National Library of Medicine; US National Heart, Lung and Blood Institute (NHLBI) [U01 HL086528] FX This manuscript represents the views and opinions of its authors and does not necessarily represent the views or policies of the NIH or the US Department of Health and Human Services. This research was supported in part by the Intramural Research Program of the NIH National Library of Medicine. D.W.C. would like to acknowledge support from the US National Heart, Lung and Blood Institute (NHLBI), award U01 HL086528. The authors thank I. Marpuri, S. Buchholtz and L. Gyi for their support in coordinating the development of this work. NR 43 TC 23 Z9 23 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD OCT PY 2011 VL 12 IS 10 BP 730 EP 736 DI 10.1038/nrg3067 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 820ZL UT WOS:000294944500013 PM 21921928 ER PT J AU Orru, M Quiroz, C Guitart, X Ferre, S AF Orru, Marco Quiroz, Cesar Guitart, Xavier Ferre, Sergi TI Pharmacological evidence for different populations of postsynaptic adenosine A(2A) receptors in the rat striatum SO NEUROPHARMACOLOGY LA English DT Article DE Adenosine A(2A) receptor; Dopamine D-2 receptor; Cannabinoid CB1 receptor; Striatum; Glutamate; Locomotor activity; Microdialysis ID CANNABINOID CB1 RECEPTORS; DOPAMINE-D-2 RECEPTORS; GLUTAMATERGIC NEUROTRANSMISSION; STRIATOPALLIDAL NEURONS; PARKINSONS-DISEASE; BASAL GANGLIA; D2 DOPAMINE; C-FOS; PHOSPHORYLATION; EXPRESSION AB Adenosine A(2A) receptors (A(2A)Rs) are highly concentrated in the striatum. Two pharmacological different functional populations of A(2A)Rs have been recently described based on their different affinities for the A(2A)R antagonist SCH-442416. This compound has high affinity for A(2A)Rs not forming heteromers or forming heteromers with adenosine A(1) receptors (A(1)Rs) while showing very low affinity for A(2A)Rs forming heteromers with dopamine D-2 receptors (D(2)Rs). It has been widely described that striatal A(1)R-A(2A)R heteromers are preferentially localized presynaptically in the glutamatergic terminals that contact GABAergic dynorphinergic neurons, and that A(2A)R-D2R heteromers are localized postsynaptically in GABAergic enkephalinergic neurons. In the present study we provide evidence suggesting that SCH-442416 also targets postsynaptic A(2A)R not forming heteromers with D2R, which are involved in the motor depressant effects induced by D2R antagonists. SCH-442416 counteracted motor depression in rats induced by the D2R antagonist raclopride at a dose that did not produce motor activation or that blocked motor depression induced by an A(2A)R agonist. Furthermore, we re-evaluated the recently suggested key role of cannabinoid CB1 receptors (CB1 Rs) in the effects of A(2A)R antagonists acting at postsynaptic A(2A)Rs. By recording locomotor activity and monitoring striatal glutamate release induced by cortical electrical stimulation in rats after administration of A(2A)R and CB1R antagonists, we did not find evidence for any significant role of endocannabinoids in the post- or presynaptic effects of A(2A)R antagonists. The present results further suggest the existence of at least two functionally and pharmacologically different populations of striatal postsynaptic A(2A)Rs. Published by Elsevier Ltd. C1 [Orru, Marco; Quiroz, Cesar; Guitart, Xavier; Ferre, Sergi] NIDA, Intramural Res Program, Dept Hlth & Human Serv, NIH, Baltimore, MD 21224 USA. RP Ferre, S (reprint author), NIDA, Intramural Res Program, Dept Hlth & Human Serv, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014 OI Ferre, Sergi/0000-0002-1747-1779 FU National Institute on Drug Abuse FX Graphic design (Fig. 1) by Jimmy Burril (Visual Media, NIDA). Work supported by the intramural funds of the National Institute on Drug Abuse. NR 32 TC 21 Z9 21 U1 0 U2 0 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 OCT-NOV PY 2011 VL 61 IS 5-6 BP 967 EP 974 DI 10.1016/j.neuropharm.2011.06.025 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 820AX UT WOS:000294879000009 PM 21752341 ER PT J AU Agrawal, Y Carey, JP Hoffman, HJ Sklare, DA Schubert, MC AF Agrawal, Yuri Carey, John P. Hoffman, Howard J. Sklare, Daniel A. Schubert, Michael C. TI The Modified Romberg Balance Test: Normative Data in US Adults SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Aging; Balance; Falls; Race; Romberg; Sex; Vestibular dysfunction ID SENSORY INTERACTION AB Objective: To generate normative values for performance on the modified Romberg Test of Standing Balance on Firm and Compliant Support Surfaces stratified by age, sex, and race/ethnicity and to determine fall risk associated with different levels of performance. Study Design: National cross-sectional survey. Setting: Ambulatory examination centers. Patients: U. S. adults 40 years and older who participated in the 2001-2004 National Health and Nutrition Examination Survey (n = 5,086). Interventions: Time to failure on the modified Romberg Test of Standing Balance on Firm and Compliant Support Surfaces. Main Outcome Measures: History of falling in the previous 12 months. Results: We observed that the time to failure decreased with increasing age across all sex and race/ethnicity categories. We found that once individuals went below a time to failure of 20 seconds, there was a significant greater than 3-fold increase in the odds of falling. In general, participants crossed the 20-second threshold at the age of 60 to 69 years. Conclusion: We established nationally representative normative values for performance on the modified Romberg test and noted differences in the rates of change across demographic groups. In addition, we demonstrated the fall risk associated with different levels of performance. These data will aid the clinician in interpreting and risk stratifying their patient's performance on this postural test. C1 [Agrawal, Yuri; Carey, John P.; Schubert, Michael C.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. [Hoffman, Howard J.; Sklare, Daniel A.] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. RP Agrawal, Y (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 601 N Caroline St, Baltimore, MD 21287 USA. EM yagrawa1@jhmi.edu FU Intramural NIH HHS [Z99 DC999999] NR 8 TC 26 Z9 26 U1 5 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD OCT PY 2011 VL 32 IS 8 BP 1309 EP 1311 DI 10.1097/MAO.0b013e31822e5bee PG 3 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 821BD UT WOS:000294948900024 PM 21892121 ER PT J AU Karron, RA Casey, R Thumar, B Surman, S Murphy, BR Collins, PL Schmidt, AC AF Karron, Ruth A. Casey, Roberta Thumar, Bhagvanji Surman, Sonja Murphy, Brian R. Collins, Peter L. Schmidt, Alexander C. TI The cDNA-derived Investigational Human Parainfluenza Virus Type 3 Vaccine rcp45 Is Well Tolerated, Infectious, and Immunogenic in Infants and Young Children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE parainfluenza; live-attenuated vaccine ID RESPIRATORY SYNCYTIAL VIRUS; ANTIBODY-RESPONSE; HEALTHY INFANTS; LIVE; EPIDEMIOLOGY; ATTENUATION; MUTATIONS; BOVINE; CHIMPANZEES; VOLUNTEERS AB Background: Human parainfluenza virus type 3 (HPIV3) is an important yet underappreciated cause of lower respiratory tract illness in children, and a licensed vaccine is not yet available. Methods: A live-attenuated investigational HPIV3 vaccine virus designated rcp45 was derived from cDNA by using reverse genetics. rcp45 is genetically similar to the biologically derived cp45 vaccine virus and contains all of the known attenuating mutations of cp45, but has the advantage of a short, well-characterized passage history. We evaluated the tolerability, infectivity, and immunogenicity of 2 intranasal doses of rcp45 administered 4 to 10 weeks apart in a placebo-controlled, double-blind trial. A total of 45 infants and children between 6 and 36 months of age participated in this study. Tolerability and antibody responses to vaccine or placebo were assessed in all recipients. Infectivity was assessed by quantitation of vaccine virus shedding in a subset of vaccinated children. Results: rcp45 was well tolerated and highly infectious in HPIV3-seronegative children. A second dose of vaccine administered 4 to 10 weeks after the first dose was restricted in replication and did not boost serum antibody responses. The stability of 9 cp45 mutations, including the 6 major attenuating mutations, was examined and confirmed for viral isolates from 10 children. Conclusions: The level of attenuation and immunogenicity of cDNA-derived rcp45 is comparable to what was previously observed with the biologically derived cp45 vaccine, and preliminary data suggest that the attenuating mutations in this vaccine virus are genetically stable. Continued clinical development of rcp45 is warranted. C1 [Karron, Ruth A.; Casey, Roberta; Thumar, Bhagvanji] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Dept Int Hlth, Baltimore, MD USA. [Surman, Sonja; Murphy, Brian R.; Collins, Peter L.; Schmidt, Alexander C.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Karron, RA (reprint author), 624 N Broadway 217, Baltimore, MD 21205 USA. EM rkarron@jhsph.edu FU NIH [N01-AI-15444, HHSN272200900010C]; National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health; NIAID; Johns Hopkins Bloomberg School of Public Health; NIAID Division of Clinical Research; NIAID Data Safety Monitoring Board FX Supported by NIH contracts N01-AI-15444 and HHSN272200900010C and by Intramural Research Program of the National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health. Clinical trials were conducted as part of contracts between NIAID and the Johns Hopkins Bloomberg School of Public Health. (N01-A1-15444 and HHSN272200900010C).; The authors thank Barbara Burns, Elizabeth Schappell, Karen Loehr, Racine Harris, Amy Hoffman, Susan DiLorenzo, and Nicole Yoder for expert clinical and technical assistance, and Romeo Paredes and Jason Morsell for data management and administrative assistance. They also thank the Regulatory Compliance and Human Subjects Protection Program within the NIAID Division of Clinical Research and the NIAID Data Safety Monitoring Board for their support. They also thank the physicians and staff of Primary Care Pediatrics, Dundalk Pediatrics, Bright Oaks Pediatrics, The Pediatric Group, and the Harriet Lane Clinic, and also the families whose children participated in this study. They are grateful to Mario Skiadopoulos for his contributions to the preclinical development of this investigational vaccine. NR 32 TC 7 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD OCT PY 2011 VL 30 IS 10 BP E186 EP E191 DI 10.1097/INF.0b013e31822ea24f PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 821BX UT WOS:000294950900002 PM 21829138 ER PT J AU Harries, LW Hernandez, D Henley, W Wood, AR Holly, AC Bradley-Smith, RM Yaghootkar, H Dutta, A Murray, A Frayling, TM Guralnik, JM Bandinelli, S Singleton, A Ferrucci, L Melzer, D AF Harries, Lorna W. Hernandez, Dena Henley, William Wood, Andrew R. Holly, Alice C. Bradley-Smith, Rachel M. Yaghootkar, Hanieh Dutta, Ambarish Murray, Anna Frayling, Timothy M. Guralnik, Jack M. Bandinelli, Stefania Singleton, Andrew Ferrucci, Luigi Melzer, David TI Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing SO AGING CELL LA English DT Article DE aging; cell senescence; mRNA processing; gene expression; predictive model ID PERIPHERAL-BLOOD; DNA-DAMAGE; RNA; PROFILES; SENESCENCE; SIGNATURES; MUTATIONS; CELLS AB Aging is a major risk factor for chronic disease in the human population, but there are little human data on gene expression alterations that accompany the process. We examined human peripheral blood leukocyte in-vivo RNA in a large-scale transcriptomic microarray study (subjects aged 30-104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n = 458), following-up findings in a replication set (n = 240). We confirmed expression of key results by real-time PCR. Of 16 571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (area under the curve in replication set; 95%). The focused nature of age-related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age-associated, in gene set enrichment analysis, notably including the processing of messenger RNAs (mRNAs); [P < 0.002, false discovery rate (FDR) q < 0.05]. This is supported by our observation of age-associated disruption to the balance of alternatively expressed isoforms for selected genes, suggesting that modification of mRNA processing may be a feature of human aging. C1 [Harries, Lorna W.; Wood, Andrew R.; Holly, Alice C.; Bradley-Smith, Rachel M.; Yaghootkar, Hanieh; Murray, Anna; Frayling, Timothy M.] Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England. [Hernandez, Dena; Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Henley, William] Univ Plymouth, Ctr Hlth & Environm Stat, Plymouth PL4 8AA, Devon, England. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, I-50125 Florence, Italy. [Ferrucci, Luigi] NIA, Clin Res Branch, Harbor Hosp, Baltimore, MD 21225 USA. RP Harries, LW (reprint author), Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Barrack Rd, Exeter EX2 5DW, Devon, England. EM Lorna.Harries@pms.ac.uk RI Singleton, Andrew/C-3010-2009; Harries, Lorna/D-2241-2014; OI Murray, Anna/0000-0002-2351-2522; Melzer, David/0000-0002-0170-3838; Dutta, Ambarish/0000-0002-4019-7472 FU National Institute on Aging; U.S. National Institutes of Health; National Institute of Health Research (NIHR) FX We thank the many people who contributed to the InCHIANTI study, including all of the anonymous participants. This study was supported in part by the Intramural Research Program, National Institute on Aging and the U.S. National Institutes of Health. We thank Luke Pilling for extra statistical analyses. William Henley completed this work while seconded to PenCLARHC which is funded by the National Institute of Health Research (NIHR). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. NR 40 TC 56 Z9 57 U1 3 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD OCT PY 2011 VL 10 IS 5 BP 868 EP 878 DI 10.1111/j.1474-9726.2011.00726.x PG 11 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 819WN UT WOS:000294864400013 PM 21668623 ER PT J AU Gabor, LR Chamberlin, AP Levy, E Perry, MB Cintas, H Paul, SM AF Gabor, Lisa R. Chamberlin, Andrew P. Levy, Ellen Perry, Monique B. Cintas, Holly Paul, Scott M. TI Digital Stereophotogrammetry as a New Technique to Quantify Truncal Deformity A Pilot Study in Persons with Osteogenesis Imperfecta SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Stereophotogrammetry; Anthropometry; Scoliosis; Osteogenesis Imperfecta ID GENETIC-HETEROGENEITY; TORSO DEFORMITIES; SPINAL DEFORMITY; SCOLIOSIS AB Gabor LR, Chamberlin AP, Levy E, Perry MB, Cintas H, Paul SM: Digital stereophotogrammetry as a new technique to quantify truncal deformity: a pilot study in persons with osteogenesis imperfecta. Am J Phys Med Rehabil 2011;90:844-850. The objective of this pilot study was to determine the usability of stereophotogrammetry (SP) as a noninvasive technique for obtaining linear measures and anatomical data of the torso in people with osteogenesis imperfecta in comparison with clinical observations. Ten participants were recruited from subjects enrolled in ongoing institutional review board-approved osteogenesis imperfecta protocols at the National Institute of Child Health and Human Development. Using a Gulick tape measure, anthropometer, and the SP system proprietary software, linear measurements of the torso were taken. In addition, the presence or absence of specific torso deformities was documented from both clinical observation and evaluation of SP images. Measurements of torso diameter and circumference by SP demonstrated strong agreement with the manual measurements (intraclass correlation coefficient = 0.995 and 0.964, respectively). Substantial and statistically significant agreement was present between SP image evaluation and clinical observation for pectus carinatum (kappa = 0.52 +/- 0.23) and thoracic scoliosis (kappa = 0.72 +/- 0.12). The kappa values between clinical observation and SP evaluations of other torso deformities were not significant. The strong correlations and P values determined by this study demonstrate the potential value of SP in studying persons with truncal deformities. However, the weak agreement between SP and some clinical observations suggests that further development of SP image analysis tools is required before SP can be used as a standard method of diagnosis or assessment of treatment success. C1 [Gabor, Lisa R.; Levy, Ellen; Perry, Monique B.; Cintas, Holly; Paul, Scott M.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Chamberlin, Andrew P.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Paul, SM (reprint author), NIH, Dept Rehabil Med, Ctr Clin, Bldg 10 CRC,Room 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. OI Paul, Scott/0000-0003-1274-6670 FU Intramural NIH HHS [Z01 CL060052-10] NR 12 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0894-9115 EI 1537-7385 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD OCT PY 2011 VL 90 IS 10 BP 844 EP 850 DI 10.1097/PHM.0b013e3182240c2c PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 817PI UT WOS:000294685900007 PM 21862911 ER PT J AU Kruth, HS AF Kruth, Howard S. TI Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native low-density lipoprotein particles SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review DE cholesterol; fluid-phase pinocytosis; low-density lipoprotein; macrophages; macropinocytosis ID COLONY-STIMULATING FACTOR; MONOCYTE-DERIVED MACROPHAGES; DENDRITIC CELLS; CHOLESTEROL ACCUMULATION; ATHEROSCLEROTIC LESIONS; REDUCES ATHEROSCLEROSIS; PLASMA-CHOLESTEROL; HUMAN FIBROBLASTS; UP-REGULATION; MACROPINOCYTOSIS AB Purpose of review Because early findings indicated that native low-density lipoprotein (LDL) did not substantially increase macrophage cholesterol content during in-vitro incubations, investigators presumed that LDL must be modified in some way to trigger its uptake by the macrophage. The purpose of this review is to discuss recent findings showing that native unmodified LDL can induce massive macrophage cholesterol accumulation mimicking macrophage foam cell formation that occurs within atherosclerotic plaques. Recent findings Macrophages that show high rates of fluid-phase pinocytosis also show similar high rates of uptake of native unmodified LDL through nonreceptor mediated uptake within both macropinosomes and micropinosomes. Nonsaturable fluid-phase uptake of LDL by macrophages converts the macrophages into foam cells. Different macrophage phenotypes demonstrate either constitutive fluid-phase pinocytosis or inducible fluid-phase pinocytosis. Fluid-phase pinocytosis has been demonstrated by macrophages within mouse atherosclerotic plaques indicating that this pathway contributes to plaque macrophage cholesterol accumulation. Summary Contrary to what has been believed previously, macrophages can take up large amounts of native unmodified LDL by receptor-independent, fluid-phase pinocytosis converting these macrophages into foam cells. Thus, targeting macrophage fluid-phase pinocytosis should be considered when investigating strategies to limit macrophage cholesterol accumulation in atherosclerotic plaques. C1 NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. RP Kruth, HS (reprint author), NHLBI, Sect Expt Atherosclerosis, NIH, Bldg 10,Room 5N113,10 Ctr Dr,MSC-1422, Bethesda, MD 20892 USA. EM kruthh@nhlbi.nih.gov FU National Institutes of Health FX Author acknowledges the intramural research programme of the National Institutes of Health for funding the research, and thanks his research colleagues who have contributed to the investigation of fluid-phase pinocytosis of lipoproteins. NR 59 TC 33 Z9 33 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-9672 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD OCT PY 2011 VL 22 IS 5 BP 386 EP 393 DI 10.1097/MOL.0b013e32834adadb PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA 818CP UT WOS:000294727600009 PM 21881499 ER PT J AU Gavara, N Manoussaki, D Chadwick, RS AF Gavara, Nuria Manoussaki, Daphne Chadwick, Richard S. TI Auditory mechanics of the tectorial membrane and the cochlear spiral SO CURRENT OPINION IN OTOLARYNGOLOGY & HEAD AND NECK SURGERY LA English DT Article DE cochlear mechanics; cochlear spiral; tectorial membrane ID HAIR CELL STEREOCILIA; BASILAR-MEMBRANE; TRAVELING-WAVES; SHAPED COCHLEA; HEARING; MODEL; FREQUENCIES; ANISOTROPY; COILING; BUNDLES AB Purpose of review This review is timely and relevant because new experimental and theoretical findings suggest that cochlear mechanics from the nanoscale to the macroscale are affected by the mechanical properties of the tectorial membrane and the cochlea's spiral shape. Recent findings Main tectorial membrane themes addressed in this review are composition and morphology, nanoscale mechanical interactions with the outer hair cell bundle, macroscale longitudinal coupling, fluid interaction with inner hair cell bundles, and macroscale dynamics and waves. Main cochlear spiral themes are macroscale, low-frequency energy focusing and microscale organ of Corti shear gain. Summary Recent experimental and theoretical findings reveal exquisite sensitivity of cochlear mechanical performance to tectorial membrane structural organization, mechanics, and its positioning with respect to hair bundles. The cochlear spiral geometry is a major determinant of low-frequency hearing. These findings suggest a number of important research directions. C1 [Gavara, Nuria; Chadwick, Richard S.] Natl Inst Deafness & Other Commun Disorders, Auditory Mech Sect, NIH, Bethesda, MD USA. [Manoussaki, Daphne] Tech Univ Crete, Dept Sci, Hania, Greece. RP Chadwick, RS (reprint author), NIDCD, NIH, Bldg 10,Room 5D-49,10 Ctr Dr,MSC 1417, Bethesda, MD 20892 USA. EM chadwick@helix.nih.gov FU National Institute on Deafness and Other Communication Disorders [DC00033-15]; Technical University of Crete FX This work was supported by the intramural program project DC00033-15 in the National Institute on Deafness and Other Communication Disorders. D.M. thanks the Technical University of Crete for their support. The authors thank Tom Friedman and Dennis Drayna for their helpful comments. NR 48 TC 12 Z9 12 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9508 J9 CURR OPIN OTOLARYNGO JI Curr. Opin. Otolaryngol. Head Neck Surg. PD OCT PY 2011 VL 19 IS 5 BP 382 EP 387 DI 10.1097/MOO.0b013e32834a5bc9 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA 817MQ UT WOS:000294678100012 PM 21785353 ER PT J AU Quan, QM Yang, M Gao, HK Zhu, L Lin, X Guo, N Zhang, GX Eden, HS Niu, G Chen, XY AF Quan, Qimeng Yang, Min Gao, Haokao Zhu, Lei Lin, Xin Guo, Ning Zhang, Guixiang Eden, Henry S. Niu, Gang Chen, Xiaoyuan TI Imaging tumor endothelial marker 8 using an F-18-labeled peptide SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE Tumor endothelial marker 8 (TEM8); Small-animal PET; F-18; Peptide ID ANTHRAX TOXIN RECEPTOR; PROTECTIVE ANTIGEN; BINDING; CELL; EXPRESSION; ANTIBODY; THERAPY; CANCER; ANGIOGENESIS; TARGET AB Tumor endothelial marker 8 (TEM8) has been reported to be upregulated in both tumor cells and tumor-associated endothelial cells in several cancer types. TEM8 antagonists and TEM8-targeted delivery of toxins have been developed as effective cancer therapeutics. The ability to image TEM8 expression would be of use in evaluating TEM8-targeted cancer therapy. A 13-meric peptide, KYNDRLPLYISNP (QQM), identified from the small loop in domain IV of protective antigen of anthrax toxin was evaluated for TEM8 binding and labeled with F-18 for small-animal PET imaging in both UM-SCC1 head-and-neck cancer and MDA-MB-435 melanoma models. A modified ELISA showed that QQM peptide bound specifically to the extracellular vWA domain of TEM8 with an IC50 value of 304 nM. Coupling 4-nitrophenyl 2-F-18-fluoropropionate with QQM gave almost quantitative yield and a high specific activity (79.2 +/- 7.4 TBq/mmol, n = 5) of F-18-FP-QQM at the end of synthesis. F-18-FP-QQM showed predominantly renal clearance and had significantly higher accumulation in TEM8 high-expressing UM-SCC1 tumors (2.96 +/- 0.84 %ID/g at 1 h after injection) than TEM8 low-expressing MDA-MB-435 tumors (1.38 +/- 0.56 %ID/g at 1 h after injection). QQM peptide bound specifically to the extracellular domain of TEM8. F-18-FP-QQM peptide tracer would be a promising lead compound for measuring TEM8 expression. Further efforts to improve the affinity and specificity of the tracer and to increase its metabolic stability are warranted. C1 [Niu, Gang] NIH, Imaging Sci Training Program Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Quan, Qimeng; Yang, Min; Gao, Haokao; Zhu, Lei; Lin, Xin; Guo, Ning; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Quan, Qimeng; Zhang, Guixiang] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 1, Dept Radiol, Shanghai 200080, Peoples R China. [Eden, Henry S.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Niu, G (reprint author), NIH, Imaging Sci Training Program Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM niug@mail.nih.gov; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health (NIH); National Science Foundation of China (NSFC) [81028009]; China Scholarship Council (CSC); Radiology and Imaging Sciences Department; NIH Clinical Center; NIBIB, NIH FX This project was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), and the International Cooperative Program of the National Science Foundation of China (NSFC) (81028009). Q.Q. is partially supported by the China Scholarship Council (CSC). G.N. currently is an Imaging Sciences Training Program (ISTP) Fellow jointly supported by the Radiology and Imaging Sciences Department, NIH Clinical Center, and the Intramural Research Program, NIBIB, NIH. NR 29 TC 7 Z9 7 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD OCT PY 2011 VL 38 IS 10 BP 1806 EP 1815 DI 10.1007/s00259-011-1871-4 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 817OT UT WOS:000294684400004 PM 21814853 ER PT J AU Schumacher, FR Berndt, SI Siddiq, A Jacobs, KB Wang, ZM Lindstrom, S Stevens, VL Chen, C Mondul, AM Travis, RC Stram, DO Eeles, RA Easton, DF Giles, G Hopper, JL Neal, DE Hamdy, FC Donovan, JL Muir, K Al Olama, AA Kote-Jarai, Z Guy, M Severi, G Gronberg, H Isaacs, WB Karlsson, R Wiklund, F Xu, JF Allen, NE Andriole, GL Barricarte, A Boeing, H Bueno-de-Mesquita, HB Crawford, ED Diver, WR Gonzalez, CA Gaziano, JM Giovannucci, EL Johansson, M Le Marchand, L Ma, J Sieri, S Stattin, P Stampfer, MJ Tjonneland, A Vineis, P Virtamo, J Vogel, U Weinstein, SJ Yeager, M Thun, MJ Kolonel, LN Henderson, BE Albanes, D Hayes, RB Feigelson, HS Riboli, E Hunter, DJ Chanock, SJ Haiman, CA Kraft, P AF Schumacher, Fredrick R. Berndt, Sonja I. Siddiq, Afshan Jacobs, Kevin B. Wang, Zhaoming Lindstrom, Sara Stevens, Victoria L. Chen, Constance Mondul, Alison M. Travis, Ruth C. Stram, Daniel O. Eeles, Rosalind A. Easton, Douglas F. Giles, Graham Hopper, John L. Neal, David E. Hamdy, Freddie C. Donovan, Jenny L. Muir, Kenneth Al Olama, Ali Amin Kote-Jarai, Zsofia Guy, Michelle Severi, Gianluca Gronberg, Henrik Isaacs, William B. Karlsson, Robert Wiklund, Fredrik Xu, Jianfeng Allen, Naomi E. Andriole, Gerald L. Barricarte, Aurelio Boeing, Heiner Bueno-de-Mesquita, H. Bas Crawford, E. David Diver, W. Ryan Gonzalez, Carlos A. Gaziano, J. Michael Giovannucci, Edward L. Johansson, Mattias Le Marchand, Loic Ma, Jing Sieri, Sabina Stattin, Par Stampfer, Meir J. Tjonneland, Anne Vineis, Paolo Virtamo, Jarmo Vogel, Ulla Weinstein, Stephanie J. Yeager, Meredith Thun, Michael J. Kolonel, Laurence N. Henderson, Brian E. Albanes, Demetrius Hayes, Richard B. Feigelson, Heather Spencer Riboli, Elio Hunter, David J. Chanock, Stephen J. Haiman, Christopher A. Kraft, Peter TI Genome-wide association study identifies new prostate cancer susceptibility loci SO HUMAN MOLECULAR GENETICS LA English DT Article ID RISK-ASSOCIATED LOCI; AGGRESSIVENESS LOCI; SEQUENCE VARIANTS; COMMON VARIANT; MULTIPLE LOCI; SCAN; GENE; 8Q24; REPLICATION; SURVIVAL AB Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade >= 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P = 4.3 x 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P = 8.6 x 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P = 0.72 and P = 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes. C1 [Lindstrom, Sara; Chen, Constance; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Schumacher, Fredrick R.; Stram, Daniel O.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Berndt, Sonja I.; Jacobs, Kevin B.; Wang, Zhaoming; Mondul, Alison M.; Weinstein, Stephanie J.; Yeager, Meredith; Albanes, Demetrius; Hayes, Richard B.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Siddiq, Afshan; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC HPA Ctr Environm & Hlth, London, England. [Jacobs, Kevin B.; Wang, Zhaoming] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv, Gaithersburg, MD USA. [Lindstrom, Sara; Chen, Constance; Giovannucci, Edward L.; Stampfer, Meir J.; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Stevens, Victoria L.; Diver, W. Ryan; Thun, Michael J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Travis, Ruth C.; Allen, Naomi E.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Travis, Ruth C.; Allen, Naomi E.] Univ Oxford, Nuffield Dept Clin Med, Oxford, England. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Eeles, Rosalind A.; Kote-Jarai, Zsofia; Guy, Michelle] Inst Canc Res, Oncogenet Team, Sutton, Surrey, England. [Easton, Douglas F.; Al Olama, Ali Amin] Univ Cambridge, Ctr Canc Genet Epidemiol, Cambridge, England. [Easton, Douglas F.; Al Olama, Ali Amin] Univ Cambridge, Dept Publ Hlth, Cambridge, England. [Easton, Douglas F.; Al Olama, Ali Amin] Univ Cambridge, Dept Primary Care, Cambridge, England. [Easton, Douglas F.; Neal, David E.] Univ Cambridge, Dept Oncol, Cambridge, England. [Giles, Graham; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Hopper, John L.] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt MEGA Epidemiol, Melbourne, Vic, Australia. [Donovan, Jenny L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Muir, Kenneth] Univ Warwick, Hlth Sci Res Inst, Coventry CV4 7AL, W Midlands, England. [Gronberg, Henrik; Karlsson, Robert; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Isaacs, William B.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. [Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Barricarte, Aurelio] Navarre Publ Hlth Inst, Pamplona, Spain. [Boeing, Heiner] Deutsch Inst Ernahrungsforsch, Dept Epidemiol, Potsdam, Germany. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Crawford, E. David] Univ Colorado, Aurora, CO USA. [Gonzalez, Carlos A.] Catalan Inst Oncol ICO IDIBELL RETICC RD06 0020, Unit Nutr Environm & Canc, Barcelona, Spain. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Ma, Jing; Stampfer, Meir J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, VA Cooperat Studies Programs, Boston, MA USA. [Gaziano, J. Michael; Ma, Jing; Stampfer, Meir J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Johansson, Mattias] Int Agcy Res Canc, F-69372 Lyon, France. [Johansson, Mattias; Stattin, Par] Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden. [Le Marchand, Loic; Kolonel, Laurence N.] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Ma, Jing; Stampfer, Meir J.] Channing Labs, Boston, MA USA. [Sieri, Sabina] Fdn IRCCS Ist Nazl Tumori, Nutr Epidemiol Unit, Milan, Italy. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Vogel, Ulla] Natl Res Ctr Working Environm, Copenhagen, Denmark. [Vogel, Ulla] Tech Univ Denmark, Natl Food Inst, Soborg, Denmark. [Hayes, Richard B.] NYU, Dept Environm Med, Inst Canc, Div Epidemiol,Langone Med Ctr, New York, NY 10016 USA. [Feigelson, Heather Spencer] Kaiser Permanente, Inst Hlth Res, Denver, CO USA. RP Kraft, P (reprint author), Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA. EM pkraft@hsph.harvard.edu RI Gonzalez, Carlos A/O-4651-2014; Albanes, Demetrius/B-9749-2015; Sieri, Sabina/K-4667-2016; Vogel, Ulla/I-5048-2012; OI Karlsson, Robert/0000-0002-8949-2587; Gonzalez, Carlos A/0000-0003-2822-9715; Sieri, Sabina/0000-0001-5201-172X; Vogel, Ulla/0000-0001-6807-1524; Eeles, Rosalind/0000-0002-3698-6241; Neal, David/0000-0002-6033-5086; Hayes, Richard/0000-0002-0918-661X; Mondul, Alison/0000-0002-8843-1416; Giles, Graham/0000-0003-4946-9099 FU U.S. National Institutes of Health, National Cancer Institute [U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758]; NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics); Cancer Research UK [C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135, C522/A8649]; Institute of Cancer Research and The Everyman Campaign; Prostate Cancer Research Foundation; Prostate Research Campaign UK; National Cancer Research Network UK; National Cancer Research Institute (NCRI) UK; NIHR Biomedical Research Centre at The Institute of Cancer Research; Royal Marsden NHS Foundation Trust; National Health and Medical Research Council, Australia [209057, 251533, 450104, 390130]; VicHealth; Cancer Council Victoria; Cancer Council Queensland; Whitten Foundation; Tattersall's; Health Technology Assessment Programme [96/20/06, 96/20/99]; Department of Health, England; Medical Research Council of England [G0500966, ID 75466]; NCRI, UK; Southwest National Health Service Research and Development; USA Dept of Defense [W81XWH-04-1-0280]; Yorkshire Cancer Research and Cancer Research UK; NCRI; NIHR; Swedish Research Council [K2010-70X-20430-04-3, 70867901]; Swedish Cancer Foundation [09-0677]; Hedlund Foundation; Soderberg Foundation; Enqvist Foundation; Stockholm County Council; National Cancer Institute [CA112517, CA133009] FX The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to M.J.T., U01-CA98216 to E.R., and U01-CA98758 to B.E.H., and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). This work was supported by Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135, and C16913/A6835. We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We acknowledge NHS funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. We also acknowledge grant support from The National Health and Medical Research Council, Australia (209057, 251533, 450104, 390130), VicHealth, The Cancer Council Victoria, Cancer Council Queensland, The Whitten Foundation, and Tattersall's. The ProtecT study is ongoing and is funded by the Health Technology Assessment Programme (projects 96/20/06, 96/20/99). The ProtecT trial and its linked ProMPT and CAP (Comparison Arm for ProtecT) studies are supported by Department of Health, England; Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466 and The NCRI, UK. The epidemiological data for ProtecT were generated though funding from the Southwest National Health Service Research and Development. DNA extraction in ProtecT was supported by USA Dept of Defense award W81XWH-04-1-0280, Yorkshire Cancer Research and Cancer Research UK. The bio-repository from ProtecT is supported by the NCRI (ProMPT) study and the Cambridge BMRC grant from NIHR. Financial support for CAPS was provided through a grant from the Swedish Research Council (grant no K2010-70X-20430-04-3 and 70867901), the Swedish Cancer Foundation (grant no 09-0677), the Hedlund Foundation, Soderberg Foundation, Enqvist Foundation, ALF funds from the Stockholm County Council. W.B.I. was supported by National Cancer Institute grants CA112517 and CA133009. NR 41 TC 93 Z9 94 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2011 VL 20 IS 19 BP 3867 EP 3875 DI 10.1093/hmg/ddr295 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 819FE UT WOS:000294810000014 PM 21743057 ER PT J AU Major, JM Yu, K Wheeler, W Zhang, H Cornelis, MC Wright, ME Yeager, M Snyder, K Weinstein, SJ Mondul, A Eliassen, H Purdue, M Hazra, A McCarty, CA Hendrickson, S Virtamo, J Hunter, D Chanock, S Kraft, P Albanes, D AF Major, Jacqueline M. Yu, Kai Wheeler, William Zhang, Hong Cornelis, Marilyn C. Wright, Margaret E. Yeager, Meredith Snyder, Kirk Weinstein, Stephanie J. Mondul, Alison Eliassen, Heather Purdue, Mark Hazra, Aditi McCarty, Catherine A. Hendrickson, Sara Virtamo, Jarmo Hunter, David Chanock, Stephen Kraft, Peter Albanes, Demetrius TI Genome-wide association study identifies common variants associated with circulating vitamin E levels SO HUMAN MOLECULAR GENETICS LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; CLINICAL-TRIAL DATA; ALPHA-TOCOPHEROL; CARDIOVASCULAR-DISEASE; GENETIC-DETERMINANTS; ANTIOXIDANT VITAMINS; PLASMA TRIGLYCERIDES; INSULIN-RESISTANCE; LOCI; CANCER AB In genome-wide association studies (GWAS) of common genetic variants associated with circulating alpha- and gamma-tocopherol concentrations in two adult cohorts comprising 5006 men of European descent, we observed three loci associated with alpha-tocopherol levels, two novel single-nucleotide polymorphisms (SNPs), rs2108622 on 19pter-p13.11 (P = 1.7 x 10(-8)) and rs11057830 on 12q24.31 (P = 2.0 x 10(-8)) and confirmed a previously reported locus marked by rs964184 on 11q23.3 (P = 2.7 x 10(-10)). The three SNPs have been reported to be associated with lipid metabolism and/or regulation. We replicated these findings in a combined meta-analysis with two independent samples, P = 7.8 x 10(-12) (rs964184 on 11q23.3 near BUD13, ZNF259 and APOA1/C3/A4/A5), P = 1.4 x 10(-10) (rs2108622 on 19pter-p13.11 near CYP4F2) and P = 8.2 x 10(-9) (rs11057830 on 12q24.31 near SCARB1). Combined, these SNPs explain 1.7% of the residual variance in log alpha-tocopherol levels. In one of the two male GWAS cohorts (n = 992), no SNPs were significantly associated with gamma-tocopherol concentrations after including data from the replication sample for 71 independent SNPs with P < 1 x 10(-4) identified. C1 [Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, EPS 320, NIH, Bethesda, MD 20852 USA. [Yeager, Meredith] NCI, Core Genotyping Facil, NIH, Bethesda, MD 20852 USA. [Wheeler, William; Snyder, Kirk] Informat Management Serv Inc, Silver Spring, MD USA. [Zhang, Hong] Fudan Univ, Sch Life Sci, Inst Biostat, Shanghai 200433, Peoples R China. [Cornelis, Marilyn C.; Hendrickson, Sara; Hunter, David] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hazra, Aditi; Hunter, David; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Hendrickson, Sara; Hunter, David; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wright, Margaret E.] Univ Illinois, Dept Pathol, Chicago, IL USA. [Eliassen, Heather] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. [McCarty, Catherine A.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP Albanes, D (reprint author), NCI, Div Canc Epidemiol & Genet, EPS 320, NIH, Bethesda, MD 20852 USA. EM daa@nih.gov RI Albanes, Demetrius/B-9749-2015; OI Mondul, Alison/0000-0002-8843-1416 FU National Institutes of Health; National Cancer Institute; National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; NIH [5 T32 CA09001-35, R01 CA131218]; US National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX This work was supported in part by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. Additionally, the research was supported by Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C) from the National Cancer Institute, Department of Health and Human Services. S.H. is supported in part by training grant NIH 5 T32 CA09001-35. H.E. is supported in part by grant NIH R01 CA131218.; Funding to pay the Open Access publication charges for this article was provided by the Intramural Program of the US National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 41 TC 32 Z9 34 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2011 VL 20 IS 19 BP 3876 EP 3883 DI 10.1093/hmg/ddr296 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 819FE UT WOS:000294810000015 PM 21729881 ER PT J AU Canhamero, T Reines, B Peters, LC Borrego, A Carneiro, PS Albuquerque, LL Cabrera, WH Ribeiro, OG Jensen, JR Starobinas, N Ibanez, OM De Franco, M AF Canhamero, Tatiane Reines, Brandon Peters, Luciana C. Borrego, Andrea Carneiro, Patricia S. Albuquerque, Layra L. Cabrera, Wafa H. Ribeiro, Orlando G. Jensen, Jose R. Starobinas, Nancy Ibanez, Olga M. De Franco, Marcelo TI Distinct Early Inflammatory Events during Ear Tissue Regeneration in Mice Selected for High Inflammation Bearing Slc11a1 R and S Alleles SO INFLAMMATION LA English DT Article DE acute inflammation; ear regeneration; Slc11a1 gene; mouse ID PRISTANE-INDUCED ARTHRITIS; QUANTITATIVE TRAIT LOCI; MRL MOUSE; GENE-EXPRESSION; NITRIC-OXIDE; NRAMP1 GENE; RESPONSIVENESS; MODEL; INFECTION; LINES AB High inflammatory AIRmax mice homozygous for Slc11a1 R and S alleles were produced. AIRmax (SS) mice showed faster ear tissue regeneration than AIRmax (RR) mice, suggesting that the S allele favored tissue restoration. Here, we investigated the gene expression profiles and the inflammatory reactions of AIRmax (RR) and AIRmax (SS) mice during the initial phase of ear tissue regeneration. We observed superior levels of analysis of wound myeloperoxidase and edema in AIRmax (SS) mice, although similar cell influx was verified in both lines. Of the genes, 794 were up- and 674 down-regulated in AIRmax (RR) , while 735 genes were found to be up- and 1616 down-regulated in AIRmax (SS) mice 48 h after punch. Both mouse lines showed significant over-represented genes related to cell proliferation; however AIRmax (SS) displayed up-regulation of inflammatory response genes. Quantitative PCR experiments showed higher expressions of Tgfb1, Dap12 and Trem1 genes in AIRmax (SS) mice. These results indicate that Slc11a1 gene modulated the early inflammatory events of ear tissue regeneration. C1 [Canhamero, Tatiane; Peters, Luciana C.; Borrego, Andrea; Carneiro, Patricia S.; Albuquerque, Layra L.; Cabrera, Wafa H.; Ribeiro, Orlando G.; Jensen, Jose R.; Starobinas, Nancy; Ibanez, Olga M.; De Franco, Marcelo] Inst Butantan, Lab Imunogenet, Sao Paulo, Brazil. [Reines, Brandon] NIAID, Ghost Lab, Lab Cellular & Mol Immunol, NIH, Bethesda, MD 20892 USA. RP De Franco, M (reprint author), Av Vital Brasil 1500, BR-05503900 Sao Paulo, Brazil. EM mdfranco@butantan.gov.br RI Borrego, Andrea/E-2234-2012; Starobinas, Nancy/B-9178-2015; Ibanez, Olga/B-9627-2015; Ribeiro, Orlando/B-5241-2016; Jensen, Jose/F-2927-2017 OI Jensen, Jose/0000-0001-6228-2988 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) FX This work was supported by grants from the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) and the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). NR 49 TC 1 Z9 1 U1 0 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-3997 J9 INFLAMMATION JI Inflammation PD OCT PY 2011 VL 34 IS 5 BP 303 EP 313 DI 10.1007/s10753-010-9235-y PG 11 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 819JC UT WOS:000294820200001 PM 20665098 ER PT J AU Kim, FM Hayes, C Williams, PL Whitford, GM Joshipura, KJ Hoover, RN Douglass, CW AF Kim, F. M. Hayes, C. Williams, P. L. Whitford, G. M. Joshipura, K. J. Hoover, R. N. Douglass, C. W. CA Natl Osteosarcoma Etiology Grp TI An Assessment of Bone Fluoride and Osteosarcoma SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE fluoride; osteosarcoma; case-control study; bone; oncology; epidemiology ID DRINKING-WATER FLUORIDATION; CANCER; AGE; EXPOSURE; CHILDREN; SARCOMA; TRENDS; RATES AB The association between fluoride and risk for osteosarcoma is controversial. The purpose of this study was to determine if bone fluoride levels are higher in individuals with osteosarcoma. Incident cases of osteosarcoma (N = 137) and tumor controls (N = 51) were identified by orthopedic physicians, and segments of tumor-adjacent bone and iliac crest bone were analyzed for fluoride content. Logistic regression adjusted for age and sex and potential confounders of osteosarcoma was used to estimate odds ratios (OR) and 95% confidence intervals (CI). There was no significant difference in bone fluoride levels between cases and controls. The OR adjusted for age, gender, and a history of broken bones was 1.33 (95% CI: 0.56-3.15). No significant association between bone fluoride levels and osteosarcoma risk was detected in our case-control study, based on controls with other tumor diagnoses. C1 [Kim, F. M.; Douglass, C. W.] Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA 02115 USA. [Kim, F. M.] Harvard Univ, Sch Dent Med, Dept Epidemiol, Boston, MA 02115 USA. [Hayes, C.] Tufts Med Ctr, Frances Stern Nutr Ctr, Boston, MA USA. [Williams, P. L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Whitford, G. M.] Med Coll Georgia, Sch Dent, Dept Oral Biol, Augusta, GA 30912 USA. [Joshipura, K. J.] Univ Puerto Rico, Sch Dent Med, Ctr Clin Res & Hlth Promot, San Juan, PR 00936 USA. [Hoover, R. N.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Douglass, C. W.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Douglass, CW (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, 188 Longwood Ave, Boston, MA 02115 USA. EM chester_douglass@hsdm.harvard.edu OI Joshipura, Kaumudi/0000-0003-1964-7579 FU National Institute of Environmental Health Sciences, National Institutes of Health (NIH) [5R01ESO6000]; National Institute of Dental and Craniofacial Research (NIH) [T32DE07151]; National Cancer Institute (NIH) FX The authors acknowledge the participation of the patients, hospitals, and surgeons in this study. This study was funded by the National Institute of Environmental Health Sciences, National Institutes of Health (NIH) grant 5R01ESO6000, National Institute of Dental and Craniofacial Research (NIH) grant T32DE07151, and National Cancer Institute (NIH). Data collection was conducted by Westat, Inc. This manuscript is based on a dissertation submitted to the faculty of the Harvard School of Public Health in partial fulfillment of the requirements for the degree of DrPH in the Department of Epidemiology (FMK). A portion was presented at the American Public Health Association 134th Annual Meeting and Exhibition, Boston, MA, 2006 (FMK). NR 30 TC 13 Z9 14 U1 1 U2 21 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD OCT PY 2011 VL 90 IS 10 BP 1171 EP 1176 DI 10.1177/0022034511418828 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 819PF UT WOS:000294838200004 PM 21799046 ER PT J AU Faruque, MU Chen, GJ Doumatey, A Huang, HX Zhou, J Dunston, GM Rotimi, CN Adeyemo, AA AF Faruque, Mezbah U. Chen, Guanjie Doumatey, Ayo Huang, Hanxia Zhou, Jie Dunston, Georgia M. Rotimi, Charles N. Adeyemo, Adebowale A. TI Association of ATP1B1, RGS5 and SELE polymorphisms with hypertension and blood pressure in African-Americans SO JOURNAL OF HYPERTENSION LA English DT Article DE African-Americans; candidate gene; haplotype; hypertension; single nucleotide polymorphism ID GENOME-WIDE ASSOCIATION; UNITED-STATES ADULTS; POPULATION; NA,K-ATPASE; PREVALENCE; AWARENESS; DISEASES; BURDEN; GENES; SCANS AB Objective Although an increasing number of whypertension-associated genetic variants is being reported, replication of these findings in independent studies has been challenging. Several genes in a human chromosome 1q linkage region have been reported to be associated with hypertension. We examined polymorphisms in three of these genes (ATP1B1, RGS5 and SELE) in relation to hypertension and blood pressure in a cohort of African-Americans. Methods We genotyped 87 single nucleotide polymorphisms (SNPs) from the ATP1B1, RGS5 and SELE genes in a well characterized cohort of 968 African-Americans and performed a case-control study to identify susceptibility alleles for hypertension and blood pressure regulation. Single SNP and haplotype association testing was done under an additive genetic model with adjustment for age, sex, BMI and ancestry-by-genotype (principal components). Results A total of 12 SNPs showed nominal association with hypertension and/or blood pressure. The strongest signal for hypertension was for rs2815272 in the RGS5 gene (P= 9.3 X 10(-3)). For SBP, rs3917420 in the SELE gene (P= 9.0 X 10(-4)) and rs4657251 in the RGS5 gene (P= 9.7 X 10(-3)) were the top hits. Effect size for each of these variants was approximately 2-3 mmHg. A five-SNP haplotype in the SELE gene also showed significant association with SBP after correction for multiple testing (P < 0.01). Conclusion These findings provide additional support for the genetic role of ATP1B1, RGS5 and SELE in hypertension and blood pressure regulation. J Hypertens 29:1906-1912 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Chen, Guanjie; Doumatey, Ayo; Huang, Hanxia; Zhou, Jie; Rotimi, Charles N.; Adeyemo, Adebowale A.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Faruque, Mezbah U.; Dunston, Georgia M.] Howard Univ, Coll Med, Natl Human Genome Ctr, Washington, DC USA. RP Adeyemo, AA (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bldg 12A,Room 4047,12 South Dr,MSC 5635, Bethesda, MD 20892 USA. EM adeyemoa@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU The Howard University Family Study (HUFS) [S06GM008016-380111, S06GM008016-320107]; National Institute of General Medical Sciences; National Institutes of Health (NIH) [2M01RR010284, RR003048, Z01HG200362]; National Center for Research Resources (NCRR), NIH [2M01RR010284]; Howard University; Division of Research Infrastructure, NCRR, NIH [RR003048]; Center for Research on Genomics and Global Health (CRGGH); National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the NIH [Z01HG200362] FX The Howard University Family Study (HUFS) was supported by grants S06GM008016-380111 to A.A.A. and S06GM008016-320107 to C.N.R., both from the MBRS/SCORE Program of the National Institute of General Medical Sciences, National Institutes of Health (NIH). Participant enrollment for the HUFS was carried out at the Howard University General Clinical Research Center, which is supported by grant 2M01RR010284 from the National Center for Research Resources (NCRR), NIH. This research was supported in part by the RCMI Program at Howard University funded by the Division of Research Infrastructure, NCRR, NIH (RR003048) and by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the NIH (Z01HG200362). NR 43 TC 15 Z9 15 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD OCT PY 2011 VL 29 IS 10 BP 1906 EP 1912 DI 10.1097/HJH.0b013e32834b000d PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 817ZU UT WOS:000294718500011 PM 21881522 ER PT J AU Glass, RI AF Glass, Roger I. TI Unexpected Benefits of Rotavirus Vaccination in the United States SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID ACUTE GASTROENTERITIS; REDUCTION; EFFICACY; CHILDREN; VACCINES; INFANTS; SAFETY C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Glass, RI (reprint author), NIH, Fogarty Int Ctr, Bldg 31,Room B2C02, Bethesda, MD 20892 USA. EM glassr@mail.nih.gov NR 20 TC 11 Z9 12 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2011 VL 204 IS 7 BP 975 EP 977 DI 10.1093/infdis/jir477 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 816KA UT WOS:000294595900001 PM 21878426 ER PT J AU Gautam, S Kumar, R Maurya, R Nylen, S Ansari, N Rai, M Sundar, S Sacks, D AF Gautam, Shalini Kumar, Rajiv Maurya, Radheshyam Nylen, Susanne Ansari, Nasim Rai, Madhukar Sundar, Shyam Sacks, David TI IL-10 Neutralization Promotes Parasite Clearance in Splenic Aspirate Cells From Patients With Visceral Leishmaniasis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID REGULATORY T-CELLS; IMMUNE-RESPONSES; INTERLEUKIN-10; TUBERCULOSIS; INFECTION AB The mechanisms underlying the failure to contain the growth of Leishmania parasites in human visceral leishmaniasis (VL) are not understood. L donovani amastigotes were quantified in cultured splenic aspirate cells to assess the function of IL-10 in lesional tissue ex vivo. In 67 patients with active VL, IL-10 neutralization promoted parasite killing in 73% and complete clearance in 30%, while 18% had more parasites and 9% did not change. The splenic cells secreted increased levels of both tumor necrosis factor a (TNF alpha) and interferon gamma (IFN gamma) under IL-10-neutralizing conditions. These findings provide direct support for targeting IL-10 as an approach to therapy in human VL. C1 [Nylen, Susanne; Ansari, Nasim; Sacks, David] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Gautam, Shalini; Kumar, Rajiv; Maurya, Radheshyam; Rai, Madhukar; Sundar, Shyam] Banaras Hindu Univ, Inst Med Sci, Dept Med, Varanasi 221005, Uttar Pradesh, India. [Maurya, Radheshyam] Univ Hyderabad, Dept Anim Sci, Sch Life Sci, Hyderabad 500134, Andhra Pradesh, India. [Nylen, Susanne] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. RP Sacks, D (reprint author), NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dsacks@nih.gov OI Nylen, Susanne/0000-0002-3875-3353; Kumar, Rajiv/0000-0003-2338-1494 FU National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID); NIAID, NIH Tropical Medicine Research Centers (TMRC) [1P50AI074321]; NIAID, NIH, USA; Indian Council of Medical Research (ICMR; New Delhi, India); Swedish Society for Medicine; Sitaram Memorial Trust, Muzaffarpur, India FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID); by NIAID, NIH Tropical Medicine Research Centers (TMRC; grant 1P50AI074321), Extramural Research Program of the NIAID, NIH, USA; by the Indian Council of Medical Research (ICMR; New Delhi, India); and by the Swedish Society for Medicine.; We thank the hospital staff at the Kala-azar Medical Research Center, Muzaffarpur, for their assistance in the collection of patient samples. The care of the patients was supported by the Sitaram Memorial Trust, Muzaffarpur, India. NR 15 TC 56 Z9 56 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 1 PY 2011 VL 204 IS 7 BP 1134 EP 1137 DI 10.1093/infdis/jir461 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 816KA UT WOS:000294595900022 PM 21881130 ER PT J AU Campbell, J AF Campbell, Joseph TI What I Learned from Howard about Using Genetics to Study the Anesthesia Response in Flies SO JOURNAL OF NEUROGENETICS LA English DT Editorial Material ID GENERAL-ANESTHETICS; DROSOPHILA-MELANOGASTER C1 NIAID, Biodef Res Resources Sect, OBRA, DMID, Bethesda, MD 20892 USA. RP Campbell, J (reprint author), NIAID, Biodef Res Resources Sect, OBRA, DMID, 6610 Rockledge Dr,Room 3604, Bethesda, MD 20892 USA. EM josephca@mail.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0167-7063 J9 J NEUROGENET JI J. Neurogenet. PD OCT PY 2011 VL 25 IS 3 BP 69 EP 71 PG 3 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 819XG UT WOS:000294867000004 ER PT J AU Sandstrom, D AF Sandstrom, David TI Howard Nash: You Need More Than Talent SO JOURNAL OF NEUROGENETICS LA English DT Editorial Material ID DROSOPHILA-MELANOGASTER; ION-CHANNEL; EXCITABILITY; SENSITIVITY; ANESTHESIA; SODIUM C1 NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sandstrom, D (reprint author), NIMH, Mol Biol Lab, NIH, MSC 3736, Bethesda, MD 20892 USA. EM sandstrd@mail.nih.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0167-7063 J9 J NEUROGENET JI J. Neurogenet. PD OCT PY 2011 VL 25 IS 3 BP 72 EP 75 PG 4 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 819XG UT WOS:000294867000006 ER PT J AU Sandstrom, DJ AF Sandstrom, David J. TI Extracellular Protons Reduce Quantal Content and Prolong Synaptic Currents at the Drosophila Larval Neuromuscular Junction SO JOURNAL OF NEUROGENETICS LA English DT Article DE acidosis; alkalosis; decay kinetics; glutamate release; pH; synaptic depression; trpml ID CARBON-DIOXIDE; RECEPTOR CHANNELS; WILD-TYPE; GLUTAMATE; CELLS; ACIDIFICATION; MUTANTS; RAT; EXCITABILITY; TRANSMITTER AB Fluctuations in extracellular pH occur in the nervous system in response to a number of physiological and pathological processes, such as ischemia, hypercapnea, and high-frequency activity. Using the Drosophila larval neuromuscular junction, the author has examined acute effects of low and high pH on excitability and synaptic transmission. Acidification rapidly and reversibly reduces the size of electrically evoked excitatory junctional currents (EJCs) in a concentration-dependent manner, with transmission nearly abolished at pH 5.0. Conversely, raising pH to 7.8 increases EJC amplitude significantly. Further elevation to pH 8.5 causes an initial increase in amplitude, followed by profound, long-lasting depression of the synapse. Amplitudes of spontaneous miniature EJCs (mEJCs) are modestly, but significantly reduced at pH 5.0. It is therefore the number of quanta released per action potential, rather than the size of individual quanta, that is most strongly affected. Decay times of both EJCs and mEJCs are dramatically lengthened at low pH, suggesting that glutamate remains in the synaptic cleft for much longer than normal. Presynaptic excitability is also reduced, as indicated by increased latency between nerve shock and EJC onset. The response to low pH was not altered by mutations in genes encoding Transient Receptor Potential, Mucolipin subfamily (TRPML) and Slowpoke ion channels, which had previously been implicated as possible targets of extracellular protons. The author concludes that extracellular protons have strong effects on the release of glutamate and the time course of synaptic currents. These phenotypes can be exploited to study the mechanisms of acid-mediated changes in neuronal function, and to pursue the way in which pH modulates synaptic function in normal and pathophysiological conditions. C1 NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sandstrom, DJ (reprint author), NIMH, Mol Biol Lab, NIH, MSC 3736, Bethesda, MD 20892 USA. EM sandstrd@mail.nih.gov FU NIMH, NIH FX This research was supported by the Intramural Program of NIMH, NIH. The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper. NR 41 TC 2 Z9 2 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0167-7063 J9 J NEUROGENET JI J. Neurogenet. PD OCT PY 2011 VL 25 IS 3 BP 104 EP 114 DI 10.3109/01677063.2011.606577 PG 11 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 819XG UT WOS:000294867000011 PM 21877902 ER PT J AU Djamshidian, A O'Sullivan, SS Papadopoulos, A Bassett, P Shaw, K Averbeck, BB Lees, A AF Djamshidian, Atbin O'Sullivan, Sean S. Papadopoulos, Andrew Bassett, Paul Shaw, Karen Averbeck, Bruno B. Lees, Andrew TI Salivary cortisol levels in Parkinson's disease and its correlation to risk behaviour SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID STRESS; SECRETION; GAMBLERS; COCAINE; NEUROENDOCRINE; DYSREGULATION; AGGRESSION; ADDICTION; DISORDER; HUMANS AB Objective To investigate salivary cortisol samples in patients with Parkinson's disease (PD) with and without impulsive compulsive behaviours (ICB) during a risk task. Methods Salivary cortisol levels were measured in 13 PD patients without ICB (PD-ICB) and in 15 PD patients with ICB (PD+ICB) before, after medication and throughout the day, and were compared with results with 14 healthy controls. All participants also performed a gambling task to assess risk taking behaviour. Results Significantly higher diurnal cortisol levels were found in the PD-ICB group compared with healthy controls but no differences were seen between the PD+ICB and the control group. Increased cortisol levels were significantly correlated with increased risk taking in PD+ICB patients but no interaction was found in the PD-ICB group. Conclusions The findings are in keeping with previous studies which have linked low cortisol levels with antisocial behaviour. The higher cortisol levels during the risk task in the PD+ICB group are consistent with reports in pathological gamblers during gambling and addicts during drug abuse. The results support the hypothesis that cortisol plays an important role in risk taking in ICBs. C1 [Lees, Andrew] UCL, Reta Lila Weston Inst Neurol Studies, UCL Inst Neurol, London WC1N 1PJ, England. [Djamshidian, Atbin; O'Sullivan, Sean S.; Shaw, Karen; Lees, Andrew] UCL, Queen Sq Brain Bank Neurol Dis, London WC1N 1PJ, England. [Papadopoulos, Andrew] S London & Maudsley NHS Fdn Trust, Natl Affect Disorders Unit, Beckenham, Kent, England. [Bassett, Paul] UCL UCLH Royal Free, Biomed Res Unit, London, England. [Averbeck, Bruno B.] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 1PJ, England. [Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Lees, A (reprint author), UCL, Reta Lila Weston Inst Neurol Studies, UCL Inst Neurol, 1 Wakefield St, London WC1N 1PJ, England. EM alees@ion.ucl.ac.uk RI O'Sullivan, Sean/C-9333-2012; Lees, Andrew/A-6605-2009 OI O'Sullivan, Sean/0000-0002-0583-7956; FU National Institutes of Health, National Institute of Mental Health; PSP Association; Reta Lila Weston Trust FX This work was supported in part by the Intramural Program of the National Institutes of Health, National Institute of Mental Health.; AL serves as historical section editor for Movement Disorders; has served as a consultant to Genus; has served on advisory boards for and received honoraria from Novartis, Teva Pharmaceutical Industries Ltd, MEDA Pharmaceuticals Inc, Boehringer Ingelheim, GlaxoSmithKline, Ipsen, Lundbeck Inc, Allergan Inc, Orion Pharma UK Ltd and Eisai Inc; and has received research support from the PSP Association and the Reta Lila Weston Trust. NR 45 TC 16 Z9 16 U1 1 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD OCT PY 2011 VL 82 IS 10 BP 1107 EP 1111 DI 10.1136/jnnp.2011.245746 PG 5 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 818EF UT WOS:000294733400011 PM 21478206 ER PT J AU Jackson, WM Aragon, AB Onodera, J Koehler, SM Ji, YM Bulken-Hoover, JD Vogler, JA Tuan, RS Nesti, LJ AF Jackson, Wesley M. Aragon, Amber B. Onodera, Jun Koehler, Steven M. Ji, Youngmi Bulken-Hoover, Jamie D. Vogler, Jared A. Tuan, Rocky S. Nesti, Leon J. TI Cytokine Expression in Muscle following Traumatic Injury SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE muscle injury; heterotopic ossification; cytokines; bone morphogenetic protein; gene expression profiling ID FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; HETEROTOPIC OSSIFICATION; PROGENITOR CELLS; TRANSFORMING GROWTH-FACTOR-BETA-1; GENETIC DISORDER; SKELETOGENESIS; REGENERATION; TGF-BETA(1); GROWTH AB Heterotopic ossification (HO) occurs at a high frequency in severe orthopaedic extremity injuries; however, the etiology of traumatic HO is virtually unknown. Osteogenic progenitor cells have previously been identified within traumatized muscle. Although the signaling mechanisms that lead to this dysregulated differentiation pathway have not been identified, it is assumed that inflammation and fibrosis, which contribute to an osteoinductive environment, are necessary for the development of HO. The hypothesis of this study was that cytokines related to chronic inflammation, fibrogenesis, and osteogenesis become up-regulated following severe muscle trauma where HO forms. Classification of these cytokines by their differential expression relative to control muscle will provide guidance for further study of the mechanisms leading to HO. Real-time RT-PCR analysis revealed no significant up-regulation of cytokines typically associated with HO (e.g., BMP-4, as observed in the genetic form of HO, fibrodysplasia ossificans progressiva). Instead, the cytokine gene expression profile associated with the traumatized muscle included up-regulation of cytokines associated with osteogenesis and fibrosis (i.e., BMP-1 and TGF-beta(1)). Using immunohistochemistry, these cytokines were localized to fibroproliferative lesions, which have previously been implicated in HO. This study identifies other cell and tissue-level interactions in traumatized muscle that should be investigated further to better define the etiology of HO. (C) 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:1613-1620, 2011 C1 [Jackson, Wesley M.; Aragon, Amber B.; Onodera, Jun; Koehler, Steven M.; Ji, Youngmi; Bulken-Hoover, Jamie D.; Vogler, Jared A.; Tuan, Rocky S.; Nesti, Leon J.] NIH, Cartilage Biol & Orthopaed Branch, Inst Arthrit & Musculoskeletal & Skin Dis, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Jackson, Wesley M.; Vogler, Jared A.; Nesti, Leon J.] NIAMSD, Clin & Expt Orthopaed Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Aragon, Amber B.; Bulken-Hoover, Jamie D.; Vogler, Jared A.; Nesti, Leon J.] Walter Reed Army Med Ctr, Dept Orthopaed & Rehabil, Washington, DC 20307 USA. [Tuan, Rocky S.] Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, Pittsburgh, PA 15219 USA. RP Nesti, LJ (reprint author), NIH, Cartilage Biol & Orthopaed Branch, Inst Arthrit & Musculoskeletal & Skin Dis, Dept Hlth & Human Serv, 50 South Dr,Room 1140,MSC 8022, Bethesda, MD 20892 USA. EM rst13@pitt.edu; leonnesti@gmail.com RI Onodera, Jun/D-7142-2012 FU WRAMC [PO5-A011]; NIH [Z01 AR41131]; Commonwealth of Pennsylvania, Department of Health; U.S. Army Medical Research & Material Command; Telemedicine & Advanced Technology Research Center [W81XWH-10-1-0618] FX This work was supported by the Military Amputee Research Program at WRAMC (PO5-A011), the NIH Intramural Research Program (Z01 AR41131), the Commonwealth of Pennsylvania, Department of Health, the U.S. Army Medical Research & Material Command, and the Telemedicine & Advanced Technology Research Center (W81XWH-10-1-0618 to Pittsburgh Tissue Engineering Initiative). NR 23 TC 25 Z9 26 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD OCT PY 2011 VL 29 IS 10 BP 1613 EP 1620 DI 10.1002/jor.21354 PG 8 WC Orthopedics SC Orthopedics GA 816IV UT WOS:000294592800023 PM 21452302 ER PT J AU Ullah, Z de Renty, C DePamphilis, ML AF Ullah, Zakir de Renty, Christelle DePamphilis, Melvin L. TI Checkpoint Kinase 1 Prevents Cell Cycle Exit Linked to Terminal Cell Differentiation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ADENOVIRUS-MEDIATED TRANSFER; CDK INHIBITOR P57(KIP2); TROPHOBLAST GIANT-CELLS; DNA-DAMAGE CHECKPOINT; MOUSE DEVELOPMENT; DROSOPHILA-MELANOGASTER; REPLICATION STRESS; GENOTOXIC STRESS; REGULATES CHK1; PROTEIN-KINASE AB Trophoblast stem (TS) cells proliferate in the presence of fibroblast growth factor 4, but in its absence, they differentiate into polyploid trophoblast giant (TG) cells that remain viable but nonproliferative. Differentiation is coincident with expression of the cyclin-dependent kinase (CDK)-specific inhibitors p21 and p57, of which p57 is essential for switching from mitotic cell cycles to endocycles. Here, we show that, in the absence of induced DNA damage, checkpoint kinase-1 (CHK1), an enzyme essential for preventing mitosis in response to DNA damage, functions as a mitogen-dependent protein kinase that prevents premature differentiation of TS cells into TG cells by suppressing expression of p21 and p57, but not p27, the CDK inhibitor that regulates mitotic cell cycles. CHK1 phosphorylates p21 and p57 proteins at specific sites, thereby targeting them for degradation by the 26S proteasome. TG cells lack CHK1, and restoring CHK1 activity in TG cells suppresses expression of p57 and restores mitosis. Thus, CHK1 is part of a "G2 restriction point" that prevents premature cell cycle exit in cells programmed for terminal differentiation, a role that CHK2 cannot play. C1 [Ullah, Zakir; de Renty, Christelle; DePamphilis, Melvin L.] NICHHD, NIH, Bethesda, MD 20892 USA. RP DePamphilis, ML (reprint author), NICHHD, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM depamphm@mail.nih.gov FU National Institute of Child Health and Human Development FX We thank the intramural research program of the National Institute of Child Health and Human Development for its financial support. NR 60 TC 20 Z9 20 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2011 VL 31 IS 19 BP 4129 EP 4143 DI 10.1128/MCB.05723-11 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 817XI UT WOS:000294710100020 PM 21791608 ER PT J AU Stemberger, S Scholz, SW Singleton, AB Wenning, GK AF Stemberger, Sylvia Scholz, Sonja W. Singleton, Andrew B. Wenning, Gregor K. TI Genetic players in multiple system atrophy: unfolding the nature of the beast SO NEUROBIOLOGY OF AGING LA English DT Review DE Multiple system atrophy; Glial cytoplasmic inclusions; Alpha-synuclein; Neurodegeneration; Ataxia; Parkinsonism ID ALPHA-SYNUCLEIN GENE; GLIAL CYTOPLASMIC INCLUSIONS; MYOTONIC-DYSTROPHY TYPE-2; PARKINSONS-DISEASE; GLUCOCEREBROSIDASE MUTATIONS; SNCA VARIANTS; RISK-FACTORS; OLIVOPONTOCEREBELLAR ATROPHY; CONSENSUS STATEMENT; SUPRANUCLEAR PALSY AB Multiple system atrophy (MSA) is a fatal oligodendrogliopathy characterized by prominent alpha-synuclein inclusions resulting in a neuronal multisystem degeneration. Until recently MSA was widely conceived as a nongenetic disorder. However, during the last years a few postmortem verified Mendelian pedigrees have been reported consistent with monogenic disease in rare cases of MSA. Further, within the last 2 decades several genes have been associated with an increased risk of MSA, first and foremost the SNCA gene coding for alpha-synuclein. Moreover, genes involved in oxidative stress, mitochondrial dysfunction, inflammatory processes, as well as parkinsonism- and ataxia-related genes have been implicated as susceptibility factors. In this review, we discuss the emerging evidence in favor of genetic players in MSA. (C) 2011 Elsevier Inc. All rights reserved. C1 [Stemberger, Sylvia; Wenning, Gregor K.] Innsbruck Med Univ, Div Clin Neurobiol, Dept Neurol, A-6020 Innsbruck, Austria. [Scholz, Sonja W.] Georgetown Univ, Dept Neurosci, Washington, DC USA. [Scholz, Sonja W.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Wenning, GK (reprint author), Innsbruck Med Univ, Div Clin Neurobiol, Dept Neurol, Anichstr 35, A-6020 Innsbruck, Austria. EM gregor.wenning@i-med.ac.at RI Singleton, Andrew/C-3010-2009; OI Scholz, Sonja/0000-0002-6623-0429 FU Austrian Research Foundation [FWF W1206]; National Institute on Aging [Z01-AG000957-06] FX This work has been supported in part by the Austrian Research Foundation graduate program SPIN (FWF W1206) and in part by the Intramural Research Program of the National Institute on Aging; project numbers Z01-AG000957-06 (SWS, ABS). NR 101 TC 2 Z9 3 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD OCT PY 2011 VL 32 IS 10 AR 1924.e5 DI 10.1016/j.neurobiolaging.2011.04.001 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 815SZ UT WOS:000294551000023 PM 21601954 ER PT J AU Xu, DS Dirks, MS Quezado, MM Lubensky, IA Zhuang, ZP Lonser, RR Asthagiri, AR AF Xu, David S. Dirks, Michael S. Quezado, Martha M. Lubensky, Irina A. Zhuang, Zhengping Lonser, Russell R. Asthagiri, Ashok R. TI A von Hippel-Lindau Disease-Associated Microcystic Adenoma of the Ethmoid Sinus: Case Report SO NEUROSURGERY LA English DT Article DE Cranial base tumor; Microcystic adenoma; von Hippel-Lindau disease ID CENTRAL-NERVOUS-SYSTEM; RENAL-CELL CARCINOMA; DIFFERENTIAL-DIAGNOSIS; IMMUNOHISTOCHEMICAL ANALYSIS; CEREBELLAR HEMANGIOBLASTOMA; PANCREAS; TUMOR; METASTASES; NEOPLASMS; INHIBIN AB BACKGROUND AND IMPORTANCE: We present a unique case of an anterior cranial base von Hippel-Lindau disease (VHL)-associated microcystic neoplasm. To determine the lesion's relationship with VHL and its appropriate management, we discuss its salient clinical, pathological, and molecular features. CLINICAL PRESENTATION: A 36-year-old woman with VHL presented with a 3-month history of phantosmia. Serial magnetic resonance imaging studies revealed a lesion within the ethmoid and frontal sinus region that was first evident 18 months before symptom development and demonstrated progressive growth over the interval period. The lesion was resected via a transbasal approach. Histopathological and immunohistochemical analysis revealed a microcystic lesion composed of bland clear cells and underlying endothelial cells consistent with a VHL-associated microcystic neoplasm that are not known to metastasize. Molecular testing demonstrated loss of heterozygosity of the VHL locus, verifying the tumor as a VHL-related neoplasm. CONCLUSION: Because primary VHL-associated microcystic tumors in the anterior cranial base have not been described previously, the natural history of these tumors remains unclear. Based on the benign features of these lesions, they can be managed conservatively with close observation and surgical intervention reserved for those that produce symptoms. C1 [Xu, David S.; Dirks, Michael S.; Zhuang, Zhengping; Lonser, Russell R.; Asthagiri, Ashok R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Quezado, Martha M.] NCI, Pathol Lab, NIH, Rockville, MD USA. [Lubensky, Irina A.] NCI, Div Canc Treatment & Diag, NIH, Rockville, MD USA. RP Asthagiri, AR (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bldg 10,Room 3D20, Bethesda, MD 20892 USA. EM asthagiri@nih.gov OI Xu, David/0000-0001-8987-4545 FU National Institutes of Neurological Disorders and Stroke at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Neurological Disorders and Stroke at the National Institutes of Health. The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. NR 22 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD OCT PY 2011 VL 69 IS 4 BP E1017 EP E1021 DI 10.1227/NEU.0b013e318223b7a7 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 817OV UT WOS:000294684600019 PM 21572360 ER PT J AU Boffetta, P Fontana, L Stewart, P Zaridze, D Szeszenia-Dabrowska, N Janout, V Bencko, V Foretova, L Jinga, V Matveev, V Kollarova, H Ferro, G Chow, WH Rothman, N van Bemmel, D Karami, S Brennan, P Moore, LE AF Boffetta, Paolo Fontana, Luc Stewart, Patricia Zaridze, David Szeszenia-Dabrowska, Neonilia Janout, Vladimir Bencko, Vladimir Foretova, Lenka Jinga, Viorel Matveev, Vsevolod Kollarova, Helena Ferro, Gilles Chow, Wong-Ho Rothman, Nathaniel van Bemmel, Dana Karami, Sara Brennan, Paul Moore, Lee E. TI Occupational exposure to arsenic, cadmium, chromium, lead and nickel, and renal cell carcinoma: a case-control study from Central and Eastern Europe SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID CANCER-RISK; MECHANISMS; CHEMICALS; MORTALITY; GERMANY; METALS; RATS AB Objectives To investigate the risk of renal cell carcinoma (RCC) in Central and Eastern Europe in relation to exposure to known and suspected carcinogenic metals. Methods During 1999-2003, the authors conducted a hospital-based study in Czech Republic, Poland, Romania and Russia, including 1097 cases of RCC and 1476 controls. Occupational exposure to arsenic, cadmium, chromium(III), chromium(VI), lead and nickel was assessed by teams of local industrial hygiene experts, based on detailed occupational questionnaires. Results The ORs for RCC were 1.55 (95% CI 1.09 to 2.21) for exposure to lead and 1.40 (95% CI 0.69 to 2.85) for exposure to cadmium. No clear monotonic exposure-response relation was apparent for either duration of exposure or cumulative exposure to either metal, although the OR for the highest category of cumulative exposure to lead was 2.25 (95% CI 1.21 to 4.19). Exposure to other metals did not entail an increased risk of RCC. Conclusions For cadmium, the lack of statistical significance of most results, potential confounding and the absence of clear dose-response relations suggest that an association with RCC is unlikely to be causal. In the case of lead, however, the elevated risk in the category of highest cumulative exposure is noteworthy and justifies further investigation. C1 [Boffetta, Paolo] Int Prevent Res Inst, F-69006 Lyon, France. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Fontana, Luc] Univ Hosp, Dept Occupat Hlth, St Etienne, France. [Stewart, Patricia; Chow, Wong-Ho; Rothman, Nathaniel; van Bemmel, Dana; Karami, Sara; Moore, Lee E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Stewart, Patricia] Stewart Exposure Assessments LLC, Arlington, VA USA. [Zaridze, David] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Szeszenia-Dabrowska, Neonilia] Nofer Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Janout, Vladimir; Kollarova, Helena] Palacky Univ, Fac Med, Dept Prevent Med, CR-77147 Olomouc, Czech Republic. [Bencko, Vladimir] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Jinga, Viorel] Carol Davila Univ Med & Pharm, Dept Urol, Bucharest, Romania. [Matveev, Vsevolod] Russian Canc Res Ctr, Dept Urol, Moscow, Russia. [Ferro, Gilles; Brennan, Paul] Int Agcy Res Canc, Lyon, France. RP Boffetta, P (reprint author), Int Prevent Res Inst, 95 Cours Lafayette, F-69006 Lyon, France. EM paolo.boffetta@i-pri.org RI Zaridze, David/K-5605-2013; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010 FU European Commission [IC15-CT98-0332]; US National Cancer Institute FX This study was supported by a grant from the European Commission's INCO-COPERNICUS Program (contract IC15-CT98-0332) and by the Intramural Research Program of the US National Cancer Institute. NR 37 TC 15 Z9 17 U1 2 U2 12 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 OCT PY 2011 VL 68 IS 10 BP 723 EP 728 DI 10.1136/oem.2010.056341 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 818SY UT WOS:000294777000004 PM 21217163 ER PT J AU Dillon, MA Harris, B Hernandez, ML Zou, BM Reed, W Bromberg, PA Devlin, RB Diaz-Sanchez, D Kleeberger, S Zhou, HB Lay, JC Alexis, NE Peden, DB AF Dillon, Madeline A. Harris, Bradford Hernandez, Michelle L. Zou, Baiming Reed, William Bromberg, Philip A. Devlin, Robert B. Diaz-Sanchez, David Kleeberger, Steven Zhou, Haibo Lay, John C. Alexis, Neil E. Peden, David B. TI Enhancement of systemic and sputum granulocyte response to inhaled endotoxin in people with the GSTM1 null genotype SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID ENVIRONMENT INTERACTION; INFLAMMATORY RESPONSE; NORMAL VOLUNTEERS; AIR-POLLUTION; OZONE; PARTICLES; DISEASE; ASTHMA; GENE AB Objective To determine if the GSTM1 null genotype is a risk factor for increased inflammatory response to inhaled endotoxin. Methods 35 volunteers who had undergone inhalation challenge with a 20 000 endotoxin unit dose of Clinical Center Reference Endotoxin (CCRE) were genotyped for the GSTM1 null polymorphism. Parameters of airway and systemic inflammation observed before and after challenge were compared in GSTM1 null (n=17) and GSTM1 (n=18) sufficient volunteers. Results GSTM1 null volunteers had significantly increased circulating white blood cells (WBCs), polymorphonuclear neutrophils (PMNs), platelets and sputum PMNs (% sputum PMNs and PMNs/mg sputum) after CCRE challenge. GSTM1 sufficient volunteers had significant, but lower increases in circulating WBCs, PMNs and % sputum PMNs, and no increase in platelets or PMNs/mg sputum. Linear regression analysis adjusted for baseline values of the entire cohort revealed that the GSTM1 null genotype significantly increased circulating WBCs, platelets and % sputum PMNs after challenge. Conclusion These data support the hypothesis that the GSTM1 null genotype is a risk factor for increased acute respiratory and systemic inflammatory response to inhaled CCRE. These data are consistent with other observations that the GSTM1 null genotype is associated with increased respiratory, systemic and cardiovascular effects linked to ambient air particulate matter exposure and indicate that the GSTM1 null genotype should be considered a risk factor for adverse health effects associated with exposure to environmental endotoxin. C1 [Dillon, Madeline A.; Harris, Bradford; Hernandez, Michelle L.; Zou, Baiming; Reed, William; Bromberg, Philip A.; Zhou, Haibo; Lay, John C.; Alexis, Neil E.; Peden, David B.] Univ N Carolina, Sch Med, Ctr Environm Med Asthma & Lung Biol, Chapel Hill, NC 27599 USA. [Devlin, Robert B.; Diaz-Sanchez, David] US EPA, Environm Publ Hlth Div, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Kleeberger, Steven] NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. RP Peden, DB (reprint author), Univ N Carolina, Sch Med, Ctr Environm Med Asthma & Lung Biol, Chapel Hill, NC 27599 USA. EM peden@med.unc.edu RI Lay, John/A-6380-2012 FU National Institute of Environmental Health Sciences [R01ES012706, RC1ES018417, P30010126]; National Institute for Allergy and Infectious Diseases [U19AI077437]; National Center for Complementary and Alternative Medicine [P01AT002620]; National Center of Research Resources of the National Institutes of Health [KL2RR025746, M01RR00046, UL1RR025747]; US Environmental Protection Agency [CR 83346301]; Purdue Pharmaceuticals-Quintiles; National Institute of Health; National Heart, Lung, and Blood Institute; National Center for Research Resources FX This research was supported in part by grants R01ES012706, RC1ES018417 and P30010126 from the National Institute of Environmental Health Sciences, U19AI077437 from the National Institute for Allergy and Infectious Diseases, P01AT002620 from the National Center for Complementary and Alternative Medicine, and KL2RR025746, M01RR00046 and UL1RR025747 from the National Center of Research Resources of the National Institutes of Health, as well as CR 83346301 from the US Environmental Protection Agency. Although the research described herein has been funded in part by the United States Environmental Protection Agency, it has not been subjected to the EPA's required peer and policy review. The findings contained in this report do not necessarily reflect the views of the Environmental Protection Agency or the National Institutes of Health, and no official endorsement should be inferred.; BH has received research support from the National Institute of Environmental Health Sciences, US Environmental Protection Agency and Purdue Pharmaceuticals-Quintiles. PAB has received support from the US Environmental Protection Agency and National Institute of Health. DBP has consulted for GlaxoSmithKline and Funxional Therapeutics and has received research support from the National Institute of Environmental Health Sciences, the National Center for Complementary and Alternative Medicine, the National Heart, Lung, and Blood Institute, the National Institute for Allergy and Infectious Diseases, the US Environmental Protection Agency and the National Center for Research Resources. The rest of the authors have declared that they have no competing interests. NR 12 TC 16 Z9 16 U1 0 U2 3 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 OCT PY 2011 VL 68 IS 10 BP 783 EP 785 DI 10.1136/oem.2010.061747 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 818SY UT WOS:000294777000014 PM 21441173 ER PT J AU Koutros, S Andreotti, G Berndt, SI Barry, KH Lubin, JH Hoppin, JA Kamel, F Sandler, DP Burdette, LA Yuenger, J Yeager, M Alavanja, MCR Freeman, LEB AF Koutros, Stella Andreotti, Gabriella Berndt, Sonja I. Barry, Kathryn Hughes Lubin, Jay H. Hoppin, Jane A. Kamel, Freya Sandler, Dale P. Burdette, Laurie A. Yuenger, Jeffrey Yeager, Meredith Alavanja, Michael C. R. Freeman, Laura E. Beane TI Xenobiotic-metabolizing gene variants, pesticide use, and the risk of prostate cancer SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE interaction; pesticides; prostate cancer; single nucleotide polymorphism; xenobiotic-metabolizing enzymes ID GENOME-WIDE ASSOCIATION; AGRICULTURAL HEALTH; HUMAN CYTOCHROME-P450; STEROID-HORMONES; EXPRESSION; POLYMORPHISMS; EXPOSURE; MYELOPEROXIDASE; SUSCEPTIBILITY; CHEMICALS AB Background To explore associations with prostate cancer and farming, it is important to investigate the relationship between pesticide use and single nucleotide polymorphisms (SNPs) in xenobiotic metabolic enzyme (XME) genes. Obective We evaluated pesticide-SNP interactions between 45 pesticides and 1913 XME SNPs with respect to prostrate cancer among 776 cases and 1444 controls in the Agricultural Health Study. Methods We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. Results A positive monotonic interaction was observed between petroleum oil/petroleum distillate use and rs1883633 in the oxidative stress gene glutamate cysteine ligase (GCLC; P interaction = 1.0 X 10(-4)); men carrying at least one variant allele (minor allele) experienced an increased prostate cancer risk (OR=3.7, 95% CI: 1.9-7.3). Among men carrying the variant allele for thioredoxin reductase 2 (TXNRD2) rs4485648, microsomal epoxide hydrolase 1 (EPHX1) rs17309872, or myeloperoxidase (MPO) rs11079344, an increased prostate cancer risk was observed with high, compared with no, petroleum oil/petroleum distillate (OR=1.9, 95% CI: 1.1-3.2, P interaction=0.01; OR=2.1, 95% CI: 1.1-4.0, P interaction=0.01), or terbufos (OR=3.0, 95% CI: 1.5-6.0, P interaction=2.0 X 10(-3)) use, respectively. No interactions were deemed noteworthy at the false discovery rate=0.20 level; the number of observed interactions in XMEs was comparable with the number expected by chance alone. Conclusion We observed several pesticide-SNP interactions in oxidative stress and phase I/II enzyme genes and risk of prostate cancer. Additional work is needed to explain the joint contribution of genetic variation in XMEs, pesticide use, and prostate cancer risk. Pharmacogenetics and Genomics 21: 615-623 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Koutros, Stella] NCI, Div Canc Epidemiol & Genet, US Dept HHS, Occupat & Environm Epidemiol Branch,NIH, Rockville, MD 20852 USA. [Burdette, Laurie A.; Yuenger, Jeffrey; Yeager, Meredith] NCI, Core Genotyping Facil, Adv Technol Program, Frederick, MD 21701 USA. [Hoppin, Jane A.; Kamel, Freya; Sandler, Dale P.] NIEHS, US Dept HHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Koutros, S (reprint author), NCI, Div Canc Epidemiol & Genet, US Dept HHS, Occupat & Environm Epidemiol Branch,NIH, 6120 Execut Blvd,EPS 8115,MSC 7240, Rockville, MD 20852 USA. EM KoutrosS@mail.nih.gov OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU National Institute of Health, National Cancer Institute, Division of Cancer Epidemiology, and Genetics [Z01CP010119]; National Institute of Environmental Health Sciences [Z01ES049030]; National Cancer Institute [T32 CA105666] FX This research was supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Division of Cancer Epidemiology, and Genetics (Z01CP010119) and National Institute of Environmental Health Sciences (Z01ES049030). K.H.B. was supported by National Cancer Institute grant T32 CA105666. The authors thank the participants in the AHS for their contributions in support of this research. NR 48 TC 18 Z9 20 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD OCT PY 2011 VL 21 IS 10 BP 615 EP 623 DI 10.1097/FPC.0b013e3283493a57 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 819ET UT WOS:000294808900001 PM 21716162 ER PT J AU Kiyatkin, EA Lenoir, M AF Kiyatkin, Eugene A. Lenoir, Magalie TI Intravenous saline injection as an interoceptive signal in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE EEG; EMG; Visceral sensory stimulus; Desynchronization; Neural activation; Vasoconstriction; Brain temperature; Repeated drug administration; Learning ID FREELY MOVING RATS; EEG DESYNCHRONIZATION; COCAINE; TEMPERATURE; SUSCEPTIBILITY; RESPONSES; HUMANS AB Addictive drugs are commonly delivered in the organism by means of intravenous (i.v.) injections. Since saline mimics the blood environment by basic ionic properties and pH, it is generally assumed that it should not have any physiological effects, serving as a control for the effects induced by drugs. The aim of the study was to examine central, behavioral, and physiological effects of stress- and cue-free i.v. saline injection in freely moving rats. We examined how a typical low-volume and slow-speed saline injections affect cortical electroencephalograpy (EEG), neck electromyography (EMG), locomotor activity as well as central and peripheral temperatures. Saline injection made during slow-wave synchronized activity induces rapid transient EEG desynchronization, manifesting as a drop of EEG total power, decrease in alpha activity, and increases in beta and gamma activities. Saline injection did not affect locomotor activity as well as brain and body temperatures, but induced a transient increase in neck EMG activity and a rapid brief drop in skin temperature, suggesting peripheral vasoconstriction. These responses were virtually fully absent when saline injection was made during naturally occurring desynchronized EEG activity during behavioral activity. Since i.v. injection is able to produce a peripheral sensory signal that is transmitted rapidly to the CNS and followed by a more prolonged effect of the injected drug on brain cells, with repeated drug administrations, the injection itself could play a role of drug-related sensory cue, thus inducing conditioned physiological responses and altering the effects of injected drugs. C1 [Kiyatkin, Eugene A.; Lenoir, Magalie] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov FU NIH, NIDA FX This research was supported by the Intramural Research Program of the NIH, NIDA. We wish to thank Jeremy Tang for his participation in exp. 2 of this study. NR 23 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2011 VL 217 IS 3 BP 387 EP 396 DI 10.1007/s00213-011-2294-4 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 817QS UT WOS:000294689500009 PM 21494787 ER PT J AU Gerber, LH Stout, N McGarvey, C Soballe, P Shieh, CY Diao, GQ Springer, BA Pfalzer, LA AF Gerber, Lynn H. Stout, Nicole McGarvey, Charles Soballe, Peter Shieh, Ching-yi Diao, Guoqing Springer, Barbara A. Pfalzer, Lucinda A. TI Factors predicting clinically significant fatigue in women following treatment for primary breast cancer SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Breast cancer; Fatigue; Rehabilitation; Function ID RANDOMIZED CONTROLLED-TRIAL; RECEIVING ADJUVANT CHEMOTHERAPY; QUALITY-OF-LIFE; PHYSICAL-ACTIVITY; PERSISTENT FATIGUE; SLEEP DISORDERS; SURVIVORS; EXERCISE; DIAGNOSIS; ANEMIA AB Cancer-related fatigue is common, complex, and distressing. It affects 70-100% of patients receiving chemotherapy and a significant number who have completed their treatments. We assessed a number of variables in women newly diagnosed with primary breast cancer (BrCa) to determine whether biological and/or functional measures are likely to be associated with the development of clinically significant fatigue (CSF). Two hundred twenty-three women participated in a study designed to document the impact of the diagnosis and treatment of primary breast cancer on function. Forty-four had complete data on all variables of interest at the time of confirmed diagnosis but prior to treatment (baseline) and a parts per thousand yen9 months post-diagnosis. Objective measures and descriptive variables included history, physical examination, limb volume, hemoglobin, white blood cell count, and glucose. Patient-reported outcomes included a verbal numerical rating of fatigue (0-10, a score of a parts per thousand yen4 was CSF), five subscales of the SF-36, Physical Activity Survey, and Sleep Questionnaire. At baseline, the entire cohort (n = 223) and the subset (n = 44) were not significantly different for demographic, biological, and self-reported data, except for younger age (p = 0.03) and ER+ (p = 0.01). Forty-five percent had body mass index (BMI) a parts per thousand yenaEuro parts per thousand 25, 52% were post-menopause, and 52% received modified radical mastectomy, 39% lumpectomy, 52% chemotherapy, 68% radiation, and 86% hormonal therapy. Number of patients with CSF increased from 1 at baseline to 11 at a parts per thousand yen9 months of follow-up. CSF at a parts per thousand yen9 months significantly correlated with BMI a parts per thousand yenaEuro parts per thousand 25, abnormal white blood cell count, and increase in limb volume and inversely correlated with vigorous activity and physical function (p < 0.05). Fatigue increases significantly following the treatment of BrCa. Predictors of CSF include high BMI and WBC count, increase in limb volume, and low level of physical activity. These are remediable. C1 [Gerber, Lynn H.] George Mason Univ, Ctr Study Chron Illness & Disabil, Fairfax, VA 22030 USA. [Gerber, Lynn H.; Diao, Guoqing] George Mason Univ, Fairfax, VA 22030 USA. [Stout, Nicole; Soballe, Peter] Natl Naval Med Ctr, Bethesda, MD USA. [McGarvey, Charles] CLM Consulting, Rockville, MD USA. [Pfalzer, Lucinda A.] Univ Michigan, Flint, MI 48503 USA. [Gerber, Lynn H.; Shieh, Ching-yi] NIH, Bethesda, MD 20892 USA. [Springer, Barbara A.] Off Surg Gen, Rockville, MD USA. RP Gerber, LH (reprint author), George Mason Univ, Ctr Study Chron Illness & Disabil, Fairfax, VA 22030 USA. EM ngerber1@gmu.edu FU Clinical Research Center, the National Institutes of Health, Bethesda, Maryland; Mrs. Marcia Di Trapani and the Dominion Guild FX This research was supported with intramural research funds of the Clinical Research Center, the National Institutes of Health, Bethesda, Maryland. In addition, support for students engaged in this research from Mrs. Marcia Di Trapani and the Dominion Guild. We would like to acknowledge valuable assistance from Ms. Angela Corriveau and Lynn Fan, graduate students in the College of Health and Human Services, George Mason University. NR 54 TC 36 Z9 36 U1 1 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD OCT PY 2011 VL 19 IS 10 BP 1581 EP 1591 DI 10.1007/s00520-010-0986-7 PG 11 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 815VV UT WOS:000294559000014 PM 20835835 ER PT J AU O'Grady, NP Heard, SO Mermel, LA Rupp, ME AF O'Grady, Naomi P. Heard, Stephen O. Mermel, Leonard A. Rupp, Mark E. TI Untitled Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID CENTRAL VENOUS CATHETERS; INTENSIVE-CARE-UNIT; PROSPECTIVE RANDOMIZED-TRIAL; CRITICALLY ILL PATIENTS; POVIDONE-IODINE; PREVENTION; INFECTION; RISK; CHLORHEXIDINE; COMPLICATIONS C1 [O'Grady, Naomi P.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Heard, Stephen O.] Univ Massachusetts, Sch Med, Dept Anesthesiol, Worcester, MA USA. [Mermel, Leonard A.] Brown Univ, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02912 USA. [Mermel, Leonard A.] Rhode Isl Hosp, Providence, RI USA. [Rupp, Mark E.] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA. RP O'Grady, NP (reprint author), NIH, Dept Crit Care Med, Bldg 10,Room 2C142,10 Ctr Dr,MSC 1662, Bethesda, MD 20892 USA. EM nogrady@mail.cc.nih.gov NR 17 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 1 PY 2011 VL 53 IS 7 BP 746 EP U216 DI 10.1093/cid/cir503 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 815AJ UT WOS:000294498200026 ER PT J AU Wang, HY Jain, A AF Wang, Hong-Ying Jain, Ashish TI Novel Sequencing-based Strategies for High-Throughput Discovery of Genetic Mutations Underlying Inherited Antibody Deficiency Disorders SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review DE High-throughput sequencing; Microarray; Next-generation sequencing; Target sequence enrichment; Sequence capture by hybridization; PCR; Cost-effective; Assay development ID COMMON VARIABLE IMMUNODEFICIENCY; HYPER-IGM SYNDROME; GENOME-WIDE ASSOCIATION; CLASS-SWITCH RECOMBINATION; AUTOSOMAL RECESSIVE FORM; CD40 LIGAND; GENERATION; ENRICHMENT; MICROARRAY; CAPTURE AB Human inherited antibody deficiency disorders are generally caused by mutations in genes involved in the pathways regulating B-cell class switch recombination; DNA damage repair; and B-cell development, differentiation, and survival. Sequencing a large set of candidate genes involved in these pathways appears to be a highly efficient way to identify novel mutations. Herein we review several high-throughput sequencing approaches as well as recent improvements in target gene enrichment technologies. Systematic improvement of enrichment and sequencing methods, along with refinement of the experimental process is necessary to develop a cost-effective high-throughput resequencing assay for a large cohort of patient samples. The Hyper-IgM/CVID chip is one example of a resequencing platform that may be used to identify known or novel mutations in patents with various types of inherited antibody deficiency. C1 [Wang, Hong-Ying; Jain, Ashish] NIAID, Host Def Lab, NIH, CRC, Bethesda, MD 20892 USA. RP Wang, HY (reprint author), NIAID, Host Def Lab, NIH, CRC, 5W-3840,10 Ctr Dr, Bethesda, MD 20892 USA. EM wanghongying@niaid.nih.gov; ajain@niaid.nih.gov FU National Institutes of Health/National Institute of Allergy and Infectious Diseases FX Preparation of this manuscript was supported by the Intramural Research Program of the National Institutes of Health/National Institute of Allergy and Infectious Diseases. NR 62 TC 1 Z9 2 U1 0 U2 1 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD OCT PY 2011 VL 11 IS 5 BP 352 EP 360 DI 10.1007/s11882-011-0211-x PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 814OS UT WOS:000294467000004 PM 21792638 ER PT J AU Rosenzweig, SD Holland, SM AF Rosenzweig, Sergio D. Holland, Steven M. TI Recent Insights into the Pathobiology of Innate Immune Deficiencies SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review DE Primary immunodeficiencies; Innate immunity; Neutrophils; Macrophages; Dendritic cells; Natural killer cells; NK cells; NKT cells; Opsonins; Complement; Pattern-recognition receptors ID CHRONIC GRANULOMATOUS-DISEASE; LEUKOCYTE ADHESION DEFICIENCY; CHRONIC MUCOCUTANEOUS CANDIDIASIS; ADAPTIVE IMMUNITY; CLINICAL-FEATURES; IFN-GAMMA; B-CELLS; MUTATION; SYSTEM; AUTOANTIBODIES AB Primary immunodeficiencies are a heterogeneous group of genetically inherited diseases affecting the innate and adaptive immune systems that confer susceptibility to infection, autoimmunity, and cancer. Innate immunity includes neutrophils, macrophages, dendritic cells, natural killer cells, and natural killer T cells in conjunction with natural barriers (mostly skin and gastrointestinal and respiratory mucosa), as well as antimicrobial agents, opsonins (e.g., complement), and cytokines. Although somewhat primitive, innate immune cells can orchestrate discrete immune responses through the recognition of diverse pathogens by different pattern-recognition receptors. In this review, we discuss the most recent discoveries as well as the already established pathophysiologic mechanisms underlying innate immunity defects associated with primary immunodeficiencies. C1 [Rosenzweig, Sergio D.; Holland, Steven M.] NIAID, Infect Dis Susceptibil Unit, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Rosenzweig, SD (reprint author), NIAID, Infect Dis Susceptibil Unit, Host Def Lab, NIH, 10 Ctr Dr,Bldg 10,CRC 6W-3750, Bethesda, MD 20892 USA. EM srosenzweig@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 50 TC 9 Z9 9 U1 1 U2 6 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD OCT PY 2011 VL 11 IS 5 BP 369 EP 377 DI 10.1007/s11882-011-0212-9 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 814OS UT WOS:000294467000006 PM 21814768 ER PT J AU Charles, N Rivera, J AF Charles, Nicolas Rivera, Juan TI Basophils and Autoreactive IgE in the Pathogenesis of Systemic Lupus Erythematosus SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review DE Autoantibody; Basophils; IgE; Interleukin-4; IL-4; Lupus; Systemic lupus erythematosus ID LYN-DEFICIENT MICE; MAST-CELL DEGRANULATION; HELPER TYPE-2 RESPONSE; B-CELL; T-CELL; AUTOIMMUNE-DISEASE; IMMUNOGLOBULIN-E; TYROSINE KINASE; NEGATIVE REGULATOR; ALLERGIC RESPONSES AB Systemic lupus erythematosus (SLE) is a heterogeneous disease that can affect multiple organs. A hallmark of this disease, as is the case for other autoimmune diseases, is the presence of large numbers of autoantibodies. As such, SLE is considered to be a B-cell disease perpetuated by the expansion of autoreactive T and B cells. The T cells involved have long been considered to be T-helper type 1 (Th1) and Th17 cells, as these potent proinflammatory cells can be found in the tissues of SLE patients. Recent advances point to a role for the Th2 environment in contributing to SLE through promotion of autoantibody production. Here we describe the recent work focusing on autoreactive IgE and the activation of basophils as promoting the production of autoantibodies in SLE. The findings, both in a murine model of SLE and in humans with SLE, support the concept that the activation of the basophil by autoreactive IgE-containing immune complexes serves to amplify the production of autoantibodies and contributes to the pathogenesis of disease. We propose that therapeutic targeting of this amplification loop by reducing the levels of circulating autoreactive IgE may have benefit in SLE. C1 [Rivera, Juan] NIAMSD, NIH, Bethesda, MD 20892 USA. [Charles, Nicolas] Univ Paris Diderot, Fac Med Xavier Bichat, INSERM, UMR699, F-75870 Paris 18, France. RP Rivera, J (reprint author), NIAMSD, NIH, Bldg 10,Room 9S205, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov RI Charles, Nicolas/P-5430-2014 OI Charles, Nicolas/0000-0002-5416-5834 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX The research of Dr. Rivera, reported herein, was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 59 TC 20 Z9 20 U1 0 U2 5 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD OCT PY 2011 VL 11 IS 5 BP 378 EP 387 DI 10.1007/s11882-011-0216-5 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA 814OS UT WOS:000294467000007 PM 21805094 ER PT J AU Gochman, P Miller, R Rapoport, JL AF Gochman, Peter Miller, Rachel Rapoport, Judith L. TI Childhood-Onset Schizophrenia: The Challenge of Diagnosis SO CURRENT PSYCHIATRY REPORTS LA English DT Editorial Material DE Schizophrenia; Childhood-onset schizophrenia; Psychiatric diagnosis; Drug-free observation; Childhood bipolar disorder AB During the past two decades, the Child Psychiatry Branch at the National Institute of Mental Health has conducted a longitudinal study (including long-term prospective follow-up) of childhood-onset schizophrenia, a rare form of the disorder. Critical to this research has been accurate diagnosis. Outpatient screening has accurately diagnosed 55% of the 121 childhood-onset schizophrenia patients in the study to date. However, inpatient observation including drug-free observation has proven crucial to ruling out 96 children with alternative diagnoses who had been provisionally admitted for inpatient study. Standardized clinical ratings from outpatient screening only predicted 62% of these nonschizophrenia patients. Historically, medication-free observation was standard clinical care for difficult and unusual patients; this should be employed when possible in similar situations. C1 [Gochman, Peter; Miller, Rachel; Rapoport, Judith L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 3 N202,10 Ctr Dr,MSC 1600, Bethesda, MD 20892 USA. EM gochmanp@mail.nih.gov; mrachel@mail.nih.gov; rapoporj@mail.nih.gov RI Masters, Alex/D-1677-2012 FU Intramural NIH HHS [ZIA MH002581-21] NR 3 TC 7 Z9 7 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD OCT PY 2011 VL 13 IS 5 BP 321 EP 322 DI 10.1007/s11920-011-0212-4 PG 2 WC Psychiatry SC Psychiatry GA 815CR UT WOS:000294504200003 PM 21713647 ER PT J AU Yaguchi, S Yaguchi, J Wei, Z Jin, YH Angerer, LM Inaba, K AF Yaguchi, Shunsuke Yaguchi, Junko Wei, Zheng Jin, Yinhua Angerer, Lynne M. Inaba, Kazuo TI Fez function is required to maintain the size of the animal plate in the sea urchin embryo SO DEVELOPMENT LA English DT Article DE BMP; Cell fate specification; Body axis; Neurogenesis ID FINGER GENES FEZF1; XENOPUS EMBRYOS; STRONGYLOCENTROTUS-PURPURATUS; NEURAL INDUCTION; REGULATORY GENES; BETA-CATENIN; EXPRESSION; PATHWAY; AXIS; PATTERNS AB Partitioning ectoderm precisely into neurogenic and non-neurogenic regions is an essential step for neurogenesis of almost all bilaterian embryos. Although it is widely accepted that antagonism between BMP and its inhibitors primarily sets up the border between these two types of ectoderm, it is unclear how such extracellular, diffusible molecules create a sharp and precise border at the single-cell level. Here, we show that Fez, a zinc finger protein, functions as an intracellular factor attenuating BMP signaling specifically within the neurogenic region at the anterior end of sea urchin embryos, termed the animal plate. When Fez function is blocked, the size of this neurogenic ectoderm becomes smaller than normal. However, this reduction is rescued in Fez morphants simply by blocking BMP2/4 translation, indicating that Fez maintains the size of the animal plate by attenuating BMP2/4 function. Consistent with this, the gradient of BMP activity along the aboral side of the animal plate, as measured by pSmad1/5/8 levels, drops significantly in cells expressing Fez and this steep decline requires Fez function. Our data reveal that this neurogenic ectoderm produces an intrinsic system that attenuates BMP signaling to ensure the establishment of a stable, well-defined neural territory, the animal plate. C1 [Yaguchi, Shunsuke; Yaguchi, Junko; Jin, Yinhua; Inaba, Kazuo] Univ Tsukuba, Shimoda Marine Res Ctr, Shizuoka 4150025, Japan. [Yaguchi, Junko] Univ Tsukuba, Initiat Promot Young Scientists Independent Res, Shizuoka 4150025, Japan. [Wei, Zheng; Angerer, Lynne M.] Natl Inst Dent & Craniofacial Res, Dev Mechanisms Sect, NIH, Bethesda, MD 20892 USA. RP Yaguchi, S (reprint author), Univ Tsukuba, Shimoda Marine Res Ctr, 5-10-1 Shimoda, Shizuoka 4150025, Japan. EM yag@kurofune.shimoda.tsukuba.ac.jp OI Yaguchi, Shunsuke/0000-0002-8326-5762 FU Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (MEXT) [22370023]; Takeda Science Foundation; National Institutes of Health; NIDCR; [20870006]; [21770227] FX This work was supported, in part, by Special Coordination Funds for Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (MEXT), by Grant-in Aid for Young Scientists (Start-up No. 20870006 and B No. 21770227) and Takeda Science Foundation to S.Y., in part by the Intramural Program of the National Institutes of Health, NIDCR to L.M.A., and in part by MEXT (No. 22370023) to K.I. Deposited in PMC for release after 12 months. NR 50 TC 14 Z9 14 U1 2 U2 7 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 OCT 1 PY 2011 VL 138 IS 19 BP 4233 EP 4243 DI 10.1242/dev.069856 PG 11 WC Developmental Biology SC Developmental Biology GA 815SB UT WOS:000294547200016 PM 21852402 ER PT J AU Kim, SM Bae, J Cho, IH Choi, KY Park, YJ Ryu, JH Chun, JS Song, WK AF Kim, Seon-Myung Bae, Jeomil Cho, In Ha Choi, Kyu Yeong Park, Yeon Jung Ryu, Jin Hee Chun, Jang-Soo Song, Woo Keun TI Control of growth cone motility and neurite outgrowth by SPIN90 SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Hippocampal; Growth cone; Neurite outgrowth; F-actin; SPIN90 knockout; DIP; WISH ID CYTOSKELETAL DYNAMICS; MICROTUBULE BEHAVIOR; HIPPOCAMPAL-NEURONS; ACTIN CYTOSKELETON; BINDING PROTEINS; ARP2/3 COMPLEX; CELL-ADHESION; AXON GUIDANCE; N-WASP; FILOPODIA AB SPIN90 is an F-actin binding protein thought to play important roles in regulating cytoskeletal dynamics. It is known that SPIN90 is expressed during the early stages of neuronal development, but details of its localization and function in growth cones have not been fully investigated. Our immunocytochemical data show that SPIN90 is enriched throughout growth cones and neuronal shafts in young hippocampal neurons. We also found that its localization correlates with and depends upon the presence of F-actin. Detailed observation of primary cultures of hippocampal neurons revealed that SPIN90 knockout reduces both growth cone areas and in the numbers of filopodia, as compared to wild-type neurons. In addition, total neurite length, the combined lengths of the longest (axonal) and shorter (dendritic) neurites, was smaller in SPIN90 knockout neurons than wild-type neurons. Finally, Cdc42 activity was down-regulated in SPIN90 knockout neurons. Taken together, our findings suggest that SPIN90 plays critical roles in controlling growth cone dynamics and neurite outgrowth. (C) 2011 Elsevier Inc. All rights reserved. C1 [Kim, Seon-Myung; Bae, Jeomil; Cho, In Ha; Park, Yeon Jung; Ryu, Jin Hee; Chun, Jang-Soo; Song, Woo Keun] Gwangju Inst Sci & Technol, Sch Life Sci, Cell Dynam & Bioimaging Res Ctr, Kwangju 500712, South Korea. [Choi, Kyu Yeong] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP Song, WK (reprint author), Gwangju Inst Sci & Technol, Sch Life Sci, Cell Dynam & Bioimaging Res Ctr, 261 Cheomdan Gwagiro, Kwangju 500712, South Korea. EM wksong@gist.ac.kr FU National Research Foundation of Korea (NRF) [20110001155, 2010K001181, 20110000095] FX This research was supported by grants from Cell Dynamics and Bioimaging Research Center (20110001155), Conversing Research Center Program (2010K001181), and the Mid-Career Research Program (20110000095), funded by the National Research Foundation of Korea (NRF). NR 55 TC 7 Z9 7 U1 0 U2 1 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 OCT 1 PY 2011 VL 317 IS 16 BP 2276 EP 2287 DI 10.1016/j.yexcr.2011.06.018 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 813UB UT WOS:000294394600005 PM 21763308 ER PT J AU Fields, D AF Fields, D. TI ACTIVITY-DEPENDENT, NONSYNAPTIC RELEASE OF NEUROTRANSMITTER FROM AXONS IN AXON-GLIA COMMUNICATION SO GLIA LA English DT Meeting Abstract DE atp; myelin; synaptic vesicle C1 [Fields, D.] NICHD, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-1491 J9 GLIA JI Glia PD OCT PY 2011 VL 59 SU 1 BP S38 EP S38 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 811CF UT WOS:000294178900147 ER PT J AU Major, E AF Major, E. TI HUMAN BRAIN DERIVED MULTIPOTENTIAL PROGENITOR CELLS ALLOWS INVESTIGATION OF FACTORS IMPORTANT FOR NEUROTROPIC VIRUS INFECTION SO GLIA LA English DT Meeting Abstract DE progenitor cells; differentiation C1 [Major, E.] NINDS, NIH, Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-1491 J9 GLIA JI Glia PD OCT PY 2011 VL 59 SU 1 BP S33 EP S33 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 811CF UT WOS:000294178900129 ER PT J AU Soliven, B Kim, HJ Dukala, D Proia, R Miron, V Ludwin, S Traka, M Antel, J AF Soliven, B. Kim, H. J. Dukala, D. Proia, R. Miron, V Ludwin, S. Traka, M. Antel, J. TI OLIGODENDROGLIAL S1P1 IN MYELINATION AND DEMYELINATION SO GLIA LA English DT Meeting Abstract DE demyelination; sphingosine 1-phosphate receptors; multiple sclerosis C1 [Soliven, B.; Kim, H. J.; Dukala, D.; Traka, M.] Univ Chicago, Chicago, IL 60637 USA. [Proia, R.] NIH, Bethesda, MD 20892 USA. [Miron, V; Antel, J.] McGill Univ, Montreal, PQ, Canada. [Ludwin, S.] Queens Univ, Kingston, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-1491 J9 GLIA JI Glia PD OCT PY 2011 VL 59 SU 1 BP S51 EP S51 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 811CF UT WOS:000294178900197 ER PT J AU Drel, VR Pacher, P Stavniichuk, R Xu, WZ Zhang, J Kuchmerovska, TM Slusher, B Obrosova, IG AF Drel, Viktor R. Pacher, Pal Stavniichuk, Roman Xu, Weizheng Zhang, Jie Kuchmerovska, Tamara M. Slusher, Barbara Obrosova, Irina G. TI Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE albuminuria; diabetic Akita mouse; peripheral diabetic neuropathy; poly(ADP-ribose) polymerase; p38 mitogen-activated protein kinase; renal hypertrophy ID ALDOSE REDUCTASE INHIBITOR; NERVE-CONDUCTION-VELOCITY; POLYMERASE INHIBITION; TRANSCRIPTION FACTORS; SENSORY NEUROPATHY; FATTY RATS; DYSFUNCTION; MOUSE; ACTIVATION; PROTEIN AB Poly(ADP-ribose) polymerase (PARP) activation has been implicated in the pathogenesis of diabetic complications, including nephropathy and peripheral neuropathy. This study aimed at evaluating the manifestations of both complications in diabetic Akita mice, a model of Type 1 (insulin-dependent) diabetes, and their amenability to treatment with the potent PARP inhibitor, 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427). Male non-diabetic C57B16/J and diabetic C57B1/6-1ns2Akita/J (Akita) mice were maintained with or without treatment with GPI-15427, 30 mg/kg/day, for 4 weeks starting from 16 weeks of age. Sixteen week-old Akita mice displayed sensory nerve conduction velocity (SNCV) deficit, whereas the motor nerve conduction velocity (MNCV) tended to decrease, but the difference with controls did not achieve statistical significance. They also developed thermal and mechanical hypoalgesia and tactile allodynia. SNCV deficit, mechanical hypoalgesia, and tactile allodynia progressed with age whereas the severity of thermal hypoalgesia was similar in 16- and 20-week-old Akita mice. PAR P inhibition alleviated, although it did not completely reverse, SNCV deficit, thermal and mechanical hypoalgesia and tactile allodynia. Sixteen-week-old Akita mice displayed MNCV deficit (41.3 +/- 2.5 vs. 51.0 +/- 1.2 m/sec in non-diabetic controls, P<0.01), axonal atrophy of myelinated fibers, kidney hypertrophy, and albuminuria. MNCV slowing, axonal atrophy, and kidney hypertrophy, but not albuminuria, were less severe in GPI-15427-treated age-matched Akita mice. Neuroprotective and nephroprotective effects of PARP inhibition were not due to alleviation of diabetic hyperglycemia, or peripheral nerve p38 mitogen-activated protein kinase activation. GPI-15427 did not affect ally variables in control mice. In conclusion, the findings support an important role for PARP activation in diabetic peripheral neuropathy and kidney hypertrophy associated with Type 1 diabetes, and provide rationale for development and further studies of PARP inhibitors, for the prevention and treatment of these complications. C1 [Drel, Viktor R.; Stavniichuk, Roman; Obrosova, Irina G.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD USA. [Xu, Weizheng; Zhang, Jie; Slusher, Barbara] Eisai Inc, Baltimore, MD USA. [Kuchmerovska, Tamara M.] Ukrainian Acad Sci, AV Palladin Biochem Inst, Kiev, Ukraine. RP Obrosova, IG (reprint author), Louisiana State Univ Syst, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM obrosoig@pbrc.edu RI Pacher, Pal/B-6378-2008; Drel, Viktor/G-8883-2016 OI Pacher, Pal/0000-0001-7036-8108; Drel, Viktor/0000-0003-4542-0132 FU National Institutes of Health [RO1DK074517, RO1DK077141, RO1DK081147]; National Institutes of Health/National Institute of Alcohol Abuse and Alcoholism FX The study was supported by the National Institutes of Health Grants RO1DK074517, RO1DK077141, and RO1DK081147 (all to I.G.O), and the Intramural Research Program of the National Institutes of Health/National Institute of Alcohol Abuse and Alcoholism (to P.P.). NR 45 TC 14 Z9 15 U1 0 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD OCT PY 2011 VL 28 IS 4 BP 629 EP 635 DI 10.3892/ijmm.2011.709 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 815NS UT WOS:000294532900023 PM 21617845 ER PT J AU Rouleau, C Smale, R Sancho, J Fu, YS Kurtzberg, L Weber, W Kruger, A Jones, C Roth, S Bormann, C Dunham, S Krumbholz, R Curiel, M Wallar, G Mascarello, J Campos-Rivera, J Horten, B Schmid, S Miller, G Teicher, BA AF Rouleau, Cecile Smale, Robert Sancho, Jose Fu, Yao-Shi Kurtzberg, Leslie Weber, William Kruger, Ariel Jones, Craig Roth, Stephanie Bormann, Christy Dunham, Sarah Krumbholz, Roy Curiel, Maritza Wallar, Gina Mascarello, James Campos-Rivera, Juanita Horten, Bruce Schmid, Steven Miller, Glenn Teicher, Beverly A. TI Endosialin: A novel malignant cell therapeutic target for neuroblastoma SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE endosialin; neuroblastoma; side population cells; flow cytometry; small cell lung cancer ID SIDE POPULATION CELLS; LUNG-CANCER; PROTEIN EXPRESSION; ENDOTHELIAL-CELLS; STEM-CELLS; TUMORS; SARCOMA; LINES; IDENTIFICATION; PERICYTES AB Endosialin emerged recently as a potential therapeutic target for sarcoma. Since some sarcoma subtypes, such as Ewing's sarcoma, show characteristics of neuroendocrine differentiation, we wondered whether cancers with neuroendocrine properties and/or neuroectodermal origin, such as neuroblastoma, small cell lung cancer and melanoma, may express endosialin. Endosialin protein expression was surveyed in neuroblastoma, small cell lung cancer and melanoma in human clinical specimens by immunohistochemistry (IHC) and in human cell lines by flow cytometry. Side population cells were examined to determine whether cancer stem cells can express endosialin. Endosialin-expressing neuroblastoma cell lines were implanted in immunodeficient mice and allowed to grow. The xenograft tumors were resected and tested for endosialin expression by IHC. In human clinical specimens, vascular endosialin staining was observed in neuroblastoma, small cell lung cancer and melanoma. Malignant cell staining was strongest in neuroblastoma, weak in melanoma and rare in small cell lung cancer. In human cell lines, endosialin was detected in neuroblastoma cell lines, including cancer stem cell-like side population (SP) cells, but was absent in melanoma and was both rare and weak in small cell lung cancer. Human neuroblastoma xenograft tumors were found to be positive for endosialin. Our work suggests that endosialin may be a suitable therapeutic target for neuroblastoma. C1 [Rouleau, Cecile; Sancho, Jose; Kurtzberg, Leslie; Weber, William; Kruger, Ariel; Jones, Craig; Campos-Rivera, Juanita; Teicher, Beverly A.] Genzyme Corp, Framingham, MA 01701 USA. [Smale, Robert; Fu, Yao-Shi; Curiel, Maritza; Wallar, Gina; Miller, Glenn] Genzyme Genet, Los Angeles, CA 90066 USA. [Roth, Stephanie; Bormann, Christy; Dunham, Sarah; Krumbholz, Roy; Schmid, Steven] Genzyme Corp, San Antonio, TX 78229 USA. [Mascarello, James] Genzyme Genet, Santa Fe, NM 87505 USA. [Horten, Bruce] Genzyme Genet, New York, NY 10019 USA. RP Teicher, BA (reprint author), NCI, Dev Therapeut Program, 6130 Execut Blvd, Rockville, MD 20852 USA. EM beverly.teicher@nih.gov NR 33 TC 4 Z9 4 U1 0 U2 0 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD OCT PY 2011 VL 39 IS 4 BP 841 EP 851 DI 10.3892/ijo.2011.1091 PG 11 WC Oncology SC Oncology GA 815NU UT WOS:000294533100010 PM 21701770 ER PT J AU Gorelick, DA Goodwin, RS Schwilke, E Schwope, DM Darwin, WD Kelly, DL McMahon, RP Liu, F Ortemann-Renon, C Bonnet, D Huestis, MA AF Gorelick, David A. Goodwin, Robert S. Schwilke, Eugene Schwope, David M. Darwin, William D. Kelly, Deanna L. McMahon, Robert P. Liu, Fang Ortemann-Renon, Catherine Bonnet, Denis Huestis, Marilyn A. TI Antagonist-Elicited Cannabis Withdrawal in Humans SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE antagonist; cannabis; marijuana; rimonabant; withdrawal ID CB1 RECEPTOR ANTAGONISTS; ENDOCANNABINOID SYSTEM; ORAL THC; DEPENDENCE; MARIJUANA; PHARMACOKINETICS; QUESTIONNAIRE; RELIABILITY; DISORDERS; TOLERANCE AB Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Delta(9)-tetrahydrocannabinol (THC) dosages (40-120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0-8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses. C1 [Gorelick, David A.; Goodwin, Robert S.; Schwilke, Eugene; Schwope, David M.; Darwin, William D.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Kelly, Deanna L.; McMahon, Robert P.; Liu, Fang] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA. [Ortemann-Renon, Catherine; Bonnet, Denis] Sanofi Aventis Rech, Montpellier, France. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd,Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov RI McMahon, Robert/C-5462-2009 FU National Institutes of Health, National Institute on Drug Abuse (NIDA); NIDA Residential Research Support Services [HHSN271200599091CADB]; Sanofi-Aventis FX This study was supported by the Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse (NIDA); by NIDA Residential Research Support Services contract no. HHSN271200599091CADB (D. L. Kelly, PI); and by Sanofi-Aventis. NR 35 TC 11 Z9 11 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2011 VL 31 IS 5 BP 603 EP 612 DI 10.1097/JCP.0b013e31822befc1 PG 10 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 814OU UT WOS:000294467300011 PM 21869692 ER PT J AU Dahl, M Bouchelouche, P Kramer-Marek, G Capala, J Nordling, J Bouchelouche, K AF Dahl, Malin Bouchelouche, Pierre Kramer-Marek, Gabriela Capala, Jacek Nordling, Jorgen Bouchelouche, Kirsten TI Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells SO MOLECULAR BIOLOGY REPORTS LA English DT Article DE HER2/neu; LNCaP; Prostate cancer; Sarcosine ID GROWTH-FACTOR RECEPTOR; HUMAN-BREAST; HER-2/NEU; PROGRESSION; ONCOGENE; PATHWAY; LEVEL AB Increasing evidence suggests that Human epidermal growth factor receptor 2 (HER2/neu) is involved in progression of prostate cancer. Recently, sarcosine was reported to be highly increased during prostate cancer progression, and exogenous sarcosine induces an invasive phenotype in benign prostate epithelial cells. The aim of this work was to investigate the effect of sarcosine on HER2/neu expression in prostate cancer cell lines LNCaP (androgen dependent), PC-3 and DU145 (both androgen independent). Relative amounts of HER2/neu and androgen receptor (AR) transcripts were determined using RT-qPCR. Total expression of HER2/neu was confirmed by Western blot (WB). HER2/neu protein on the surface of living LNCaP cells was visualized by confocal microscopy using a HER2/neu-specific fluorescent probe. Exposure of LNCaP cells to 50 mu M sarcosine for 24 h resulted in a 58% increase of the HER2/neu mRNA level (P < 0.001) indicating that sarcosine effects HER2/neu expression on the level of transcription. Control experiments with alanine, an isomer of sarcosine, showed no significant effect on HER2/neu transcription. The upregulation of HER2/neu mRNA preceded the corresponding increment of the protein level after the 48-h exposure to sarcosine as shown by WB and confocal microscopy. Interestingly, sarcosine had no effect on the activated (phosphorylated) form of HER2/neu. No significant change in AR expression was observed after exposure to sarcosine. This is the first report indicating that sarcosine is involved in the regulation of the oncoprotein HER2/neu. Thus, sarcosine may induce prostate cancer progression by increased HER2/neu expression. However, detailed information on cellular mechanisms remains to be elucidated. C1 [Dahl, Malin; Bouchelouche, Pierre; Bouchelouche, Kirsten] Univ Copenhagen, Koege Hosp, Canc & Mol Imaging Unit, Res Div Clin Biochem, DK-4600 Koege, Denmark. [Kramer-Marek, Gabriela; Capala, Jacek] NCI, Mol Targeting Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Nordling, Jorgen] Univ Copenhagen, Herlev Hosp, Dept Urol, DK-2730 Herlev, Denmark. [Bouchelouche, Kirsten] Univ Copenhagen, Rigshosp, PET & Cyclotron Unit, DK-2100 Copenhagen, Denmark. RP Dahl, M (reprint author), Univ Copenhagen, Koege Hosp, Canc & Mol Imaging Unit, Res Div Clin Biochem, DK-4600 Koege, Denmark. EM mjda@regionsjaelland.dk FU Holger K. Christiansen Foundation, Denmark [74272 KB]; Foundation of Region of Zealand, Denmark [1-01-83-0011-07]; NIH, National Cancer Institute, Center for Cancer Research FX We thank Majken Madvig Jansen (Cancer and Molecular Imaging Unit, Department of Clinical Biochemistry, Koege Hospital, Denmark) for expert technical assistance. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. This work was sponsored by the Holger K. Christiansen Foundation, Denmark, Grant no. 74272 KB; Foundation of Region of Zealand, Denmark, Grant no. 1-01-83-0011-07. The contribution of JC and GKM to this work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 20 TC 13 Z9 14 U1 0 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-4851 J9 MOL BIOL REP JI Mol. Biol. Rep. PD OCT PY 2011 VL 38 IS 7 BP 4237 EP 4243 DI 10.1007/s11033-010-0442-2 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 813JK UT WOS:000294362500001 PM 21755295 ER PT J AU Kitanaka, J Kitanaka, N Hall, FS Uhl, GR Tatsuta, T Morita, Y Tanaka, K Nishiyama, N Takemura, M AF Kitanaka, Junichi Kitanaka, Nobue Hall, F. Scott Uhl, George R. Tatsuta, Tomohiro Morita, Yoshio Tanaka, Koh-ichi Nishiyama, Nobuyoshi Takemura, Motohiko TI Histamine H-3 Receptor Agonists Decrease Hypothalamic Histamine Levels and Increase Stereotypical Biting in Mice Challenged with Methamphetamine SO NEUROCHEMICAL RESEARCH LA English DT Article DE Methamphetamine; Histamine; Hypothalamus; Behavior ID RAT STRIATAL SLICES; BEHAVIORAL SENSITIZATION; AMPHETAMINE PSYCHOSIS; DOPAMINERGIC-NEURONS; ANIMAL-MODELS; BRAIN; INHIBITION; RELEASE; ANTAGONIST; (R)-ALPHA-METHYLHISTAMINE AB The effects of the histamine H-3 receptor agonists (R)-alpha-methylhistamine, imetit and immepip on methamphetamine (METH)-induced stereotypical behavior were examined in mice. The administration of METH (10 mg/kg, i.p.) to male ddY mice induced behaviors including persistent locomotion and stereotypical behaviors, which were classified into four categories: stereotypical head-bobbing (1.9%), circling (1.7%), sniffing (14.3%), and biting (82.1%). Pretreatment with (R)-alpha-methylhistamine (3 and 10 mg/kg, i.p.) significantly decreased stereotypical sniffing, but increased stereotypical biting induced by METH, in a dose-dependent manner. This effect of (R)-alpha-methylhistamine on behavior was mimicked by imetit or immepip (brain-penetrating selective histamine H-3 receptor agonists; 10 mg/kg, i.p. for each drug). Hypothalamic histamine levels 1 h after METH challenge were significantly increased in mice pretreated with saline. These increases in histamine levels were significantly decreased by pretreatment with histamine H-3 receptor agonists, effects which would appear to underlie the shift from METH-induced stereotypical sniffing to biting. C1 [Kitanaka, Junichi; Kitanaka, Nobue; Takemura, Motohiko] Hyogo Coll Med, Dept Pharmacol, Nishinomiya, Hyogo 6638501, Japan. [Hall, F. Scott; Uhl, George R.] NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Morita, Yoshio] Baika Womens Univ, Fac Nursing, Osaka 5678578, Japan. RP Kitanaka, J (reprint author), Hyogo Coll Med, Dept Pharmacol, Nishinomiya, Hyogo 6638501, Japan. EM kitanaka-hyg@umin.net RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan [21790254]; Hyogo College of Medicine; National Institute on Drug Abuse (NIH/DHHS, USA, GRU, FSH) FX The authors are grateful to Ms. A. Yoshioka of the Department of Pharmacology, Hyogo College of Medicine, for preparing the animal study proposal. This research was supported, in part, by a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (No. 21790254 to N.K.), a Grant-in-Aid for Researchers from Hyogo College of Medicine (2009-2010 to J.K.), and intramural funding from the National Institute on Drug Abuse (NIH/DHHS, USA, GRU, FSH). NR 31 TC 3 Z9 3 U1 1 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD OCT PY 2011 VL 36 IS 10 BP 1824 EP 1833 DI 10.1007/s11064-011-0500-8 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 812BL UT WOS:000294262600014 PM 21573995 ER PT J AU Derringer, J Krueger, RF Manz, N Porjesz, B Almasy, L Bookman, E Edenberg, HJ Kramer, JR Tischfield, JA Bierut, LJ AF Derringer, Jaime Krueger, Robert F. Manz, Niklas Porjesz, Bernice Almasy, Laura Bookman, Ebony Edenberg, Howard J. Kramer, John R. Tischfield, Jay A. Bierut, Laura J. CA GENEVA Consortium TI Nonreplication of an association of SGIP1 SNPs with alcohol dependence and resting theta EEG power SO PSYCHIATRIC GENETICS LA English DT Article DE alcoholism; candidate gene association study; electroencephalogram ID GENOME-WIDE ASSOCIATION AB A recent study in a sample of Plains Indians showed association between eight single nucleotide polymorphisms (SNPs) located in the SGIP1 gene and resting theta electroencephalogram (EEG) power. This association appeared to generalize to alcohol use disorders, for which EEG power is a potential endophenotype. We analyzed a large, diverse sample for replication of the association of these implicated SGIP1 SNPs (genotyped on the Illumina 1M platform) with alcohol dependence (N = 3988) and theta EEG power (N = 1066). We found no evidence of association of the earlier implicated SGIP1 SNPs with either alcohol dependence or theta EEG power (all P > 0.15) in this sample. The earlier implicated SNPs located in SGIP1 gene showed no association with alcohol dependence or theta EEG power in this sample of individuals with European and/or African ancestry. This failure to replicate may be the result of differences in ancestry between this sample and the original sample. Psychiatr Genet 21:265-266 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Derringer, Jaime; Krueger, Robert F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Manz, Niklas; Porjesz, Bernice] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Bookman, Ebony] NHGRI, Bethesda, MD 20892 USA. [Edenberg, Howard J.] Indiana Univ, Indiana, PA USA. [Kramer, John R.] Univ Iowa, Iowa City, IA USA. [Tischfield, Jay A.] Rutgers State Univ, Piscataway, NJ 08855 USA. [Bierut, Laura J.] Washington Univ, St Louis, MO USA. RP Derringer, J (reprint author), Univ Minnesota, Dept Psychol, N218 Elliott Hall,75 E River Rd, Minneapolis, MN 55455 USA. EM derri023@umn.edu RI Manz, Niklas/A-3234-2009; OI Manz, Niklas/0000-0003-1483-915X; Derringer, Jaime/0000-0002-7352-9859; Tischfield, Jay/0000-0003-3217-8287; Edenberg, Howard/0000-0003-0344-9690 FU NIH [AA008401, CA089392, DA013423, DA029377, GM081739, HG004422, HG004438, HG004446, HHSN268200782096C] FX This study was funded by NIH AA008401, NIH CA089392, NIH DA013423, NIH DA029377 (J.D.), NIH GM081739 (J.D.), NIH HG004422, NIH HG004438, NIH HG004446, NIH HHSN268200782096C. NR 4 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD OCT PY 2011 VL 21 IS 5 BP 265 EP 266 DI 10.1097/YPG.0b013e32834371fd PG 2 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 814LH UT WOS:000294454100008 PM 21317682 ER PT J AU Thanos, PK Subrize, M Lui, W Puca, Z Ananth, M Michaelides, M Wang, GJ Volkow, ND AF Thanos, Panayotis K. Subrize, Mike Lui, Wendy Puca, Zachary Ananth, Mala Michaelides, Michael Wang, Gene-Jack Volkow, Nora D. TI D-Cycloserine Facilitates Extinction of Cocaine Self-Administration in c57 Mice SO SYNAPSE LA English DT Article DE D-cycloserine; NMDA; agonist; extinction; cocaine ID CONDITIONED PLACE PREFERENCE; NUCLEUS-ACCUMBENS; EXPOSURE THERAPY; FEAR EXTINCTION; DRUG-DEPENDENCE; RATS; MECHANISMS; RECEPTOR; SEEKING; CONSOLIDATION AB Introduction: Cocaine is a highly addictive drug of abuse for which there are currently no medications. In rats and mice d-cycloserine (DCS), a partial NMDA agonist, accelerates extinction of cocaine seeking behavior. Since cues delay extinction here, we evaluated the effects d-cycloserine in extinction with and without the presence of cues. Methods: Two doses of DCS (15 and 30 mg/kg) were studied in C57 mice. Mice self-administered cocaine (1 mg/kg) for 2 weeks and then underwent a 20-day extinction period where DCS was administered i.p. immediately following each daily session. Extinction was conducted in some mice with the presence of cocaine-paired cues; while others were in the absence of these cues. Results: DCS treated mice (either dose) showed significantly reduced lever pressing during extinction with cue exposures when compared with vehicle treated mice. Without cues, animals showed much lower levels of lever pressing but the differences between vehicle and DCS were not significant. Conclusion: DCS accelerated extinction with the presence of cues, but there were no differences on extinction without cues as compared with vehicle. These findings are consistent with DCS disrupting the memory process associated with the cues. Since drug cues are significantly involved in relapse, these findings support research to assess the therapeutic potential of DCS in cocaine addiction. Synapse 65:1099-1105, 2011. Published 2011 Wiley-Liss, Inc.(dagger) C1 [Thanos, Panayotis K.; Volkow, Nora D.] NIAAA, Lab Neuroimaging, NIH, Bethesda, MD USA. [Thanos, Panayotis K.; Subrize, Mike; Lui, Wendy; Puca, Zachary; Ananth, Mala; Michaelides, Michael; Wang, Gene-Jack] Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, Upton, NY 11973 USA. [Thanos, Panayotis K.; Subrize, Mike; Michaelides, Michael] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. RP Thanos, PK (reprint author), NIAAA, Lab Neuroimaging, NIH, Bethesda, MD USA. EM thanos@bnl.gov RI Michaelides, Michael/K-4736-2013 OI Michaelides, Michael/0000-0003-0398-4917 FU NIDA, NIAAA FX Contract grant sponsors: NIDA, NIAAA (Intramural Research Program, LNI) NR 36 TC 14 Z9 14 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-4476 EI 1098-2396 J9 SYNAPSE JI Synapse PD OCT PY 2011 VL 65 IS 10 BP 1099 EP 1105 DI 10.1002/syn.20944 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 815UN UT WOS:000294555400015 PM 21584863 ER PT J AU Ludwig, DB Webb, JN Fernandez, C Carpenter, JF Randolph, TW AF Ludwig, D. Brett Webb, Jonathan N. Fernandez, Cristina Carpenter, John F. Randolph, Theodore W. TI Quaternary Conformational Stability: The Effect of Reversible Self-Association on the Fibrillation of Two Insulin Analogs SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE protein aggregation; reversible self-association; quaternary structure; conformational stability ID PROTEIN SECONDARY STRUCTURE; CIRCULAR-DICHROISM SPECTROSCOPY; AQUEOUS-SOLUTIONS; AGGREGATION KINETICS; MECHANISM; PH; STABILIZATION; INTERMEDIATE; PROINSULIN; MUTANTS AB Under conditions relevant to the manufacturing of insulin (e. g., pH 3, room temperature), biosynthetic human insulin (BHI), and Lispro insulin (Lispro) require a nucleation step to initiate aggregation. However, upon seeding with preformed aggregates, both insulins rapidly aggregate into nonnative fibrils. Far ultraviolet circular dichroism (far-UV CD) and second derivative Fourier transform infrared (2D-FTIR) spectroscopic analyses show that the fibrillation process involves a change in protein secondary structure from alpha-helical in native insulin to predominantly beta-sheet in the nonnative fibrils. After seeding, Lispro aggregates faster than BHI, likely because of a reduced propensity to reversibly self-associate. Composition gradient multi-angle light scattering (CG-MALS) analyses show that Lispro is more monomeric than BHI, whereas their conformational stabilities measured by denaturant-induced unfolding are statistically indistinguishable. For both BHI and Lispro, as the protein concentration increases, the apparent first-order rate constant for soluble protein loss decreases. To explain these phenomena, we propose an aggregation model that assumes fibril growth through monomer addition with competitive inhibition by insulin dimers. Biotechnol. Bioeng. 2011; 108: 2359-2370. (C) 2011 Wiley Periodicals, Inc. C1 [Ludwig, D. Brett; Randolph, Theodore W.] Univ Colorado, Ctr Pharmaceut Biotechnol, Dept Chem & Biol Engn, Boulder, CO 80309 USA. [Webb, Jonathan N.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Fernandez, Cristina] NIDDKD, Lab Biochem & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Carpenter, John F.] Univ Colorado Denver, Dept Pharmaceut Sci, Univ Colorado, Ctr Pharmaceut Biotechnol, Aurora, CO USA. RP Randolph, TW (reprint author), Univ Colorado, Ctr Pharmaceut Biotechnol, Dept Chem & Biol Engn, Boulder, CO 80309 USA. EM theodore.randolph@colorado.edu RI randolph, theodore/A-3301-2013; Fernandez, Cristina/G-2269-2015 OI Fernandez, Cristina/0000-0003-3792-4015 NR 60 TC 4 Z9 4 U1 0 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD OCT PY 2011 VL 108 IS 10 BP 2359 EP 2370 DI 10.1002/bit.23188 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 810EH UT WOS:000294107700012 PM 21520027 ER PT J AU Sridhar, SS Winquist, E Eisen, A Hotte, SJ McWhirter, E Tannock, IF Mukherjee, SD Wang, LS Blattler, C Wright, JJ Moore, MJ AF Sridhar, Srikala S. Winquist, Eric Eisen, Andrea Hotte, Sebastien J. McWhirter, Elaine Tannock, Ian F. Mukherjee, Som D. Wang, Lisa Blattler, Chantale Wright, John J. Moore, Malcolm J. TI A phase II trial of sorafenib in first-line metastatic urothelial cancer: a study of the PMH Phase II Consortium SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Sorafenib; Metastatic urothelial cancer; Phase II; First-line ID ADVANCED HEPATOCELLULAR-CARCINOMA; URINARY-BLADDER CANCER; GROWTH-FACTOR; CELL CARCINOMA; GEMCITABINE; PROGRESSION; EXPRESSION; RECEPTOR; RAS; MULTICENTER AB Background Sorafenib is an oral multikinase inhibitor that blocks cell proliferation via the ERK pathway and angiogenesis via the VEGF pathway. This phase II trial was conducted to determine the efficacy and tolerability of sorafenib for the treatment of patients with metastatic urothelial cancer (UC) who had not had prior chemotherapy for advanced disease. Patients and Methods Seventeen chemo-na < ve UC patients with adequate performance status and organ function were treated with sorafenib 400 mg twice daily on a continuous basis until progression or unacceptable toxicity. The primary endpoint was objective tumor response rate as measured by RECIST criteria. Secondary endpoints included rate of prolonged stable disease (> 3 months), time to progression, median and 1 yr survival and safety and tolerability. Results There were no objective responses. Only one patient had stable disease by RECIST criteria and remained on treatment more than 3 months. Three patients had stable disease by RECIST criteria but were on treatment less than 3 months due to progressive disease (PD) or adverse events (AE). Eight patients had PD by RECIST criteria as their best overall response. Two patients had symptomatic PD prior to cycle 2 evaluation, and three patients were inevaluable (1 death, 1 AE, 1 withdrew consent).The time to progression was 1.9 months (range 0.7-8.7 months) and median survival was 5.9 months. The most common grade 3+ toxicities were abdominal pain, back pain, hand-foot reaction and bladder infection. Conclusions Sorafenib does not show sufficient activity as a single agent in first-line metastatic urothelial cancer to warrant further investigation. C1 [Sridhar, Srikala S.; Tannock, Ian F.; Wang, Lisa; Blattler, Chantale; Moore, Malcolm J.] Phase 2 Consortium, Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. [Winquist, Eric] London Reg Canc Ctr, London, ON N6A 4L6, Canada. [Eisen, Andrea] Odette Canc Ctr, Toronto, ON, Canada. [Hotte, Sebastien J.; McWhirter, Elaine; Mukherjee, Som D.] Juravinski Canc Ctr, Hamilton, ON, Canada. [Wright, John J.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Sridhar, SS (reprint author), Phase 2 Consortium, Princess Margaret Hosp, 610 Univ Ave,Suite 5-222, Toronto, ON M5G 2M9, Canada. EM srikala.sridhar@uhn.on.ca NR 25 TC 44 Z9 44 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD OCT PY 2011 VL 29 IS 5 BP 1045 EP 1049 DI 10.1007/s10637-010-9408-4 PG 5 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 811PC UT WOS:000294223500036 PM 20191303 ER PT J AU Peters, JA Kenen, R Hoskins, LM Koehly, LM Graubard, B Loud, JT Greene, MH AF Peters, June A. Kenen, Regina Hoskins, Lindsey M. Koehly, Laura M. Graubard, Barry Loud, Jennifer T. Greene, Mark H. TI Unpacking the Blockers: Understanding Perceptions and Social Constraints of Health Communication in Hereditary Breast Ovarian Cancer (HBOC) Susceptibility Families SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE Health communication; Hereditary breast-ovarian cancer; Family; Social network; Social constraint; Social support ID GENETIC RELATIONSHIP MAP; BREAST/OVARIAN CANCER; MUTATION CARRIERS; PROSTATE-CANCER; RISK ASSESSMENT; INFORMATION; MEMBERS; BRCA2; WOMEN; RELATIVES AB Family communication is essential for accurate cancer risk assessment and counseling; family blockers play a role in this communication process. This qualitative analysis of social exchanges is an extension of earlier work characterizing those who are perceived by study participants as health information gatherers, disseminators, and blockers within families with Hereditary Breast and Ovarian Cancer (HBOC) susceptibility. Eighty-nine women, ages 23-56 years, enrolled in a Breast Imaging Study (BIS) and participated in a sub-study utilizing a social assessment tool known as the Colored Ecological Genetic Relational Map (CEGRM). Purposive sampling ensured that participants varied according to numbers of participating family members e.g., ranging from 1 to 6. Eighty-nine women from 42 families (1-8 relatives/family) participated. They collectively designated 65 blockers, both male and female. Situational factors, beliefs, attitudes and cultural traditions, privacy and protectiveness comprised perceived reasons for blocking intra-family health communications. Longitudinal data collected over 4 years showed families where blocking behavior was universally recognized and stable over time, as well as other families where blocking was less consistent. Self-blocking was observed among a significant minority of participating women. Blocking of health communications among family members with HBOC was variable, complex, and multifaceted. The reasons for blocking were heterogeneous; duration of the blocking appeared to depend on the reasons for blocking. Blocking often seemed to involve bi-directional feedback loops, in keeping with Lepore's Social Constraints and Modulation Theory. Privacy and protectiveness predominated as explanations for long-term blocking. C1 [Peters, June A.; Hoskins, Lindsey M.; Loud, Jennifer T.; Greene, Mark H.] NCI, Clin Genet Branch CGB, Div Canc Epidemiol & Genet DCEG, NIH,Dept Hlth & Human Serv DHHS, Rockville, MD 20852 USA. [Kenen, Regina] Coll New Jersey, Ewing, NJ USA. [Koehly, Laura M.] NHGRI, Social & Behav Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Graubard, Barry] NCI, Biostat Branch, DCEG, NIH,DHHS, Rockville, MD USA. RP Peters, JA (reprint author), NCI, Clin Genet Branch CGB, Div Canc Epidemiol & Genet DCEG, NIH,Dept Hlth & Human Serv DHHS, 6120 Execut Blvd, Rockville, MD 20852 USA. EM petersju@mail.nih.gov FU US National Cancer Institute; National Human Genome Research Institute, National Institutes of Health; Westat, Inc., Rockville, MD, USA [NO2-CP-11019-50, N02-CP-65504] FX This work was supported by the Intramural Research Programs of the US National Cancer Institute and National Human Genome Research Institute, National Institutes of Health, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD, USA. NR 61 TC 9 Z9 9 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 J9 J GENET COUNS JI J. Genet. Couns. PD OCT PY 2011 VL 20 IS 5 BP 450 EP 464 DI 10.1007/s10897-011-9370-0 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 811PH UT WOS:000294224200005 PM 21547418 ER PT J AU Chechneva, OV Mayrhofer, F Daugherty, DJ Pleasure, DE Hong, JS Deng, WD AF Chechneva, Olga V. Mayrhofer, Florian Daugherty, Daniel J. Pleasure, David E. Hong, Jau-Shyong Deng, Wenbin TI Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Low dose dextromethorphan; EAE; NOX2 NADPH oxidase; Microglia; CNS infiltration; Demyelination; Axonal loss ID INJURY FOLLOWING TRANSIENT; MULTIPLE-SCLEROSIS; DOPAMINERGIC-NEURONS; NADPH OXIDASE; INFLAMMATORY DAMAGE; OXIDATIVE STRESS; OPIOID RECEPTORS; FOCAL ISCHEMIA; MICE; PROTECTS AB Dextromethorphan (DM) is a dextrorotary morphinan and a widely used component of cough medicine. Relatively high doses of DM in combination with quinidine are used for the treatment of mood disorders for patients with multiple sclerosis (MS). However, at lower doses, morphinans exert anti-inflammatory activities through the inhibition of NOX2-dependent superoxide production in activated microglia. Here we investigated the effects of high (10 mg/kg, i.p., "DM-10") and low (0.1 mg/kg, i.p., "DM-0.1") doses of DM on the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found no protection by high dose DM treatment. Interestingly, a minor late attenuation by low dose DM treatment was seen in severe EAE that was characterized by a chronic disease course and a massive spinal cord infiltration of CD45(+) cells including T-lymphocytes, macrophages and neutrophils. Furthermore, in a less severe form of EAE, where lower levels of CD4(+) and CD8(+) T-cells, Iba1(+) microglia/macrophages and no significant infiltration of neutrophils were seen in the spinal cord, the treatment with DM-0.1 was remarkably more beneficial. The effect was the most significant at the peak of disease and was associated with an inhibition of NOX2 expression and a decrease in infiltration of monocytes and lymphocytes into the spinal cord. In addition, chronic treatment with low dose DM resulted in decreased demyelination and reduced axonal loss in the lumbar spinal cord. Our study is the first report to show that low dose DM is effective in treating EAE of moderate severity. Our findings reveal that low dose morphinan DM treatment may represent a new promising protective strategy for treating MS. (C) 2011 Elsevier Inc. All rights reserved. C1 [Chechneva, Olga V.; Mayrhofer, Florian; Daugherty, Daniel J.; Deng, Wenbin] Univ Calif Davis, Dept Cell Biol & Human Anat, Sch Med, Sacramento, CA 95817 USA. [Deng, Wenbin] Shriners Hosp Children, Inst Pediat Regenerat Med, Sacramento, CA 95817 USA. [Hong, Jau-Shyong] Natl Inst Environm Sci, Neuropharmacol Sect, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Deng, WD (reprint author), UC Davis Sch Med, 2425 Stockton Blvd,Room 6538, Sacramento, CA 95817 USA. EM wbdeng@ucdavis.edu FU National Institutes of Health [R01NS061983, R01ES015988]; National Multiple Sclerosis Society; Shriners Hospitals for Children FX The authors thank Dr. Vimal Selvaraj and Dr. Athena Soulika for insightful suggestions, Joy X. Jiang for help in establishing lucigenin-enhanced chemiluminescence assay, John Avery for technical assistance and Eunyoung Lee for providing the CCL2 primers and CD4 antibody. This work was in part supported by grants to W.D. from the National Institutes of Health (R01NS061983, R01ES015988), National Multiple Sclerosis Society, and Shriners Hospitals for Children. NR 45 TC 14 Z9 14 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 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD OCT PY 2011 VL 44 IS 1 BP 63 EP 72 DI 10.1016/j.nbd.2011.06.004 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 811HO UT WOS:000294197700007 PM 21704706 ER PT J AU Reynolds, CP Kang, MH Keir, ST Gorlick, R Kolb, EA Lock, R Maris, JM Carol, H Morton, CL Billups, CA Smith, MA Houghton, PJ AF Reynolds, C. Patrick Kang, Min H. Keir, Stephen T. Gorlick, Richard Kolb, E. Anders Lock, Richard Maris, John M. Carol, Hernan Morton, Christopher L. Billups, Catherine A. Smith, Malcolm A. Houghton, Peter J. TI Initial Testing of Lenalidomide by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; lenalidomide; preclinical testing ID CHRONIC LYMPHOCYTIC-LEUKEMIA; REFRACTORY MULTIPLE-MYELOMA; MANTLE CELL LYMPHOMA; IN-VIVO; MYELODYSPLASTIC SYNDROMES; DELETION 5Q; TUMOR MICROENVIRONMENT; ANTITUMOR-ACTIVITY; CANCER MODELS; EFFICACY AB Background. Lenalidomide, a novel immunomodulatory agent, is reported to modulate stem cell differentiation, and have direct antiproliferative activity as well as inhibit inflammation and hyperalgesia. On the basis of this varied pharmacological profile, lenalidomide is under investigation as a treatment for a range of oncologic indications. Procedures. Lenalidomide was evaluated against the PPTP in vitro panel using 96-hr exposure at concentrations ranging from 1 nM to 10 mu M. It was tested against the PPTP in vivo panels at a dose of 30 mg/kg administered orally (PO) once daily for a planned for 6 weeks. Results. In vitro activity was not observed at concentrations up to 10 mu M. Lenalidomide was well tolerated, and induced significant differences in EFS distribution compared to control in 7 of 37 (18.9%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. The best response in the solid tumor panel was PD2 [progressive disease with growth delay (EFS TIC > 1.5)], observed in 4 of 37 (10.8%) solid tumor xenografts. A single ALL xenograft showed a PD2 response. Conclusions. Direct antiproliferative effects of lenalidomide were not observed in vitro. In vivo lenalidomide demonstrated low activity against tumors in immune-deficient mice. Our results suggest that lenalidomide's utility in the pediatric clinical setting may depend upon its ability to induce antitumor activity through effects on host immune and stromal cells rather than through direct effects on tumor cells. Pediatr Blood Cancer 2011;57:606-611. (C) 2011 Wiley-Liss, Inc. C1 [Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Ctr Canc, Lubbock, TX 79430 USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders; Lock, Richard; Carol, Hernan] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Maris, John M.] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [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. [Morton, Christopher L.; Billups, Catherine A.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. RP Reynolds, CP (reprint author), Texas Tech Univ, Hlth Sci Ctr, Ctr Canc, 3601 4th St,STOP 9445, Lubbock, TX 79430 USA. EM patrick.reynolds@ttuhsc.edu 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 National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, CA21765, CA108786. NR 54 TC 3 Z9 3 U1 2 U2 3 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 OCT PY 2011 VL 57 IS 4 BP 606 EP 611 DI 10.1002/pbc.22877 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 810QA UT WOS:000294140000015 PM 21360651 ER PT J AU Bhagia, P Colanta, AB Abramson, DH Carlson, DL Kleinerman, RA Kraus, D Dunkel, IJ AF Bhagia, Pooja Colanta, Agnes Basas Abramson, David H. Carlson, Diane L. Kleinerman, Ruth A. Kraus, Dennis Dunkel, Ira J. TI Sinonasal Adenocarcinoma: A Rare Second Malignancy in Long Term Retinoblastoma Survivors SO PEDIATRIC BLOOD & CANCER LA English DT Article DE retinoblastoma; sinonasal adenocarcinoma; second malignancy ID BILATERAL RETINOBLASTOMA; NONOCULAR TUMORS; CHILDHOOD-CANCER; FOLLOW-UP; RISK; RADIOTHERAPY AB Retinoblastoma is the most common primary cancer of the eye in children. The incidence of second tumors in survivors of bilateral retinoblastoma and in survivors of unilateral retinoblastoma who presumably carry a germline RB1 mutation is documented. This article describes the previously unrecognized association of sinonasal adenocarcinoma as a second malignancy in retinoblastoma Key words: retinoblastoma; sinonasal survivors. We present three cases who received radiation therapy as a part of their treatment and developed sinonasal adenocarcinoma as a second malignancy. Sinonasal adenocarcinoma should be considered as a second malignancy in retinoblastoma survivors who present with vague sinus symptoms. Pediatr Blood Cancer 2011; 57:693-695. (C) 2011 Wiley-Liss, Inc. C1 [Bhagia, Pooja; Dunkel, Ira J.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA. [Colanta, Agnes Basas] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Abramson, David H.] Mem Sloan Kettering Canc Ctr, Ophthalm Oncol Serv, New York, NY 10021 USA. [Carlson, Diane L.] Cleveland Clin, Director Breast & Head & Neck Pathol, New York, NY USA. [Kleinerman, Ruth A.] NCI, Div Canc Epidemiol & Genet, New York, NY USA. [Kraus, Dennis] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. RP Bhagia, P (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pediat, POB 139, New York, NY 10065 USA. EM bhagiap@mskcc.org OI Dunkel, Ira/0000-0001-8091-6067; Kleinerman, Ruth/0000-0001-7415-2478 FU National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 20 TC 2 Z9 2 U1 0 U2 0 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 OCT PY 2011 VL 57 IS 4 BP 693 EP 695 DI 10.1002/pbc.23161 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 810QA UT WOS:000294140000033 PM 21548012 ER PT J AU Oh, A Dodd, K Ballard-Barbash, R Perna, FM Berrigan, D AF Oh, April Dodd, Kevin Ballard-Barbash, Rachel Perna, Frank M. Berrigan, David TI Language Use and Adherence to Multiple Cancer Preventive Health Behaviors Among Hispanics SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE Adherence; Behavior patterns; Language use; Acculturation; Hispanic ID NUTRITION EXAMINATION SURVEY; OLDER MEXICAN-AMERICANS; QUALITY-OF-LIFE; UNITED-STATES; CIGARETTE-SMOKING; PHYSICAL-ACTIVITY; NATIONAL-HEALTH; RISK BEHAVIORS; TOBACCO USE; ACCULTURATION AB Hispanics have lower cancer mortality rates than non-Hispanic Whites and Blacks, despite demographic profiles previously associated with higher cancer mortality. Differences in adherence to multiple cancer-preventive behaviors by acculturation may offer one explanation for this "Hispanic paradox," but the relationship is not well understood. We examined this relationship using the 2000 National Health Interview Survey, which provides cross-sectional data on a nationally representative sample of US Hispanics. Multinomial logistic regression models estimated relationships between language use (a measure of acculturation) and patterns of adherence, by gender, to multiple cancer-preventive health behaviors using adherence scores. Hispanics had greater odds of adherence to multiple behaviors compared to Non-Hispanics (OR = 2.76 [2.27, 3.36]). Hispanics with greater English language use had lower odds of adherence (OR = 0.45 [0.29, 0.69]). Women were more adherent than men (P < 0.01) and their language use was associated with patterns of behavioral adherence more so than among men. Differences by gender and language use were identified in patterns of adherence to behavioral recommendations among the Hispanic population. Greater English language use was negatively associated with tobacco, alcohol, fruit and vegetable recommendation adherence but not with exercise. Study findings support evidence behaviors occur in combination and contributes to understanding of the role of language use in patterns of behavioral adherence. C1 [Oh, April; Perna, Frank M.] NCI, Div Canc Control & Prevent, Behav Researchn Program, Hlth Promot Res Branch, Rockville, MD 20852 USA. [Dodd, Kevin] NCI, Biometry Res Grp, Rockville, MD 20852 USA. [Ballard-Barbash, Rachel; Berrigan, David] NCI, Div Canc Control & Prevent, Appl Res Program, Rockville, MD 20852 USA. RP Oh, A (reprint author), NCI, Div Canc Control & Prevent, Behav Researchn Program, Hlth Promot Res Branch, 6130 Execut Blvd,Room 4087B,MSC 7335, Rockville, MD 20852 USA. EM ohay@mail.nih.gov NR 64 TC 5 Z9 5 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD OCT PY 2011 VL 13 IS 5 BP 849 EP 859 DI 10.1007/s10903-011-9456-7 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 806ZN UT WOS:000293857400007 PM 21431332 ER PT J AU Qin, HD Jia, WH Zhang, LL Liu, N Zhou, XX Wang, MH Feng, QS Chen, LZ Zhang, Y Jorgensen, TJ Zeng, YX Shugart, YY AF Qin, Hai-De Jia, Wei-Hua Zhang, Lin-Lin Liu, Na Zhou, Xin-Xi Wang, Ming-Hsi Feng, Qi-Sheng Chen, Li-Zhen Zhang, Ying Jorgensen, Timothy J. Zeng, Yi-Xin Shugart, Yin Yao TI Elevated Epstein-Barr Virus Seroreactivity Among Unaffected Members of Families With Nasopharyngeal Carcinoma SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE Epstein Barr virus; nasopharyngeal carcinoma; seroreactivity; familial correlation; multiplex and sporadic families ID CIGARETTE-SMOKING; SALTED FISH; WUZHOU-CITY; MASS SURVEY; RISK; ANTIBODY; TAIWAN; CHINA; CONSUMPTION; ALCOHOL AB Serum antibodies to Epstein Barr virus (EBV) antigens can be used to predict the risk of nasopharyngeal carcinoma (NPC). To investigate whether EBV seropositivity rates were higher among healthy family members from multiplex and sporadic families with NPC (i.e., families with multiple or single cases) compared to the general population, a study was conducted on 2,665 unaffected individuals from 140 multiplex and 413 sporadic families. The titers of the IgA antibody to the EBV capsid antigen (VCA-IgA) were compared to those of 904 controls from the general population. The VCA-IgA titer was correlated among sibling pairs to a high significance in both family types (P < 0.0001 and P = 0.0005 for the multiplex and the sporadic families, respectively); parent offspring pairs also showed significant correlation (P < 0.0001 and P = 0.0002, respectively); and spouse pairs were correlated, but at lower significance levels (P = 0.0790 and P = 0.0040, respectively). When compared to the controls, among first-degree relatives in the multiplex families, the age- and gender-adjusted odds ratio (OR) was 2.06 (95% confidence interval 1.56-2.71), 3.55 (2.24-5.64), and 2.25 (1.57-3.23) for siblings, parents, and children, respectively. In the sporadic families, the adjusted OR was 1.55 (1.21-2.00) and 2.08 (1.51-2.86) for siblings and parents, respectively. The adjusted P-value of spouses lost significance in the multiplex families, but remained significant in the sporadic families (P = 0.0146). In conclusion, EBV seropositivity rates were elevated among unaffected family members in both multiplex and sporadic families with NPC. J. Med. Virol. 83:1792-1798, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Qin, Hai-De; Jia, Wei-Hua; Zhang, Lin-Lin; Liu, Na; Zhou, Xin-Xi; Feng, Qi-Sheng; Chen, Li-Zhen; Zeng, Yi-Xin] Sun Yat Sen Univ, State Key Lab Oncol S China, Dept Expt Res, Ctr Canc, Guangzhou 510060, Guangdong, Peoples R China. [Wang, Ming-Hsi; Zhang, Ying] Sun Yat Sen Univ, Clin Dept Nasopharyngeal Carcinoma, Ctr Canc, Guangzhou 510060, Guangdong, Peoples R China. [Jorgensen, Timothy J.] Georgetown Univ, Dept Radiat Med, Lombardi Comprehens Canc Ctr, Jess & Mildred Fisher Ctr Familial Canc Res, Washington, DC USA. [Shugart, Yin Yao] NIMH, Unit Stat Genom, Div Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Jia, WH (reprint author), Sun Yat Sen Univ, State Key Lab Oncol S China, Dept Expt Res, Ctr Canc, 651 Dongfeng Rd E, Guangzhou 510060, Guangdong, Peoples R China. EM jiaweih@mail.sysu.edu.cn; kay1yao@mail.nih.gov FU National Natural Science Foundation of China [30671798, 30471487, 81000925]; National Science and Technology Support Program of China [2006BAI02A11]; National Major Basic Research Program of China [863: 2006AA02A404]; Science Technology Ministry of China [2004DFA05700]; UICC [RO3CA113240] FX Grant sponsor: National Natural Science Foundation of China; Grant numbers: 30671798; 30471487; 81000925; Grant sponsor: National Science and Technology Support Program of China; Grant number: 2006BAI02A11; Grant sponsor: National Major Basic Research Program of China; Grant number: 863: 2006AA02A404; Grant sponsor: Key International Collaborative Project by the Science Technology Ministry of China; Grant number: 2004DFA05700; Grant sponsor: UICC YY Award (Year 2005); Grant number: RO3CA113240. NR 22 TC 6 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD OCT PY 2011 VL 83 IS 10 BP 1792 EP 1798 DI 10.1002/jmv.22121 PG 7 WC Virology SC Virology GA 808NO UT WOS:000293985900017 PM 21837797 ER PT J AU Topol, I Collins, J Savitsky, A Nemukhin, A AF Topol, I. Collins, J. Savitsky, A. Nemukhin, A. TI Computational strategy for tuning spectral properties of red fluorescent proteins SO BIOPHYSICAL CHEMISTRY LA English DT Article DE Red fluorescent proteins; Photoabsorption spectra; Quantum calculations; Electric field influence ID MONOMERIC RED; CHROMOPHORE; VARIANTS; MFRUITS; ASFP595; COLOR AB Computational methods of quantum chemistry are used to characterize structures and vertical excitation energies of the S-0-S-1 optical transitions in the chromophore binding pockets of the red fluorescent proteins DsRed and of its artificial mutant mCherry. As previously shown, optimizing the equilibrium geometry configurations with B3LYP density functional theory, followed by ZINDO calculations of the electronic excitations, yields positions of the optical bands in good agreement with experimental data. These large scale quantum calculations elucidate the role of the hydrogen bonded network as well as point mutations in the absorption spectra of the DsRed and mCherry proteins. The effect of an external electric field applied to the fluorescent protein chromophores is examined and shows that such fields may result in large shifts in spectral bands. These strategies can be applied for rational design of the fluorescent proteins by site-directed mutagenesis. (C) 2011 Elsevier B.V. All rights reserved. C1 [Topol, I.; Collins, J.] NCI, SAIC Frederick Inc, Informat Syst Program, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. [Savitsky, A.; Nemukhin, A.] Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119991, Russia. [Savitsky, A.] Russian Acad Sci, AN Bach Inst Biochem, Moscow 119071, Russia. [Nemukhin, A.] Russian Acad Sci, NM Emanuel Inst Biochem Phys, Moscow 119334, Russia. RP Topol, I (reprint author), NCI, SAIC Frederick Inc, Informat Syst Program, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. EM topoli@mail.nih.gov RI Savitsky, Alexander/O-9799-2015; Nemukhin, Alexander/P-9662-2015 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Russian Foundation for Basic Research [10-03-00085]; Russian Academy of Sciences FX We thank the staff and administration of the Advanced Biomedical Computing Center for their support of this project. We thank Dr. Brian Luke for very helpful comments. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government. This work is partly supported by the Russian Foundation for Basic Research (project 10-03-00085) and the Program of Molecular and Cell Biology from the Russian Academy of Sciences. NR 21 TC 14 Z9 14 U1 2 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD OCT PY 2011 VL 158 IS 2-3 BP 91 EP 95 DI 10.1016/j.bpc.2011.05.016 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 804SI UT WOS:000293673900001 PM 21652139 ER PT J AU Younes, A Lukyanenko, YO Lyashkov, AE Lakatta, EG Sollott, SJ AF Younes, Antoine Lukyanenko, Yevgeniya O. Lyashkov, Alexey E. Lakatta, Edward G. Sollott, Steven J. TI A bioluminescence method for direct measurement of phosphodiesterase activity SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Phosphodiesterase; Assay; Bioluminescence ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; ADENYLATE KINASE; BAKERS-YEAST; ATP; MYOCYTES; CLONING; ASSAY; AMP AB We have adapted bioluminescence methods to be able to measure phosphodiesterase (PDE) activity in a one-step technique. The method employs a four-enzyme system (PDE, adenylate kinase (AK) using excess CTP instead of ATP as substrate, pyruvate kinase (PK), and firefly luciferase) to generate ATP, with measurement of the concomitant luciferase-light emission. Since AK, PK, and luciferase reactions are coupled to recur in a cyclic manner, AMP recycling maintains a constant rate of ATP formation, proportional to the steady-state AMP concentration. The cycle can be initiated by the PDE reaction that yields AMP. As long as the PDE reaction is rate limiting, the system is effectively at steady state and the bioluminescence kinetics progresses at a constant rate proportional to the PDE activity. In the absence of cAMP and PDE, low concentrations of AMP trigger the AMP cycling, which allows standardizing the system. The sensitivity of the method enables detection of <1 mu U (pmol/min) of PDE activity in cell extracts containing 0.25-10 mu g protein. Assays utilizing pure enzyme showed that 0.2 mM IBMX completely inhibited PDE activity. This single-step enzyme- and substrate-coupled cyclic-reaction system yields a simplified, sensitive, reproducible, and accurate method for quantifying PDE activities in small biological samples. Published by Elsevier Inc. C1 [Younes, Antoine; Lukyanenko, Yevgeniya O.; Lyashkov, Alexey E.; Lakatta, Edward G.; Sollott, Steven J.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, 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 National Institutes of Health, NIA FX This work was supported by the National Institutes of Health Intramural Research Program, NIA. NR 21 TC 4 Z9 4 U1 0 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD OCT 1 PY 2011 VL 417 IS 1 BP 36 EP 40 DI 10.1016/j.ab.2011.05.036 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 802ZB UT WOS:000293548400004 PM 21693101 ER PT J AU Tai, AW Bojjireddy, N Balla, T AF Tai, Andrew W. Bojjireddy, Naveen Balla, Tamas TI A homogeneous and nonisotopic assay for phosphatidylinositol 4-kinases SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Phosphoinositides; Phosphatidylinositol 4-kinase; Kinase assay; High-throughput screening assays ID C VIRUS-REPLICATION; CLONING; BIOLUMINESCENT; EXPRESSION; EXTRACTS; KINASES; ENZYMES; ALPHA; GOLGI; BETA AB Phosphatidylinositol 4-kinases (PI 4-kinases) catalyze the conversion of phosphatidylinositol to phosphatidylinositol 4-phosphate (PtdIns4P). The four known mammalian PI 4-kinases, PI4KA, PI4KB, PI4K2A, and PI4K2B have roles in intracellular lipid and protein trafficking. PI4KA and PI4KB also assist in the replication of several positive-sense RNA viruses. The identification of selective inhibitors of these kinases would be facilitated by assays suitable for high-throughput screening. We describe a homogeneous and nonisotopic assay for PI 4-kinase activity based on the bioluminescent detection of the ADP produced by kinase reactions. We have evaluated this assay with known nonselective inhibitors of PI 4-kinases and show that it performs similar to radiometric assay formats previously described in the literature. In addition, this assay generates Z-factor values of >0.7 for PI4KA in a 384-well format, demonstrating its suitability for high-throughput screening applications. (C) 2011 Elsevier Inc. All rights reserved. C1 [Tai, Andrew W.] Univ Michigan, Div Gastroenterol, Dept Internal Med, Ann Arbor, MI 48105 USA. [Tai, Andrew W.] Ann Arbor Vet Adm Hlth Syst, Div Gastroenterol, Dept Internal Med, Ann Arbor, MI 48105 USA. [Bojjireddy, Naveen; Balla, Tamas] NICHD, Sect Mol Signal Transduct, Ctr Dev Neurosci, NIH, Bethesda, MD USA. RP Tai, AW (reprint author), Univ Michigan, Div Gastroenterol, Dept Internal Med, 6520 MSRB I SPC 5682,1150W Med Ctr Dr, Ann Arbor, MI 48105 USA. EM andrewwt@med.umich.edu OI Balla, Tamas/0000-0002-9077-3335; Tai, Andrew/0000-0002-6877-450X FU National Institutes of Health [AI083785]; Foundation of the American Gastroenterological Association; Greenview Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported in part by Grant AI083785 of the National Institutes of Health, the Foundation of the American Gastroenterological Association, and the Greenview Foundation (to A.W.T.), as well as the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (to T.B.). The generous gift of the human FLAG-tagged PI4KB by Drs. Gordon Polevoy and Julie Brill is highly appreciated. NR 23 TC 28 Z9 28 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 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD OCT 1 PY 2011 VL 417 IS 1 BP 97 EP 102 DI 10.1016/j.ab.2011.05.046 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 802ZB UT WOS:000293548400012 PM 21704602 ER PT J AU Ohtsuka, H Oikawa, M Ariake, K Rikiyama, T Motoi, F Katayose, Y Unno, M Johnson, AC AF Ohtsuka, Hideo Oikawa, Masaya Ariake, Kyohei Rikiyama, Toshiki Motoi, Fuyuhiko Katayose, Yu Unno, Michiaki Johnson, Alfred C. TI GC-binding factor 2 interacts with Dishevelled and regulates Wnt signaling pathways in human carcinoma cell lines SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE GCF2; dishevelled; Wnt; RhoA; migration; LRRFIP1 ID FLIGHTLESS-I PROTEIN; LEUCINE-RICH REPEAT; EMBRYONIC-DEVELOPMENT; CONVERGENT EXTENSION; AXIS FORMATION; RHO-GTPASES; ACTIVATION; POLARITY; FAMILY; GASTRULATION AB GC-binding factor 2 (GCF2), a transcriptional repressor that decreases the activity of several genes is capable of binding directly to the GC-rich sequence of the EGFR promoter and repressing the transcriptional activity of EGFR. In addition to its function as a transcriptional repressor, GCF2 can directly interact with other proteins such as flightless-1 (Fli-1). Many previous findings pertaining to the function of Fli-1 have suggested a role for fli-1 in providing a direct link between molecules involved in signal transduction pathways and the actin cytoskeleton. We hypothesized that GCF2, together with Fli-1, plays a role in regulating cytoskeleton function, cell migration, and/or morphology. In our study, we observed that GCF2 is crucial for the activation of RhoA, a small GTPase that plays a key role in the regulation of the actin cytoskeleton. RhoA was markedly inactivated as a result of the decreased expression of GCF2. Co-immunoprecipitations were subsequently performed to further investigate the mechanism for the repressive function. We identified dishevelled (Dvl), which is the key mediator for the Wnt pathway, as a binding partner with GCF2. These results strongly suggest that GCF2 plays a role in the Wnt-noncanonical planar cell polarity (PCP) signaling pathway. Consequently, GCF2 may regulate the cytoskeleton or migration via Dvls and RhoA. C1 [Ohtsuka, Hideo] Tohoku Univ, Div Gastroenterol Surg, Dept Surg, Aoba Ku, Sendai, Miyagi 9808574, Japan. [Ohtsuka, Hideo; Oikawa, Masaya; Rikiyama, Toshiki; Johnson, Alfred C.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ohtsuka, H (reprint author), Tohoku Univ, Div Gastroenterol Surg, Dept Surg, Aoba Ku, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan. EM ohtsuka@surg1.med.tohoku.ac.jp RI Unno, Michiaki/A-8633-2010 OI Unno, Michiaki/0000-0002-2145-6416 NR 46 TC 6 Z9 10 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 1 PY 2011 VL 129 IS 7 BP 1599 EP 1610 DI 10.1002/ijc.25837 PG 12 WC Oncology SC Oncology GA 798XX UT WOS:000293246600006 PM 21140450 ER PT J AU Kosaka, N Mitsunaga, M Longmire, MR Choyke, PL Kobayashi, H AF Kosaka, Nobuyuki Mitsunaga, Makoto Longmire, Michelle R. Choyke, Peter L. Kobayashi, Hisataka TI Near infrared fluorescence-guided real-time endoscopic detection of peritoneal ovarian cancer nodules using intravenously injected indocyanine green SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cancer; endoscopy; near infrared; indocyanine green; surgery assistance ID IN-VIVO; GASTRIC-CANCER; SENTINEL NODE; BREAST; METASTASES; CONJUGATE; PROTEINS; TARGET; PROBE AB Near infrared fluorescence-guidance can be used for the detection of small cancer metastases and can aid in the endoscopic management of cancer. Indocyanine green (ICG) is a Food and Drug Administration (FDA)-approved fluorescence agent. Through non-specific interactions with serum proteins, ICG achieves enhanced permeability and retention (EPR) effects. Yet, ICG demonstrates rapid clearance from the circulation. Therefore, ICG may be an ideal contrast agent for real-time fluorescence imaging of tumors. To evaluate the usefulness of real-time dual fluorescence and white light endoscopic optical imaging to detect tumor implants using the contrast agent ICG, fluorescence-guided laparoscopic procedures were performed in mouse models of peritoneally disseminated ovarian cancers. Animals were administered intravenous ICG or a control contrast agent, IR800-conjugated to albumin. The ability to detect small ovarian cancer implants was then compared. Using the dual view microendoscope, ICG clearly enabled visualization of peritoneal ovarian cancer metastatic nodules derived from SHIN3 and OVCAR5 cells at 6 and 24 hr after injection with significantly higher tumor-to-background ratio than the control agent, IR800-albumin (p < 0.001). In conclusion, ICG has the desirable properties of having both EPR effects and rapid clearance for the real-time endoscopic detection of tiny ovarian cancer peritoneal implants compared to a control macromolecular agent with theoretically better EPR effects but longer circulatory retention. Given that ICG is already FDA-approved and has a long track record of human use, this method could be easily translated to the clinic as a robust tool for fluorescence-guided endoscopic procedures for the management and treatment of cancer. C1 [Kosaka, Nobuyuki; Mitsunaga, Makoto; Longmire, Michelle R.; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69,MSC1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX Grant sponsors: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 25 TC 43 Z9 44 U1 1 U2 23 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 1 PY 2011 VL 129 IS 7 BP 1671 EP 1677 DI 10.1002/ijc.26113 PG 7 WC Oncology SC Oncology GA 798XX UT WOS:000293246600013 PM 21469142 ER PT J AU Genkinger, JM Spiegelman, D Anderson, KE Bernstein, L van den Brandt, PA Calle, EE English, DR Folsom, AR Freudenheim, JL Fuchs, CS Giles, GG Giovannucci, E Horn-Ross, PL Larsson, SC Leitzmann, M Mannisto, S Marshall, JR Miller, AB Patel, AV Rohan, TE Stolzenberg-Solomon, RZ Verhage, BAJ Virtamo, J Willcox, BJ Wolk, A Ziegler, RG Smith-Warner, SA AF Genkinger, Jeanine M. Spiegelman, Donna Anderson, Kristin E. Bernstein, Leslie van den Brandt, Piet A. Calle, Eugenia E. English, Dallas R. Folsom, Aaron R. Freudenheim, Jo L. Fuchs, Charles S. Giles, Graham G. Giovannucci, Edward Horn-Ross, Pamela L. Larsson, Susanna C. Leitzmann, Michael Mannisto, Satu Marshall, James R. Miller, Anthony B. Patel, Alpa V. Rohan, Thomas E. Stolzenberg-Solomon, Rachael Z. Verhage, Bas A. J. Virtamo, Jarmo Willcox, Bradley J. Wolk, Alicja Ziegler, Regina G. Smith-Warner, Stephanie A. TI A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE pancreatic cancer; anthropometry; pooled analysis; deceased ID BODY-MASS INDEX; LARGE US COHORT; PHYSICAL-ACTIVITY; ALCOHOL-CONSUMPTION; UNITED-STATES; GLYCEMIC INDEX; OBESITY; WEIGHT; HEIGHT; WOMEN AB Epidemiologic studies of pancreatic cancer risk have reported null or nonsignificant positive associations for obesity, while associations for height have been null. Waist and hip circumference have been evaluated infrequently. A pooled analysis of 14 cohort studies on 846,340 individuals was conducted; 2,135 individuals were diagnosed with pancreatic cancer during follow-up. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Compared to individuals with a body mass index (BMI) at baseline between 21-22.9 kg/m(2), pancreatic cancer risk was 47% higher (95% CI:23-75%) among obese (BMI >= 30 kg/m(2)) individuals. A positive association was observed for BMI in early adulthood (pooled multivariate [MV]RR = 1.30, 95%CI = 1.09-1.56 comparing BMI >= 25 kg/m(2) to a BMI between 21 and 22.9 kg/m(2)). Compared to individuals who were not overweight in early adulthood (BMI < 25 kg/m(2)) and not obese at baseline (BMI < 30 kg/m(2)), pancreatic cancer risk was 54% higher (95%CI = 24-93%) for those who were overweight in early adulthood and obese at baseline. We observed a 40% higher risk among individuals who had gained BMI >= 10 kg/m(2) between BMI at baseline and younger ages compared to individuals whose BMI remained stable. Results were either similar or slightly stronger among never smokers. A positive association was observed between waist to hip ratio (WHR) and pancreatic cancer risk (pooled MVRR = 1.35 comparing the highest versus lowest quartile, 95%CI = 1.03-1.78). BMI and WHR were positively associated with pancreatic cancer risk. Maintaining normal body weight may offer a feasible approach to reducing morbidity and mortality from pancreatic cancer. C1 [Genkinger, Jeanine M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Spiegelman, Donna; Giovannucci, Edward; Smith-Warner, Stephanie A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Spiegelman, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Anderson, Kristin E.; Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Anderson, Kristin E.; Folsom, Aaron R.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Div Canc Etiol, Duarte, CA 91010 USA. [van den Brandt, Piet A.; Verhage, Bas A. J.] Maastricht Univ, Dept Epidemiol, Sch Oncol & Dev Biol GROW, Maastricht, Netherlands. [Calle, Eugenia E.; Patel, Alpa V.] Amer Canc Soc, Atlanta, GA 30329 USA. [English, Dallas R.; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [English, Dallas R.; Giles, Graham G.] Univ Melbourne, Melbourne, Vic, Australia. [Freudenheim, Jo L.; Marshall, James R.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Fuchs, Charles S.; Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Fuchs, Charles S.; Giovannucci, Edward] Harvard Univ, Sch Med, Boston, MA USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. [Giovannucci, Edward; Smith-Warner, Stephanie A.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Horn-Ross, Pamela L.] No Calif Canc Ctr, Fremont, CA USA. [Larsson, Susanna C.; Wolk, Alicja] Karolinska Inst, Div Nutr Epidemiol, Natl Inst Environm Med, Stockholm, Sweden. [Leitzmann, Michael; Stolzenberg-Solomon, Rachael Z.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Leitzmann, Michael] Univ Regensburg, Inst Epidemiol & Prevent Med, Regensburg, Germany. [Mannisto, Satu; Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Miller, Anthony B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Rohan, Thomas E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Willcox, Bradley J.] Univ Hawaii, John A Burns Sch Med, Manoa, HI USA. [Willcox, Bradley J.] Okinawa Res Ctr Longev Sci, Okinawa, Japan. [Willcox, Bradley J.] Pacific Hlth Res Inst, Honolulu, HI USA. [Willcox, Bradley J.] Queens Med Ctr, Honolulu, HI USA. [Ziegler, Regina G.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Genkinger, JM (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 722 W 168th St, New York, NY 10032 USA. EM jg3081@columbia.edu RI Larsson, Susanna/F-6065-2015; OI Larsson, Susanna/0000-0003-0118-0341; Mannisto, Satu/0000-0002-8668-3046; Giles, Graham/0000-0003-4946-9099; English, Dallas/0000-0001-7828-8188 FU National Institutes of Health [CA098566, CA55075] FX Grant sponsor: National Institutes of Health; Grant numbers: CA098566 and CA55075 NR 44 TC 70 Z9 71 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 1 PY 2011 VL 129 IS 7 BP 1708 EP 1717 DI 10.1002/ijc.25794 PG 10 WC Oncology SC Oncology GA 798XX UT WOS:000293246600017 PM 21105029 ER PT J AU Kwon, D Landi, MT Vannucci, M Issaq, HJ Prieto, D Pfeiffer, RM AF Kwon, Deukwoo Landi, Maria Teresa Vannucci, Marina Issaq, Haleem J. Prieto, DaRue Pfeiffer, Ruth M. TI An efficient stochastic search for Bayesian variable selection with high-dimensional correlated predictors SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article DE Correlated predictors; Correlation-based search; Proteomic data ID REGRESSION; MODELS; BINARY AB We present a Bayesian variable selection method for the setting in Which the number of independent variables or predictors in a particular dataset is much larger than the available sample size. While most of the existing methods allow some degree of correlations among predictors but do not consider these correlations for variable selection, our method accounts for correlations among the predictors in variable selection. Our correlation-based stochastic search (CBS) method, the hybrid-CBS algorithm, extends a popular search algorithm for high-dimensional data, the stochastic search variable selection (SSVS) method. Similar to SSVS, we search the space of all possible models using variable addition, deletion or swap moves. However, our moves through the model space are designed to accommodate correlations among the variables. We describe our approach for continuous, binary, ordinal, and count outcome data. The impact of choices of prior distributions and hyperparameters is assessed in simulation studies. We also examined the performance of variable selection and prediction as the correlation structure of the predictors varies. We found that the hybrid-CBS resulted in lower prediction errors and identified better the true outcome associated predictors than SSVS when predictors were moderately to highly correlated. We illustrate the method on data from a proteomic profiling study of melanoma, a type of skin cancer. Published by Elsevier B.V. C1 [Kwon, Deukwoo; Landi, Maria Teresa; Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Vannucci, Marina] Rice Univ, Dept Stat, Houston, TX 77251 USA. [Issaq, Haleem J.; Prieto, DaRue] SAIC Frederick Inc, Lab Prote & Analyt Technol, Frederick, MD 21702 USA. RP Kwon, D (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. EM kwonde@mail.nih.gov FU NIH National Cancer Institute; NIH [R01-HG0033190-05]; NSF [DMS1007871] FX We thank the Editor, Associate Editor and two referees for constructive suggestions that led to a significant improvement of the paper. Kwon, Landi, and Pfeiffer are supported by the Intramural Research Program of the NIH National Cancer Institute. Vannucci is partially supported by NIH grant R01-HG0033190-05 and NSF grant DMS1007871. NR 30 TC 5 Z9 5 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD OCT 1 PY 2011 VL 55 IS 10 BP 2807 EP 2818 DI 10.1016/j.csda.2011.04.019 PG 12 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 791JY UT WOS:000292662700003 PM 21686315 ER PT J AU Nam, JM AF Nam, Jun-mo TI Power and sample size requirements for non-inferiority in studies comparing two matched proportions where the events are correlated SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article DE Binary outcomes; Clustered matched pair; Intra-class correlation coefficient; Non-inferiority; Power; Sample size ID PAIR DATA; DESIGN; EQUIVALENCE AB Consider clustered matched-pair studies for non-inferiority where clusters are independent but units in a cluster are correlated. An inexpensive new procedure and the expensive standard one are applied to each unit and outcomes are binary responses. Appropriate statistics testing non-inferiority of a new procedure have been developed recently by several investigators. In this paper, we investigate power and sample size requirement of the clustered matched-pair study for non-inferiority. Power of a test is related primarily to the number of clusters. The effect of a cluster size on power is secondary. The efficiency of a clustered matched-pair design is inversely related to the intra-class correlation coefficient within a cluster. We present an explicit formula for obtaining the number of clusters for a given cluster size and the cluster size for a given number of clusters for a specific power. We also provide alternative sample size calculations when available information regarding parameters are limited. The formulas can be useful in designing a clustered matched-pair study for non-inferiority. An example for determining sample size to establish non-inferiority for a clustered matched-pair study is illustrated. Published by Elsevier B.V. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. RP Nam, JM (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd, Rockville, MD 20852 USA. EM namj@mail.nih.gov FU NIH, National Cancer Institute FX The author thanks two referees for their careful review and constructive comments that improved the manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 15 TC 7 Z9 7 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD OCT 1 PY 2011 VL 55 IS 10 BP 2880 EP 2887 DI 10.1016/j.csda.2011.04.020 PG 8 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 791JY UT WOS:000292662700009 PM 21949460 ER PT J AU Micozzi, D Pucciarelli, S Carpi, FM Costanzi, S De Sanctis, G Polzonetti, V Natalini, P Santarelli, IF Vita, A Vincenzetti, S AF Micozzi, Daniela Pucciarelli, Stefania Carpi, Francesco M. Costanzi, Stefano De Sanctis, Giampiero Polzonetti, Valeria Natalini, Paolo Santarelli, Ivano F. Vita, Alberto Vincenzetti, Silvia TI Role of tyrosine33 residue for the stabilization of the tetrameric structure of human cytidine deaminase (vol 47, pg 471, 2010) SO INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES LA English DT Correction C1 [Vita, Alberto; Vincenzetti, Silvia] Univ Camerino, Sch Vet Med Sci, I-62032 Camerino, Italy. [Micozzi, Daniela; Pucciarelli, Stefania; Carpi, Francesco M.; De Sanctis, Giampiero; Polzonetti, Valeria; Natalini, Paolo] Sch Biosci & Biotechnol, I-62032 Camerino, Italy. [Costanzi, Stefano] NIDDK, Lab Biol Modeling, NIH, DHHS, Bethesda, MD 20892 USA. [Santarelli, Ivano F.] Univ Camerino, Sch Pharm, I-62032 Camerino, Italy. RP Vincenzetti, S (reprint author), Univ Camerino, Sch Vet Med Sci, Via Gentile Ill da Varano, I-62032 Camerino, Italy. EM silvia.vincenzetti@unicam.it NR 1 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0141-8130 J9 INT J BIOL MACROMOL JI Int. J. Biol. Macromol. PD OCT 1 PY 2011 VL 49 IS 3 BP 439 EP 439 DI 10.1016/j.ijbiomac.2011.05.008 PG 1 WC Biochemistry & Molecular Biology; Chemistry, Applied; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 793WF UT WOS:000292853900030 ER PT J AU Schmitz, A Merikangas, K Swendsen, H Cui, LH Heaton, L Grillon, C AF Schmitz, Anja Merikangas, Kathleen Swendsen, Haruka Cui, Lihong Heaton, Leanne Grillon, Christian TI Measuring anxious responses to predictable and unpredictable threat in children and adolescents SO JOURNAL OF EXPERIMENTAL CHILD PSYCHOLOGY LA English DT Article DE Fear; Anxiety; Unpredictability; Psychophysiology; Startle reflex; Sex differences ID POSTTRAUMATIC-STRESS-DISORDER; COMMON MENTAL-DISORDERS; RCMAS LIE SCALE; ANXIETY DISORDERS; POTENTIATED STARTLE; AVERSIVE STIMULI; BED NUCLEUS; FEAR; MODULATION; AMYGDALA AB Research has highlighted the need for new methods to assess emotions in children on multiple levels to gain better insight into the complex processes of emotional development. The startle reflex is a unique translational tool that has been used to study physiological processes during fear and anxiety in rodents and in human participants. However, it has been challenging to implement developmentally appropriate startle experiments in children. This article describes a procedure that uses predictable and unpredictable aversive events to distinguish between phasic fear and sustained anxiety in children and adolescents. We investigated anxious responses, as measured with the startle reflex, in youths (N = 36, mean age = 12.63 years, range = 7-17) across three conditions: no aversive events (N), predictable aversive events (P), and unpredictable aversive events (U). Short-duration cues were presented several times in each condition. Aversive events were signaled by the cues in the P condition but were presented randomly in the U condition. Participants showed fear-potentiated startle to the threat cue in the P condition. Startle responses were also elevated between cues in the U condition compared with the N condition, suggesting that unpredictable aversive events can evoke a sustained state of anxiety in youths. This latter effect was influenced by sex, being greater in girls than in boys. These findings indicate the feasibility of this experimental induction of the startle reflex in response to predictable and unpredictable events in children and adolescents, enabling future research on interindividual differences in fear and anxiety and their development in youths. Published by Elsevier Inc. C1 [Schmitz, Anja; Merikangas, Kathleen; Swendsen, Haruka; Cui, Lihong; Heaton, Leanne] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, Bethesda, MD 20892 USA. RP Schmitz, A (reprint author), NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. EM schmitza2@mail.nih.gov FU Intramural NIH HHS [ZIA MH002804-08] NR 39 TC 13 Z9 14 U1 2 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-0965 J9 J EXP CHILD PSYCHOL JI J. Exp. Child Psychol. PD OCT PY 2011 VL 110 IS 2 SI SI BP 159 EP 170 DI 10.1016/j.jecp.2011.02.014 PG 12 WC Psychology, Developmental; Psychology, Experimental SC Psychology GA 791JE UT WOS:000292660700003 PM 21440905 ER PT J AU Esposito, G Venuti, P Bornstein, MH AF Esposito, G. Venuti, P. Bornstein, M. H. TI Assessment of distress in young children: A comparison of autistic disorder, developmental delay, and typical development SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Article DE Autism; Expression of distress; Cry ID SPECTRUM DISORDER; INFANTS CRY; PERCEPTION; AGE; CRIES AB Distress emotions in very young children are manifest in vocal, facial, and bodily cues. Moreover, children with different developmental conditions (i.e. autistic disorder, AD; developmental delay, DD; typically developing, TD) appear to manifest their distress emotions via different channels. To decompose channel of emotional distress display by group, we conducted a study in which video clips of crying of 18 children 18 months of age belonging to three groups (AD, DD, TD) were modified to isolate vocal, facial, or bodily cues, and 42 female adults were asked to judge the distress and typicality (expected normality) of the different stimuli. We find variation in adult judgements of distress and typicality by child group (AD, DD, TD) and by isolated cues (vocal, facial, or body). Although there is some overlap between responses to episodes of crying of children with AD and those with DD, the different cues of crying of children with AD tend to be considered more atypical and distressed than those of the other two groups (DD and TD). Early assessment of different cues of the expression of distress, and more generally of emotional expressivity in a child, may provide useful information for pediatricians and practitioners who are in contact with young children and must make clinical screening decisions. The findings also alert parents of children with AD to important aspects of their cries. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Esposito, G.] RIKEN, Brain Sci Inst, Kuroda Res Unit Affiliat Social Behav, Wako, Saitama, Japan. [Esposito, G.; Venuti, P.] Univ Trent, Observ & Funct Diag Lab DiSCoF, Trento, Italy. [Bornstein, M. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Esposito, G (reprint author), RIKEN, Brain Sci Inst, Kuroda Res Unit Affiliat Social Behav, Wako, Saitama, Japan. EM gesposito@brain.riken.jp RI Esposito, Gianluca/B-1374-2012 OI Esposito, Gianluca/0000-0002-9442-0254 FU Intramural NIH HHS [Z01 HD001119-20] NR 27 TC 9 Z9 9 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1750-9467 J9 RES AUTISM SPECT DIS JI Res. Autism Spectr. Disord. PD OCT-DEC PY 2011 VL 5 IS 4 BP 1510 EP 1516 DI 10.1016/j.rasd.2011.02.013 PG 7 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA 785NL UT WOS:000292235600026 PM 21647245 ER PT J AU Berta, AI Boesze-Battaglia, K Genini, S Goldstein, O O'Brien, PJ Szel, A Acland, GM Beltran, WA Aguirre, GD AF Berta, Agnes I. Boesze-Battaglia, Kathleen Genini, Sem Goldstein, Orly O'Brien, Paul J. Szel, Agoston Acland, Gregory M. Beltran, William A. Aguirre, Gustavo D. TI Photoreceptor Cell Death, Proliferation and Formation of Hybrid Rod/S-Cone Photoreceptors in the Degenerating STK38L Mutant Retina SO PLOS ONE LA English DT Article ID NUCLEAR RECEPTOR NR2E3; NEURAL REGENERATION; VISUAL PIGMENT; FACTOR NRL; MOUSE; EXPRESSION; PROTEIN; MODEL; GENE; TRANSCRIPTION AB A homozygous mutation in STK38L in dogs impairs the late phase of photoreceptor development, and is followed by photoreceptor cell death (TUNEL) and proliferation (PCNA, PHH3) events that occur independently in different cells between 7-14 weeks of age. During this period, the outer nuclear layer (ONL) cell number is unchanged. The dividing cells are of photoreceptor origin, have rod opsin labeling, and do not label with markers specific for macrophages/microglia (CD18) or Muller cells (glutamine synthetase, PAX6). Nestin labeling is absent from the ONL although it labels the peripheral retina and ciliary marginal zone equally in normals and mutants. Cell proliferation is associated with increased cyclin A1 and LATS1 mRNA expression, but CRX protein expression is unchanged. Coincident with photoreceptor proliferation is a change in the photoreceptor population. Prior to cell death the photoreceptor mosaic is composed of L/M-and S-cones, and rods. After proliferation, both cone types remain, but the majority of rods are now hybrid photoreceptors that express rod opsin and, to a lesser extent, cone S-opsin, and lack NR2E3 expression. The hybrid photoreceptors renew their outer segments diffusely, a characteristic of cones. The results indicate the capacity for terminally differentiated, albeit mutant, photoreceptors to divide with mutations in this novel retinal degeneration gene. C1 [Berta, Agnes I.; Genini, Sem; Beltran, William A.; Aguirre, Gustavo D.] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. [Berta, Agnes I.; Szel, Agoston] Semmelweis Univ, Dept Human Morphol & Dev Biol, H-1085 Budapest, Hungary. [Boesze-Battaglia, Kathleen] Univ Penn, Sch Dent Med, Philadelphia, PA 19104 USA. [Goldstein, Orly; Acland, Gregory M.] Cornell Univ, Coll Vet Med, JA Baker Inst, Ithaca, NY 14853 USA. [O'Brien, Paul J.] NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Berta, AI (reprint author), Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. EM gda@vet.upenn.edu FU National Eye Institute, National Institutes of Health [EY-06855, -13132, -17549, -10420, 18705, P30 EY-001583]; Foundation Fighting Blindness center; Van Sloun Fund for Canine Genetic Research; Hope for Vision; ONCE International Prize for R&D in Biomedicine; New Technologies for the Blind FX This work was supported by the National Eye Institute, National Institutes of Health grants EY-06855, -13132, -17549, -10420, 18705, P30 EY-001583, a Fulbright Educational Exchange Program Fellowship, Foundation Fighting Blindness center and individual grants, Van Sloun Fund for Canine Genetic Research, Hope for Vision, The ONCE International Prize for R&D in Biomedicine, and New Technologies for the Blind. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 15 Z9 15 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 30 PY 2011 VL 6 IS 9 AR e24074 DI 10.1371/journal.pone.0024074 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834ED UT WOS:000295941300004 PM 21980341 ER PT J AU Engel, ME Stander, R Vogel, J Adeyemo, AA Mayosi, BM AF Engel, Mark E. Stander, Raphaella Vogel, Jonathan Adeyemo, Adebowale A. Mayosi, Bongani M. TI Genetic Susceptibility to Acute Rheumatic Fever: A Systematic Review and Meta-Analysis of Twin Studies SO PLOS ONE LA English DT Review ID FAMILIAL DISEASE; CANCER AB Background: Acute rheumatic fever is considered to be a heritable condition, but the magnitude of the genetic effect is unknown. The objective of this study was to conduct a systematic review and meta-analysis of twin studies of concordance of acute rheumatic fever in order to derive quantitative estimates of the size of the genetic effect. Methods: We searched PubMed/MEDLINE, ISI Web of Science, EMBASE, and Google Scholar from their inception to 31 January 2011, and bibliographies of retrieved articles, for twin studies of the concordance for acute rheumatic fever or rheumatic heart disease in monozygotic versus dizygotic twins that used accepted diagnostic criteria for acute rheumatic fever and zygosity without age, gender or language restrictions. Twin similarity was measured by probandwise concordance rate and odds ratio (OR), and aggregate probandwise concordance risk was calculated by combining raw data from each study. ORs from separate studies were combined by random-effects meta-analysis to evaluate association between zygosity status and concordance. Heritability was estimated by fitting a variance components model to the data. Results: 435 twin pairs from six independent studies met the inclusion criteria. The pooled probandwise concordance risk for acute rheumatic fever was 44% in monozygotic twins and 12% in dizygotic twins, and the association between zygosity and concordance was strong (OR 6.39; 95% confidence interval, 3.39 to 12.06; P<0.001), with no significant study heterogeneity (P = 0.768). The estimated heritability across all the studies was 60%. Conclusions: Acute rheumatic fever is an autoimmune disorder with a high heritability. The discovery of all genetic susceptibility loci through whole genome scanning may provide a clinically useful genetic risk prediction tool for acute rheumatic fever and its sequel, rheumatic heart disease. C1 [Engel, Mark E.; Stander, Raphaella; Vogel, Jonathan; Mayosi, Bongani M.] Groote Schuur Hosp, Dept Med, ZA-7925 Cape Town, South Africa. [Engel, Mark E.; Stander, Raphaella; Vogel, Jonathan; Mayosi, Bongani M.] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Adeyemo, Adebowale A.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Engel, ME (reprint author), Groote Schuur Hosp, Dept Med, ZA-7925 Cape Town, South Africa. EM bongani.mayosi@uct.ac.za OI Adeyemo, Adebowale/0000-0002-3105-3231; Mayosi, Bongani/0000-0001-6641-8950 FU South African Medical Research Council; National Research Foundation of South Africa; Lily and Hausmann Research Trust FX Dr. A. A. Adeyemo was a Mellon Visiting Scholar to the University of Cape Town in July 2007 when the study was initiated. This study was funded in part by the South African Medical Research Council, National Research Foundation of South Africa, and Lily and Hausmann Research Trust. No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 30 Z9 30 U1 1 U2 6 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 SEP 30 PY 2011 VL 6 IS 9 AR e25326 DI 10.1371/journal.pone.0025326 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834ED UT WOS:000295941300024 PM 21980428 ER PT J AU Kim, S Sandler, DP Carswell, G Weinberg, CR Taylor, JA AF Kim, Sangmi Sandler, Dale P. Carswell, Gleta Weinberg, Clarice R. Taylor, Jack A. TI Reliability and Short-Term Intra-Individual Variability of Telomere Length Measurement Using Monochrome Multiplexing Quantitative PCR SO PLOS ONE LA English DT Article ID INSULIN-RESISTANCE; OXIDATIVE STRESS; BLADDER-CANCER; CELLS; RISK; DISEASE; MEN; AGE AB Background: Studies examining the association between telomere length and cancer risk have often relied on measurement of telomere length from a single blood draw using a real-time PCR technique. We examined the reliability of telomere length measurement using sequential samples collected over a 9-month period. Methods and Findings: Relative telomere length in peripheral blood was estimated using a single tube monochrome multiplex quantitative PCR assay in blood DNA samples from 27 non-pregnant adult women ( aged 35 to 74 years) collected in 7 visits over a 9-month period. A linear mixed model was used to estimate the components of variance for telomere length measurements attributed to variation among women and variation between time points within women. Mean telomere length measurement at any single visit was not significantly different from the average of 7 visits. Plates had a significant systematic influence on telomere length measurements, although measurements between different plates were highly correlated. After controlling for plate effects, 64% of the remaining variance was estimated to be accounted for by variance due to subject. Variance explained by time of visit within a subject was minor, contributing 5% of the remaining variance. Conclusion: Our data demonstrate good short-term reliability of telomere length measurement using blood from a single draw. However, the existence of technical variability, particularly plate effects, reinforces the need for technical replicates and balancing of case and control samples across plates. C1 [Kim, Sangmi; Sandler, Dale P.; Taylor, Jack A.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Carswell, Gleta; Taylor, Jack A.] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC USA. [Weinberg, Clarice R.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. RP Kim, S (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM kims3@niehs.nih.gov OI taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES044005, Z01 ES049033] FX This research was supported by the Intramural Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES044005 and Z01 ES049033). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 4 Z9 4 U1 0 U2 7 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 SEP 30 PY 2011 VL 6 IS 9 AR e25774 DI 10.1371/journal.pone.0025774 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834ED UT WOS:000295941300057 PM 21984947 ER PT J AU Thayer, JF Loerbroks, A Sternberg, EM AF Thayer, Julian F. Loerbroks, Adrian Sternberg, Esther M. TI Inflammation and cardiorespiratory control: The role of the vagus nerve SO RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY LA English DT Review DE Neural-immune; Vagus; Heart rate variability; Immune; Respiration; Asthma ID HEART-RATE-VARIABILITY; TO-BRAIN COMMUNICATION; CHOLINERGIC ANTIINFLAMMATORY PATHWAY; C-REACTIVE PROTEIN; SYMPATHETIC-NERVE; IMMUNE-SYSTEM; RAT SPLEEN; ASTHMA; NOREPINEPHRINE; INNERVATION AB Inflammation and immunity have been implicated in a wide variety of diseases and disorders ranging from asthma to cardiovascular disease to hemorrhagic shock. In this review we will briefly consider the evidence for the neural concomitants of immunomodulation. First, we will briefly review the anatomy and physiology of the cardiorespiratory system. Then we will review the anatomy and physiology of neural-immune communication. The nucleus of the solitary tract is a site of integration of both the afferent and efferent neural regulation of the cardiorespiratory as well as the immune system. Then we will provide an overview of what is known about neuroimmunomodulation from both animal and human studies including neuroimaging and clinical studies. Finally, we will discuss a possible role of this neural circuitry in asthma related health disparities. (C) 2011 Elsevier B.V. All rights reserved. C1 [Thayer, Julian F.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [Thayer, Julian F.; Loerbroks, Adrian] Heidelberg Univ, Mannheim Inst Publ Hlth, D-6800 Mannheim, Germany. [Sternberg, Esther M.] NIMH, NIH, Bethesda, MD 20892 USA. RP Thayer, JF (reprint author), Ohio State Univ, Dept Psychol, 1835 Neil Ave, Columbus, OH 43210 USA. EM Thayer.39@osu.edu FU Alexander von Humboldt Senior Research Award FX This work was supported by an Alexander von Humboldt Senior Research Award to Julian F. Thayer. NR 84 TC 31 Z9 32 U1 2 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9048 EI 1878-1519 J9 RESP PHYSIOL NEUROBI JI Respir. Physiol. Neuro. PD SEP 30 PY 2011 VL 178 IS 3 SI SI BP 387 EP 394 DI 10.1016/j.resp.2011.05.016 PG 8 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 829GX UT WOS:000295567700006 PM 21642019 ER PT J AU Manolio, TA Green, ED AF Manolio, Teri A. Green, Eric D. TI Genomics Reaches the Clinic: From Basic Discoveries to Clinical Impact SO CELL LA English DT Editorial Material ID MEDICINE AB Today, more than ever, basic science research provides significant opportunities to advance our understanding about the genetic basis of human disease. Close interactions among laboratory, computational, and clinical research communities will be crucial to ensure that genomic discoveries advance medical science and, ultimately, improve human health. C1 [Manolio, Teri A.; Green, Eric D.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Green, ED (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM egreen@nhgri.nih.gov NR 11 TC 20 Z9 20 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 30 PY 2011 VL 147 IS 1 BP 14 EP 16 DI 10.1016/j.cell.2011.09.012 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 827AJ UT WOS:000295396700007 PM 21962499 ER PT J AU Klein, IA Resch, W Jankovic, M Oliveira, T Yamane, A Nakahashi, H Di Virgilio, M Bothmer, A Nussenzweig, A Robbiani, DF Casellas, R Nussenzweig, MC AF Klein, Isaac A. Resch, Wolfgang Jankovic, Mila Oliveira, Thiago Yamane, Arito Nakahashi, Hirotaka Di Virgilio, Michela Bothmer, Anne Nussenzweig, Andre Robbiani, Davide F. Casellas, Rafael Nussenzweig, Michel C. TI Translocation-Capture Sequencing Reveals the Extent and Nature of Chromosomal Rearrangements in B Lymphocytes SO CELL LA English DT Article ID CLASS-SWITCH RECOMBINATION; CYTIDINE DEAMINASE AID; SOMATIC HYPERMUTATION; CELL LYMPHOMA; C-MYC; DNA BREAKS; FOLLICULAR LYMPHOMA; GENOMIC INSTABILITY; CANCER GENOME; BCL6 GENE AB Chromosomal rearrangements, including translocations, require formation and joining of DNA double strand breaks (DSBs). These events disrupt the integrity of the genome and are frequently involved in producing leukemias, lymphomas and sarcomas. Despite the importance of these events, current understanding of their genesis is limited. To examine the origins of chromosomal rearrangements we developed-Translocation Capture Sequencing (TC-Seq), a method to document chromosomal rearrangements genome-wide, in primary cells. We examined over 180,000 rearrangements obtained from 400 million B lymphocytes, revealing that proximity between DSBs, transcriptional activity and chromosome territories are key determinants of genome rearrangement. Specifically, rearrangements tend to occur in cis and to transcribed genes. Finally, we find that activation-induced cytidine deaminase (AID) induces the rearrangement of many genes found as translocation partners in mature B cell lymphoma. C1 [Yamane, Arito; Nakahashi, Hirotaka; Casellas, Rafael] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Klein, Isaac A.; Jankovic, Mila; Oliveira, Thiago; Di Virgilio, Michela; Bothmer, Anne; Robbiani, Davide F.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Nussenzweig, Andre] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Resch, Wolfgang; Yamane, Arito; Nakahashi, Hirotaka; Casellas, Rafael] NIAMSD, NIH, Bethesda, MD 20892 USA. [Oliveira, Thiago] Univ Sao Paulo, Natl Inst Sci & Technol Stem Cells & Cell Therapy, Dept Genet, Med Sch Ribeirao Preto, BR-14051140 Ribeirao Preto, SP, Brazil. [Oliveira, Thiago] Ctr Cell Based Therapy, BR-14051140 Ribeirao Preto, SP, Brazil. RP Casellas, R (reprint author), NCI, Ctr Canc Res, Bethesda, MD 20892 USA. EM casellar@mail.nih.gov; nussen@mail.rockefeller.edu RI Yamane, Arito/A-2959-2013; OI Oliveira, Thiago/0000-0002-2654-0879 FU NIH MSTP [GM07739]; NIH [AI037526]; NYSTEM [C023046]; Starr Cancer Consortium; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX We thank all the members of the Nussenzweig and Casellas labs for valuable input and advice; Klara Velinzon and Svetlana Mazel for FACSorting; and David Bosque and Thomas Eisenreich for animal management. We also thank Scott Dewell of the Rockefeller Genomics Resource Center and Gustavo Gutierrez of the NIAMS genome facility for high-throughput sequencing and guidance; as well as Christopher Mason of the Weill Cornell Medical College for assistance with data analysis. I. A. K. was supported by NIH MSTP grant GM07739, and is a Cancer Research Institute Predoctoral Fellow and a William Randolph Hearst Foundation Fellow. A. B. is a Cancer Research Institute Predoctoral Fellow. This work was supported by NIH grant #AI037526 to M.C.N., NYSTEM #C023046, The Starr Cancer Consortium and the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. M.C.N. is an HHMI investigator. NR 66 TC 163 Z9 165 U1 3 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 30 PY 2011 VL 147 IS 1 BP 95 EP 106 DI 10.1016/j.cell.2011.07.048 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 827AJ UT WOS:000295396700018 PM 21962510 ER PT J AU Chappie, JS Mears, JA Fang, SM Leonard, M Schmid, SL Milligan, RA Hinshaw, JE Dyda, F AF Chappie, Joshua S. Mears, Jason A. Fang, Shunming Leonard, Marilyn Schmid, Sandra L. Milligan, Ronald A. Hinshaw, Jenny E. Dyda, Fred TI A Pseudoatomic Model of the Dynamin Polymer Identifies a Hydrolysis-Dependent Powerstroke SO CELL LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; PLECKSTRIN HOMOLOGY DOMAIN; CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURE; GTPASE ACTIVITY; STALK REGION; IN-VIVO; MEMBRANE; CONSTRICTION; MECHANISM AB The GTPase dynamin catalyzes membrane fission by forming a collar around the necks of clathrin-coated pits, but the specific structural interactions and conformational changes that drive this process remain a mystery. We present the GMPPCP-bound structures of the truncated human dynamin 1 helical polymer at 12.2 angstrom and a fusion protein, GG, linking human dynamin 1's catalytic G domain to its GTPase effector domain (GED) at 2.2 angstrom. The structures reveal the position and connectivity of dynamin fragments in the assembled structure, showing that G domain dimers only form between tetramers in sequential rungs of the dynamin helix. Using chemical crosslinking, we demonstrate that dynamin tetramers are made of two dimers, in which the G domain of one molecule interacts in trans with the GED of another. Structural comparison of GG(GMPPCP) to the GG transition-state complex identifies a hydrolysis-dependent powerstroke that may play a role in membrane-remodeling events necessary for fission. C1 [Mears, Jason A.; Fang, Shunming; Hinshaw, Jenny E.] NIDDKD, Lab Cell Biochem & Biol, Bethesda, MD 20892 USA. [Chappie, Joshua S.; Dyda, Fred] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Mears, Jason A.] Case Western Reserve Univ, Dept Pharmacol, Sch Med, Cleveland, OH 44106 USA. [Leonard, Marilyn; Schmid, Sandra L.; Milligan, Ronald A.] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. RP Hinshaw, JE (reprint author), NIDDKD, Lab Cell Biochem & Biol, Bethesda, MD 20892 USA. EM jennyh@helix.nih.gov; dyda@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); NIH [GM52468, GM75820, GM42455]; National Institutes of Health through the National Center for Research Resources [RR017573] FX We thank Vasyl Lukiyanchuk and Sharmistha Acharya for assistance in cloning and purification, Rodolfo Ghirlando for assistance with sedimentation velocity experiments, Juha-Pekka Mattila for communication of unpublished data, Joshua Zimmerberg for insightful discussions, Alison B. Hickman for technical advice and critical reading of the manuscript, and Yihong Ye for critical reading of the manuscript. We especially thank Marijn Ford and Jodi Nunnari for the ongoing open dialogue regarding the intricacies of dynamin structure and assembly. This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and NIH grants GM52468 and GM75820 (to R.A.M.) and GM42455 (to S.L.S.). J.S.C. was supported by a Nancy Nossal Fellowship award from NIDDK. A portion of the work presented here was conducted at the National Resource for Automated Molecular Microscopy, which is supported by the National Institutes of Health through the National Center for Research Resources' P41 program (RR017573). NR 49 TC 87 Z9 89 U1 0 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 30 PY 2011 VL 147 IS 1 BP 209 EP 222 DI 10.1016/j.cell.2011.09.003 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 827AJ UT WOS:000295396700027 PM 21962517 ER PT J AU Zhong, YW Wang, Y Yang, H Ballar, P Lee, JG Ye, YH Monteiro, MJ Fang, SY AF Zhong, Yongwang Wang, Yang Yang, Hui Ballar, Petek Lee, Jin-gu Ye, Yihong Monteiro, Mervyn J. Fang, Shengyun TI Importin beta Interacts with the Endoplasmic Reticulum-associated Degradation Machinery and Promotes Ubiquitination and Degradation of Mutant alpha 1-Antitrypsin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ER-ASSOCIATED DEGRADATION; PROTEIN-QUALITY CONTROL; NUCLEAR-PORE COMPLEX; RETRO-TRANSLOCATION; MEMBRANE-PROTEIN; AAA-ATPASE; IN-VITRO; MISFOLDED GLYCOPROTEINS; DEUBIQUITINATING ENZYME; LIGASE AB The mechanism by which misfolded proteins in the endoplasmic reticulum (ER) are retrotranslocated to the cytosol for proteasomal degradation is still poorly understood. Here, we show that importin beta, a well established nucleocytoplasmic transport protein, interacts with components of the retrotranslocation complex and promotes ER-associated degradation (ERAD). Knockdown of importin beta specifically inhibited the degradation of misfolded ERAD substrates but did not affect turnover of non-ERAD proteasome substrates. Genetic studies and in vitro reconstitution assays demonstrate that importin beta is critically required for ubiquitination of mutant beta 1-antitrypsin, a luminal ERAD substrate. Furthermore, we show that importin beta cooperates with Ran GTPase to promote ubiquitination and proteasomal degradation of mutant beta 1-antitrypsin. These results establish an unanticipated role for importin beta in ER protein quality control. C1 [Zhong, Yongwang; Wang, Yang; Fang, Shengyun] Univ Maryland, Dept Physiol, Baltimore, MD 21201 USA. [Zhong, Yongwang; Wang, Yang; Yang, Hui; Ballar, Petek; Monteiro, Mervyn J.; Fang, Shengyun] Univ Maryland, Ctr Biomed Engn & Technol, Baltimore, MD 21201 USA. [Lee, Jin-gu; Ye, Yihong] NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Zhong, YW (reprint author), 725 W Lombard St,Rm N360, Baltimore, MD 21201 USA. EM sfang@umaryland.edu RI Monteiro, Mervyn/H-3813-2011; Zhong, Yongwang/A-2527-2012; Fang, Shengyun/H-3802-2011; OI Ballar, Petek/0000-0002-6189-1818 FU National Institutes of Health [GM06696, GM066287] FX This work was supported, in whole or in part, by National Institutes of Health Grants GM06696 (to S. F.) and GM066287 (to M. J. M.). NR 69 TC 13 Z9 13 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 SEP 30 PY 2011 VL 286 IS 39 BP 33921 EP 33930 DI 10.1074/jbc.M111.272906 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 823WW UT WOS:000295159200024 PM 21832065 ER PT J AU Ma, BY Nussinov, R AF Ma, Buyong Nussinov, Ruth TI Polymorphic Triple beta-Sheet Structures Contribute to Amide Hydrogen/Deuterium (H/D) Exchange Protection in the Alzheimer Amyloid beta 42 Peptide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; A-BETA; MOLECULAR-DYNAMICS; FIBRIL FORMATION; EXPERIMENTAL CONSTRAINTS; SECONDARY STRUCTURE; SOLVENT PROTECTION; PRION PROTEIN; WILD-TYPE; OLIGOMERS AB Characterization of the polymorphic structural range of A beta oligomers is important to the understanding of the mechanisms of toxicity. Yet for highly polymorphic ensembles, experimental structural elucidation is difficult. Here, we use a combination of NMR solvent protection experiments and computational structural screening to identify major species in the amyloid conformational ensemble. We examined the polymorphic pentamer and fibril seeds of A beta 42 and its mutants and compared the theoretical backbone amide protection obtained from simulations with experimental hydrogen/deuterium (H/D) exchange protection ratio. Weobserved that highly flexible pentamers do not share structural similarities with fibril seed oligomers, except the turn regions. We found that a novel amyloid structural motif of a triple beta-sheet, with the N-terminal residues interacting with the core (Lys(17)-Glu(22)) beta-sheet region, correlates with H/D exchange protection. The triple beta-sheet A beta 42 oligomer has a minimal exposure of hydrophobic residues and is further stabilized by the E22Q (Dutch) mutation in Alzheimer disease. The experimental H/D exchange solvent protection ratio implies that triple beta-sheet fibrils and globulomers could coexist in the A beta 42 ensemble, pointing to a broad heterogeneous aggregate population. Our results suggest that an approach that combines computational modeling with NMR protection data can be a useful strategy for obtaining clues to the preferred conformational species of the assemblies in solution and help in alleviating experimental difficulties and consequently possible errors in the exchange data for A beta 42 fibrils. C1 [Ma, Buyong; Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program,NIH, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Ma, BY (reprint author), NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program,NIH, Bldg 469,Rm 151, Frederick, MD 21702 USA. EM mabuyong@mail.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU National Institutes of Health, NCI [HHSN261200800001E]; NCI, CCR FX This work was supported, in whole or in part, by National Institutes of Health Grant HHSN261200800001E from the NCI and by the Intramural Research Program NCI, CCR. NR 45 TC 22 Z9 22 U1 1 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 SEP 30 PY 2011 VL 286 IS 39 BP 34244 EP 34253 DI 10.1074/jbc.M111.241141 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 823WW UT WOS:000295159200054 PM 21832091 ER PT J AU Sakurai, A Jian, XY Lee, CJ Manavski, Y Chavakis, E Donaldson, J Randazzo, PA Gutkind, JS AF Sakurai, Atsuko Jian, Xiaoying Lee, Charity J. Manavski, Yosif Chavakis, Emmanouil Donaldson, Julie Randazzo, Paul A. Gutkind, J. Silvio TI Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through Arf6 Protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE-EXCHANGE PROTEIN; POSTSYNAPTIC DENSITY; ACTIN CYTOSKELETON; TUMOR ANGIOGENESIS; CELL-ADHESION; MEMBRANE; DOMAIN; ALPHA; 4,5-BISPHOSPHATE; ENDOCYTOSIS AB The semaphorins are a family of secreted or membrane-bound proteins that are known to guide axons in the developing nervous system. Genetic evidence revealed that a class III semaphorin, semaphorin 3E (Sema3E), and its receptor Plexin-D1 also control the vascular patterning during development. At the molecular level, we have recently shown that Sema3E acts on Plexin-D1 expressed in endothelial cells, thus initiating a novel antiangiogenic signaling pathway that results in the retraction of filopodia in endothelial tip cells. Sema3E induces the rapid disassembly of integrin-mediated adhesive structures, thereby inhibiting endothelial cell adhesion to the extracellular matrix. This process requires the activation of small GTPase Arf6 (ADP-ribosylation factor 6), which regulates intracellular trafficking of beta 1 integrin. However, the molecular mechanisms by which Sema3E-Plexin-D1 activates Arf6 remained to be identified. Here we show that GEP100 (guanine nucleotide exchange protein 100)/Brag2, a guanine nucleotide exchange factor for Arf6, mediates Sema3E-induced Arf6 activation in endothelial cells. We provide evidence that upon activation by Sema3E, Plexin-D1 recruits phosphatidylinositol-4-phosphate 5-kinase, and its enzymatic lipid product, phosphatidylinositol 4,5-bisphosphate, binds to the pleckstrin homology domain of GEP100. Phosphatidylinositol 4,5-bisphosphate binding to GEP100 enhances its guanine nucleotide exchange factor activity toward Arf6, thus resulting in the disassembly of integrin-mediated focal adhesions and endothelial cell collapse. Our present study reveals a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix and migration. C1 [Sakurai, Atsuko; Lee, Charity J.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Jian, Xiaoying; Randazzo, Paul A.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Manavski, Yosif; Chavakis, Emmanouil] Goethe Univ, Inst Cardiovasc Regenerat, Ctr Mol Med, Frankfurt, Germany. [Chavakis, Emmanouil] Goethe Univ Frankfurt, Dept Internal Med 3, D-6000 Frankfurt, Germany. [Donaldson, Julie] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Rm 211, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009 FU National Institute of Dental and Craniofacial Research; Japan Society for the Promotion of Science; Deutsche Forschungsgemeinschaft [TR-SFB23, A2] FX This work was supported, in whole or in part, by a National Institutes of the extracellular matrix and causing the retraction of filopodia Health grant from Intramural Research Program of the National Institute of Dental and Craniofacial Research.; Supported by Japan Society for the Promotion of Science postdoctoral fellowships for research abroad.; Supported by Deutsche Forschungsgemeinschaft Grant TR-SFB23, Project A2. NR 45 TC 23 Z9 25 U1 1 U2 5 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 SEP 30 PY 2011 VL 286 IS 39 BP 34335 EP 34345 DI 10.1074/jbc.M111.259499 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 823WW UT WOS:000295159200062 PM 21795701 ER PT J AU Gloyd, M Ghirlando, R Guarne, A AF Gloyd, Melanie Ghirlando, Rodolfo Guarne, Alba TI The Role of MukE in Assembling a Functional MukBEF Complex SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE MukE; MukF; kleisin; MukB; chromosome segregation ID ESCHERICHIA-COLI; SMC PROTEINS; SEDIMENTATION-VELOCITY; BACILLUS-SUBTILIS; ANALYTICAL ULTRACENTRIFUGATION; CHROMOSOME; CONDENSIN; LOCALIZATION; BACTERIAL; KLEISINS AB The MukB-MukE-MukF protein complex is essential for chromosome condensation and segregation in Escherichia coli. The central component of this complex, the MukB protein, is related functionally and structurally to the ubiquitous SMC (structural maintenance of chromosomes) proteins. In a manner similar to SMC, MukB requires the association of two accessory proteins (MukE and MukF) for its function. MukF is a constitutive dimer that bridges the interaction between MukB and MukE. While MukB can condense DNA on its own, it requires MukF and MukE to ensure proper chromosome segregation. Here, we present a novel structure of the E. coli MukE MukF complex, in which the intricate crystal packing interactions reveal an alternative MukE dimerization interface spanning both N- and C-terminal winged-helix domains of the protein. The structure also unveils additional cross-linking interactions between adjacent MukE MukF complexes mediated by MukE. A variant of MukE encompassing point mutations on one of these surfaces does not affect assembly of the MukB-MukE-MukF complex and yet cannot restore the temperature sensitivity of the mukE::kan strain, suggesting that this surface may mediate critical protein-protein interactions between MukB-MukE-MukF complexes. Since the dimerization interface of MukE overlaps with the region of the protein that interacts with MukB in the MukB-MukE-MukF complex, we suggest that competing MukB-MukE and MukE-MukE interactions may regulate the formation of higher-order structures of bacterial condensin. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Gloyd, Melanie; Guarne, Alba] McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8S 4K1, Canada. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Guarne, A (reprint author), McMaster Univ, Dept Biochem & Biomed Sci, HSC 4N57A,1280 Main St W, Hamilton, ON L8S 4K1, Canada. EM guarnea@mcmaster.ca FU Canadian Institutes of Health Research [MOP 67189]; National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) FX We are grateful to Ms. Y. S. Chung and the PXRR staff at the Brookhaven National Laboratory for assistance during data collection. This work has been funded by the Canadian Institutes of Health Research (MOP 67189) to A.G. and the Intramural Research Program of the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) to R.G. NR 35 TC 9 Z9 9 U1 1 U2 4 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 SEP 30 PY 2011 VL 412 IS 4 BP 578 EP 590 DI 10.1016/j.jmb.2011.08.009 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 828JE UT WOS:000295496500004 PM 21855551 ER PT J AU Fu, TM Almqvist, J Liang, YH Li, LF Huang, YF Su, XD AF Fu, Tian-Min Almqvist, Jonas Liang, Yu-He Li, Lanfen Huang, Yafei Su, Xiao-Dong TI Crystal Structures of Cobalamin-Independent Methionine Synthase (MetE) from Streptococcus mutans: A Dynamic Zinc-Inversion Model SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE MetE; dynamic equilibrium; methionine synthase; homocysteine; methyltetrahydrofolate ID ESCHERICHIA-COLI; HOMOCYSTEINE; ENZYMES; METHYLTETRAHYDROFOLATE; ADENOSYLMETHIONINE; SITE AB Cobalamin-independent methionine synthase (MetE) catalyzes the direct transfer of a methyl group from methyltetrahydrofolate to L-homocysteine to form methionine. Previous studies have shown that the MetE active site coordinates a zinc atom, which is thought to act as a Lewis acid and plays a role in the activation of thiol. Extended X-ray absorption fine structure studies and mutagenesis experiments identified the zinc-binding site in MetE from Escherichia coli. Further structural investigations of MetE from Thermotoga maritima lead to the proposition of two models: "induced fit" and "dynamic equilibrium", to account for the catalytic mechanisms of MetE. Here, we present crystal structures of oxidized and zinc-replete MetE from Streptococcus mutans at the physiological pH. The structures reveal that zinc is mobile in the active center and has the possibility to invert even in the absence of homocysteine. These structures provide evidence for the dynamic equilibrium model. (C) 2011 Elsevier Ltd. All rights C1 [Almqvist, Jonas; Huang, Yafei] Swedish Univ Agr Sci, Dept Mol Biol, Uppsala Biomed Ctr, S-75124 Uppsala, Sweden. [Fu, Tian-Min; Li, Lanfen; Su, Xiao-Dong] Peking Univ, State Key Lab Prot & Plant Gene Res, Sch Life Sci, Beijing 100871, Peoples R China. [Almqvist, Jonas] Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA. [Liang, Yu-He] NCI, Frederick, MD 21702 USA. RP Huang, YF (reprint author), Swedish Univ Agr Sci, Dept Mol Biol, Uppsala Biomed Ctr, POB 590, S-75124 Uppsala, Sweden. EM yafei.huang@molbio.slu.se; xdsu@pku.edu.cn RI LIANG, YUHE/B-6704-2012 FU National Natural Science Foundation of China [30530190, 30325012]; Swedish Research Council; Swedish Governmental Agency for Innovation Systems; Wenner-Gren Foundation FX We are grateful to Xiang Liu for the assistance in structure determination and refinement. We thank Yanfeng Zhou and Xiaojun Wang for comments on the manuscript. This work was supported by funds from National Natural Science Foundation of China, grant numbers 30530190 and 30325012. Y.H. wishes to thank the Swedish Research Council and the Swedish Governmental Agency for Innovation Systems for their financial supports. J.A. is a postdoctoral fellow supported by the Wenner-Gren Foundation. NR 25 TC 7 Z9 8 U1 0 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 SEP 30 PY 2011 VL 412 IS 4 BP 688 EP 697 DI 10.1016/j.jmb.2011.08.005 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 828JE UT WOS:000295496500012 PM 21840320 ER PT J AU Greenstein, D Lenroot, R Clausen, L Chavez, A Vaituzis, AC Tran, L Gogtay, N Rapoport, J AF Greenstein, Deanna Lenroot, Rhoshel Clausen, Liv Chavez, Alex Vaituzis, A. C. Tran, Lan Gogtay, Nitin Rapoport, Judith TI Cerebellar development in childhood onset schizophrenia and non-psychotic siblings SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE MRI; Psychosis; Neurodevelopment ID NEUROLOGICAL SOFT SIGNS; 1ST-EPISODE SCHIZOPHRENIA; HEALTHY SIBLINGS; BRAIN ABNORMALITIES; LONGITUDINAL MRI; VERMIS; VOLUME; DISORDERS; CHILDREN; MORPHOMETRY AB We explored regional and total volumetric cerebellar differences in probands and their unaffected full siblings relative to typically developing participants. Participants included 94 (51 males) patients diagnosed with childhood onset schizophrenia (COS), 80 related non-psychotic siblings (37 males) and 110 (64 males) typically developing participants scanned longitudinally. The sample mean age was 16.87(S.D.= 4.7; range 6.5 to 29). We performed mixed model regressions to examine group differences in trajectory and volume. The COS group had smaller bilateral anterior lobes and anterior and total vermis volumes than controls. The COS group diverged from controls over time in total, left, right, and bilateral posterior inferior cerebellum. Siblings did not have any fixed volumetric differences relative to controls but differed from controls in developmental trajectories of total and right cerebellum, left inferior posterior, left superior posterior, and superior vermis. Results are consistent with previous COS findings and several reports of decreased cerebellar volume in adult onset schizophrenia. Sibling trajectories may represent a trait marker, although the effect size for volumetric differences in early adulthood may be small. Published by Elsevier Ireland Ltd. C1 [Greenstein, Deanna; Lenroot, Rhoshel; Clausen, Liv; Chavez, Alex; Vaituzis, A. C.; Tran, Lan; Gogtay, Nitin; Rapoport, Judith] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Lenroot, Rhoshel] Univ New S Wales, Sch Psychiat, Randwick, NSW, Australia. [Lenroot, Rhoshel] Neurosci Res Australia, Sydney, NSW, Australia. RP Greenstein, D (reprint author), Room 3N202,Bldg 10, Bethesda, MD 20892 USA. EM greenstd@mail.nih.gov RI Gogtay, Nitin/A-3035-2008; OI Chavez, Alexis/0000-0003-1322-4532 FU Intramural NIH HHS [Z99 MH999999] NR 52 TC 20 Z9 20 U1 3 U2 10 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 SEP 30 PY 2011 VL 193 IS 3 BP 131 EP 137 DI 10.1016/j.pscychresns.2011.02.010 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 822TV UT WOS:000295073400001 PM 21803550 ER PT J AU Johnson, RF Yellayi, S Cann, JA Johnson, A Smith, AL Paragas, J Jahrling, PB Blaney, JE AF Johnson, Reed F. Yellayi, Srikanth Cann, Jennifer A. Johnson, Anthony Smith, Alvin L. Paragas, Jason Jahrling, Peter B. Blaney, Joseph E. TI Cowpox virus infection of cynomolgus macaques as a model of hemorrhagic smallpox SO VIROLOGY LA English DT Article DE Orthopoxvirus; Animal model; Cowpox virus; Variola virus; Smallpox; Hemorrhagic disease; Pathogenesis ID MONKEYPOX VIRUS; HAEMORRHAGIC SMALLPOX; NONHUMAN-PRIMATES; LETHAL MONKEYPOX; EBOLA-VIRUS; ORTHOPOXVIRUS INFECTION; VACCINIA VIRUS; CONGO BASIN; COAGULATION; PROTECTION AB Hemorrhagic smallpox was a rare but severe manifestation of variola virus infection that resulted in nearly 100% mortality. Here we describe intravenous (IV) inoculation of cowpox virus Brighton Red strain in cynomolgus macaques (Macaca fascicularis) which resulted in disease similar in presentation to hemorrhagic smallpox in humans. IV inoculation of macaques resulted in a uniformly lethal disease within 12 days post-inoculation in two independent experiments. Clinical observations and hematological and histopathological findings support hemorrhagic disease. Cowpox virus replicated to high levels in blood (8.0-9.0 log(10) gene copies/mL) and tissues including lymph nodes, thymus, spleen, bone marrow, and lungs. This unique model of hemorrhagic orthopoxvirus infection provides an accessible means to further study orthopoxvirus pathogenesis and to identify virus-specific and nonspecific therapies. Such studies will serve to complement the existing nonhuman primate models of more classical poxviral disease. Published by Elsevier Inc. C1 [Johnson, Reed F.; Smith, Alvin L.; Jahrling, Peter B.; Blaney, Joseph E.] NIAID, NIH, EVPS, Bethesda, MD 20892 USA. [Yellayi, Srikanth; Cann, Jennifer A.; Johnson, Anthony; Paragas, Jason; Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Frederick, MD 21702 USA. RP Johnson, RF (reprint author), NIAID, NIH, EVPS, Bldg 33,Rm 2E19A,33 N Dr, Bethesda, MD 20892 USA. EM johnsonreed@mail.nih.gov FU NIAID Division of Intramural Research FX This work, in part, was supported by the NIAID Division of Intramural Research. We are grateful to Sharon Altmann, Catherine Jett, Haifeng Song, Kurt Cooper, Marisa St. Claire, Russell Byrum, and Dan Ragland for their contributions to these studies. We thank Marisa St. Claire, Laura Bollinger and Fabian De Kok Mercado for their contribution to the preparation of this manuscript. We thank Grant McFadden University of Florida for providing Cowpox Brighton Red. NR 67 TC 11 Z9 11 U1 0 U2 3 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 SEP 30 PY 2011 VL 418 IS 2 BP 102 EP 112 DI 10.1016/j.virol.2011.07.013 PG 11 WC Virology SC Virology GA 819NI UT WOS:000294833200003 PM 21840027 ER PT J AU Morgan, TM House, JA Cresci, S Jones, P Allayee, H Hazen, SL Patel, Y Patel, RS Eapen, DJ Waddy, SP Quyyumi, AA Kleber, ME Marz, W Winkelmann, BR Boehm, BO Krumholz, HM Spertus, JA AF Morgan, Thomas M. House, John A. Cresci, Sharon Jones, Philip Allayee, Hooman Hazen, Stanley L. Patel, Yesha Patel, Riyaz S. Eapen, Danny J. Waddy, Salina P. Quyyumi, Arshed A. Kleber, Marcus E. Maerz, Winfried Winkelmann, Bernhard R. Boehm, Bernhard O. Krumholz, Harlan M. Spertus, John A. TI Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome SO BMC MEDICAL GENETICS LA English DT Article ID MULTIPLE DISPLACEMENT AMPLIFICATION; ARTERY-DISEASE; MYOCARDIAL-INFARCTION; POLYMORPHISMS; CONSENSUS; RISK AB Background: Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated. Methods: We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients. Results: After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086). Conclusions: We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post ACS survival. Large scale, collaborative, genome wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease. C1 [Morgan, Thomas M.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. [House, John A.; Jones, Philip; Spertus, John A.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [House, John A.; Jones, Philip; Spertus, John A.] Univ Missouri, Kansas City, MO 64110 USA. [Cresci, Sharon] Washington Univ, Sch Med, Div Cardiovasc, Dept Internal Med, St Louis, MO 63110 USA. [Allayee, Hooman; Patel, Yesha; Krumholz, Harlan M.] USC Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Hazen, Stanley L.] Cleveland Clin, Lerner Res Inst, Dept Cell Biol, Ctr Cardiovasc Diagnost & Prevent, Cleveland, OH 44106 USA. [Patel, Riyaz S.] Cardiff Univ, Cardiff, S Glam, Wales. [Patel, Riyaz S.; Eapen, Danny J.; Quyyumi, Arshed A.] Emory Univ, Sch Med, Atlanta, GA USA. [Waddy, Salina P.] NINDS, NIH, Bethesda, MD 20892 USA. [Kleber, Marcus E.] LURIC Non Profit LLC, Freiburg, Germany. [Kleber, Marcus E.; Maerz, Winfried] Univ Heidelberg, Mannheim Inst Publ Hlth, Med Fac Mannheim, D-6900 Heidelberg, Germany. [Maerz, Winfried] Synlab Serv GmbH, Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Boehm, Bernhard O.] Cardiol Grp Sachenhausen, Frankfurt, Sachsenhausen, Germany. [Boehm, Bernhard O.] Univ Ulm, Div Endocrinol Diabet & Metab, Grad Sch Mol Diabetol & Endocrinol, D-89069 Ulm, Germany. Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. Yale Univ, Robert Wood Johnson Clin Scholars Program, New Haven, CT 06510 USA. RP Morgan, TM (reprint author), Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. EM thomas.morgan@vanderbilt.edu RI Morgan, Tom/C-3478-2012; Boehm, Bernhard/F-8750-2015; OI Kleber, Marcus/0000-0003-0663-7275 FU Saint Luke's Hospital Foundation, Kansas City, MO; Agency for Healthcare Research and Quality, Rockville, MD [R-01 HS11282-01]; National Heart, Lung and Blood Institute [P50 HL077113]; Mentored Patient-Oriented Research Grant [NHLBI K23 HI77272] FX This project was funded by grants from the Saint Luke's Hospital Foundation, Kansas City, MO, and by grants R-01 HS11282-01 from the Agency for Healthcare Research and Quality, Rockville, MD and P50 HL077113 from the National Heart, Lung and Blood Institute. Dr. Morgan's research was supported by a Mentored Patient-Oriented Research Grant (NHLBI K23 HI77272). These funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Dr. Morgan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 25 TC 5 Z9 6 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD SEP 29 PY 2011 VL 12 AR 127 DI 10.1186/1471-2350-12-127 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 832CP UT WOS:000295779100001 PM 21957892 ER PT J AU Yang, Y Tao-Cheng, JH Reese, TS Dosemeci, A AF Yang, Y. Tao-Cheng, J. -H. Reese, T. S. Dosemeci, A. TI SynGAP MOVES OUT OF THE CORE OF THE POSTSYNAPTIC DENSITY UPON DEPOLARIZATION SO NEUROSCIENCE LA English DT Article DE SynGAP; PSD-95; AMPA receptor; postsynaptic density; electron microscopy; immunogold ID GTPASE-ACTIVATING PROTEIN; LONG-TERM POTENTIATION; NMDA RECEPTOR; KINASE-II; SYNAPTIC PLASTICITY; HIPPOCAMPAL-NEURONS; SYNAPSES; ORGANIZATION; INDUCTION; COMPLEX AB SynGAP is a Ras GTPase activating protein present at the postsynaptic density (PSD) in quantities matching those of the core scaffold protein PSD-95. SynGAP is reported to inhibit synaptic accumulation of AMPA receptors. Here, we characterize by immunogold electron microscopy the distribution of SynGAP at the PSD under basal and depolarizing conditions in rat hippocampal neuronal cultures. The PSD core, extending up to 40 nm from the postsynaptic membrane, typically shows label for SynGAP, while half of the synapses exhibit additional labeling in a zone 40-120 nm from the postsynaptic membrane. Upon depolarization with high K(+), labeling for SynGAP significantly decreases at the core of the PSD and concomitantly increases at the 40-120 nm zone. Under the same depolarization conditions, label for PSD-95, the presumed binding partner of SynGAP, does not change its localization at the PSD. Depolarization-induced redistribution of SynGAP is reversible and also occurs upon application of N-methyl-D-aspartic acid (NMDA). Activity-in-duced movement of SynGAP could vacate sites in the PSD core allowing other elements to bind to these sites, such as transmembrane AMPA receptor regulatory proteins (TARPs), and simultaneously facilitate access of SynGAP to CaMKII and Ras, elements of a regulatory cascade. Published by Elsevier Ltd on behalf of IBRO. C1 [Yang, Y.; Reese, T. S.; Dosemeci, A.] Natl Inst Neurol Disorders & Stroke, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Tao-Cheng, J. -H.] Natl Inst Neurol Disorders & Stroke, EM Facil, NIH, Bethesda, MD USA. RP Yang, Y (reprint author), Natl Inst Neurol Disorders & Stroke, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. EM yangy7@mail.nih.gov FU NIH; NINDS FX We thank Christine A. Winters for hippocampal neuronal cultures and hippocampal slice cultures, Virginia Crocker and Rita Azzam for EM technical support. This research was supported by the Intramural Research Program of the NIH, NINDS. NR 29 TC 14 Z9 14 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD SEP 29 PY 2011 VL 192 BP 132 EP 139 DI 10.1016/j.neuroscience.2011.06.061 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 829DB UT WOS:000295555100013 PM 21736925 ER PT J AU Cuellar-Rodriguez, J Gea-Banacloche, J Freeman, AF Hsu, AP Zerbe, CS Calvo, KR Wilder, J Kurlander, R Olivier, KN Holland, SM Hickstein, DD AF Cuellar-Rodriguez, Jennifer Gea-Banacloche, Juan Freeman, Alexandra F. Hsu, Amy P. Zerbe, Christa S. Calvo, Katherine R. Wilder, Jennifer Kurlander, Roger Olivier, Kenneth N. Holland, Steven M. Hickstein, Dennis D. TI Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; RECONSTITUTION INFLAMMATORY SYNDROME; CORD BLOOD TRANSPLANTATION; SPORADIC MONOCYTOPENIA; AUTOSOMAL-DOMINANT; MYELODYSPLASIA; OUTCOMES AB We performed nonmyeloablative HSCT in 6 patients with a newly described genetic immunodeficiency syndrome caused by mutations in GATA2-a disease characterized by nontuberculous mycobacterial infection, monocytopenia, B- and NK-cell deficiency, and the propensity to transform to myelodysplastic syndrome/acute myelogenous leukemia. Two patients received peripheral blood stem cells (PBSCs) from matched-related donors, 2 received PBSCs from matched-unrelated donors, and 2 received stem cells from umbilical cord blood (UCB) donors. Recipients of matched-related and -unrelated donors received fludarabine and 200 cGy of total body irradiation (TBI); UCB recipients received cyclophosphamide in addition to fludarabine and TBI as conditioning. All patients received tacrolimus and sirolimus posttransplantation. Five patients were alive at a median follow-up of 17.4 months (range, 10-25). All patients achieved high levels of donor engraftment in the hematopoietic compartments that were deficient pretransplantation. Adverse events consisted of delayed engraftment in the recipient of a single UCB, GVHD in 4 patients, and immune-mediated pancytopenia and nephrotic syndrome in the recipient of a double UCB transplantation. Nonmyeloablative HSCT in GATA2 deficiency results in reconstitution of the severely deficient monocyte, B-cell, and NK-cell populations and reversal of the clinical phenotype. Registered at www.clinicaltrials.gov as NCT00923364. (Blood. 2011; 118(13):3715-3720) C1 [Cuellar-Rodriguez, Jennifer; Freeman, Alexandra F.; Hsu, Amy P.; Zerbe, Christa S.; Olivier, Kenneth N.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Gea-Banacloche, Juan; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Calvo, Katherine R.; Kurlander, Roger] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Wilder, Jennifer] NCI Frederick, Clin Res Directorate, CMRP, Sci Applicat Int Corp SAIC Frederick Inc, Frederick, MD USA. RP Hickstein, DD (reprint author), 9000 Rockville Pike,Bldg 10 CRC,3-3142, Bethesda, MD 20892 USA. EM hicksted@mail.nih.gov RI Calvo, Katherine/A-8109-2009; OI Calvo, Katherine/0000-0002-0771-4191 FU National Cancer Institute, National Institutes of Health; Division of Intramural Research; [HHSN261200800001E] FX This work has been supported with federal funds from the National Cancer Institute, National Institutes of Health, in part by the Division of Intramural Research, and in part under contract no. HHSN261200800001E. NR 19 TC 37 Z9 38 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 29 PY 2011 VL 118 IS 13 BP 3715 EP 3720 DI 10.1182/blood-2011-06-365049 PG 6 WC Hematology SC Hematology GA 826MW UT WOS:000295359300039 PM 21816832 ER PT J AU Fodeke, AA Minton, AP AF Fodeke, Adedayo A. Minton, Allen P. TI Quantitative Characterization of Temperature-Independent and Temperature-Dependent Protein-Protein Interactions in Highly Nonideal Solutions SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID TRACER SEDIMENTATION EQUILIBRIUM; BOVINE SERUM-ALBUMIN; HARD PARTICLE MODEL; PHYSIOLOGICAL CONSEQUENCES; CONCENTRATED-SOLUTIONS; OSMOTIC-PRESSURE; ASSOCIATION; MIXTURES; POLYMER AB The interaction among each of three dilute "tracer" proteins (bovine serum albumin, superoxide dismutase, and ovomucoid) at a concentration of 2 mg/mL and each of two "crowder" proteins (ovomucoid and BSA) at concentrations up to 100 mg/mL was characterized by analysis of dependence of the equilibrium gradients of both tracer and crowder upon the concentration of crowder. The equilibrium gradients of both crowder proteins were found to be independent of temperature over the range 5-37 degrees C. The equilibrium gradients of tracer BSA and ovomucoid in the complementary crowder species were likewise found to be independent of temperature over this range, indicating that interaction among these tracers and crowders is predominantly repulsive and essentially entirely entropic in nature. The equilibrium gradient of tracer SOD in BSA was also found to be independent of temperature over this range, but the gradient of tracer SOD in ovomucoid depended significantly upon temperature in a manner indicating a significant enthalpic (attractive) component of the overall interaction between SOD and ovomucoid. The experimental data are analyzed using model-free expansions of the thermodynamic activity coefficients of tracer and crowder in powers of the concentration of crowder and using approximate statistical thermodynamic models based upon highly simplified descriptions of molecular structure and interactions. Detailed analysis of the results indicates a relatively small contribution of nonspecific attraction to the total protein-protein interaction, which is dominated by steric repulsion. C1 [Fodeke, Adedayo A.; Minton, Allen P.] NIDDK, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDK, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. EM minton@helix.nih.gov OI Minton, Allen/0000-0001-8459-1247 FU National Institute of Diabetes and Digestive and Kidney Diseases FX The authors thank Dr. Peter McPhie, NIDDK, for a careful reading of a draft of this manuscript and for helpful suggestions. This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 26 TC 6 Z9 6 U1 0 U2 13 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 SEP 29 PY 2011 VL 115 IS 38 BP 11261 EP 11268 DI 10.1021/jp2049266 PG 8 WC Chemistry, Physical SC Chemistry GA 822OL UT WOS:000295057900025 PM 21846103 ER PT J AU Zitserman, VY Berezhkovskii, AM Antipov, AE Makhnovskii, YA AF Zitserman, V. Yu. Berezhkovskii, A. M. Antipov, A. E. Makhnovskii, Yu. A. TI Communication: Drift velocity of Brownian particle in a periodically tapered tube induced by a time-periodic force with zero mean: Dependence on the force period SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID TRANSPORT; MOTORS; DIFFUSION AB We study the drift of a Brownian particle in a periodically tapered tube, induced by a longitudinal time-periodic force of amplitude vertical bar F vertical bar that alternates in sign every half-period. The focus is on the velocity dependence on the force period, which is usually considered not tractable analytically. For large vertical bar F vertical bar we derive an analytical solution that gives the velocity as a function of the amplitude and the period of the force as well as the geometric parameters of the tube. The solution shows how the velocity decreases from its maximum value to zero as the force period decreases from infinity (adiabatic regime) to zero. Our analytical results are in excellent agreement with those obtained from 3D Brownian dynamics simulations. (C) 2011 American Institute of Physics. [doi:10.1063/1.3647873] C1 [Berezhkovskii, A. M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Zitserman, V. Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. [Antipov, A. E.] Moscow MV Lomonosov State Univ, Dept Phys, Moscow 119992, Russia. [Makhnovskii, Yu. A.] Russian Acad Sci, Topchiev Inst Petrochem Synth, Moscow 119992, Russia. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. EM berezh@mail.nih.gov RI Makhnovskii, Yurii/B-1223-2014 OI Makhnovskii, Yurii/0000-0002-1517-536X FU Russian Foundation for Basic Research [10-03-0093]; National Institutes of Health (NIH), Center for Information Technology FX This study was supported by the Russian Foundation for Basic Research (Grant No. 10-03-0093) and the Intramural Research Program of the National Institutes of Health (NIH), Center for Information Technology. NR 26 TC 10 Z9 10 U1 1 U2 7 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD SEP 28 PY 2011 VL 135 IS 12 AR 121102 DI 10.1063/1.3647873 PG 4 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 829XM UT WOS:000295619700002 PM 21974505 ER PT J AU Charmandari, E Chrousos, GP Lambrou, GI Pavlaki, A Koide, H Sinnie, SMN Kino, T AF Charmandari, Evangelia Chrousos, George P. Lambrou, George I. Pavlaki, Aikaterini Koide, Hisashi Sinnie Sin Man Ng Kino, Tomoshige TI Peripheral CLOCK Regulates Target-Tissue Glucocorticoid Receptor Transcriptional Activity in a Circadian Fashion in Man SO PLOS ONE LA English DT Article ID NF-KAPPA-B; INFLAMMATION; MONONUCLEAR; RHYTHMS; STRESS; SYSTEM; CELLS AB Context and Objective: Circulating cortisol fluctuates diurnally under the control of the "master'' circadian CLOCK, while the peripheral "slave'' counterpart of the latter regulates the transcriptional activity of the glucocorticoid receptor (GR) at local glucocorticoid target tissues through acetylation. In this manuscript, we studied the effect of CLOCK-mediated GR acetylation on the sensitivity of peripheral tissues to glucocorticoids in humans. Design and Participants: We examined GR acetylation and mRNA expression of GR, CLOCK-related and glucocorticoid-responsive genes in peripheral blood mononuclear cells (PBMCs) obtained at 8 am and 8 pm from 10 healthy subjects, as well as in PBMCs obtained in the morning and cultured for 24 hours with exposure to 3-hour hydrocortisone pulses every 6 hours. We used EBV-transformed lymphocytes (EBVLs) as non-synchronized controls. Results: GR acetylation was higher in the morning than in the evening in PBMCs, mirroring the fluctuations of circulating cortisol in reverse phase. All known glucocorticoid-responsive genes tested responded as expected to hydrocortisone in non-synchronized EBVLs, however, some of these genes did not show the expected diurnal mRNA fluctuations in PBMCs in vivo. Instead, their mRNA oscillated in a Clock-and a GR acetylation-dependent fashion in naturally synchronized PBMCs cultured ex vivo in the absence of the endogenous glucocorticoid, suggesting that circulating cortisol might prevent circadian GR acetylation-dependent effects in some glucocorticoid-responsive genes in vivo. Conclusions: Peripheral CLOCK-mediated circadian acetylation of the human GR may function as a target-tissue, gene-specific counter regulatory mechanism to the actions of diurnally fluctuating cortisol, effectively decreasing tissue sensitivity to glucocorticoids in the morning and increasing it at night. C1 [Charmandari, Evangelia; Chrousos, George P.; Lambrou, George I.; Pavlaki, Aikaterini] Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Dept Pediat 1, GR-11527 Athens, Greece. [Charmandari, Evangelia; Chrousos, George P.] Acad Athens, Div Endocrinol & Metab, Biomed Res Fdn, Athens, Greece. [Koide, Hisashi] Eunice Kennedy Shriver Inst Child Hlth & Human De, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Sinnie Sin Man Ng; Kino, Tomoshige] Eunice Kennedy Shriver Inst Child Hlth & Human De, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Sinnie Sin Man Ng] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. RP Charmandari, E (reprint author), Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Dept Pediat 1, GR-11527 Athens, Greece. EM kinot@mail.nih.gov RI Charmandari, Evangelia/B-6701-2011; OI Lambrou, George/0000-0001-8389-1360; Koide, Hisashi/0000-0002-8545-7530 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National and Kapodistrian University of Athens FX This study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and the National and Kapodistrian University of Athens. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 28 TC 47 Z9 48 U1 1 U2 3 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 SEP 28 PY 2011 VL 6 IS 9 AR e25612 DI 10.1371/journal.pone.0025612 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834CT UT WOS:000295936900080 PM 21980503 ER PT J AU Nagy, KJ Giano, MC Jin, A Pochan, DJ Schneider, JP AF Nagy, Katelyn J. Giano, Michael C. Jin, Albert Pochan, Darrin J. Schneider, Joel P. TI Enhanced Mechanical Rigidity of Hydrogels Formed from Enantiomeric Peptide Assemblies SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID INTERPENETRATING POLYMER NETWORKS; STEREOCOMPLEXATION; BIOMATERIALS; ORGANIZATION; MODEL AB Chirality can be used as a design tool to control the mechanical rigidity of hydrogels formed from self-assembling peptides. Hydrogels prepared from enantiomeric mixtures of self-assembling beta-hairpins show nonadditive, synergistic, enhancement in material rigidity compared to gels prepared from either pure enantiomer, with the racemic hydrogel showing the greatest effect. CD spectroscopy, TEM, and AFM indicate that this enhancement is defined by nanoscale interactions between enantiomers in the self-assembled state. C1 [Nagy, Katelyn J.; Giano, Michael C.; Schneider, Joel P.] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Nagy, Katelyn J.; Giano, Michael C.] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Jin, Albert] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, Bethesda, MD 20892 USA. [Pochan, Darrin J.] Univ Delaware, Dept Mat Sci, Newark, DE 19716 USA. RP Schneider, JP (reprint author), NCI, Ctr Canc Res, Frederick, MD 21701 USA. EM joel.schneider@nih.gov RI Schneider, Joel/N-2610-2014; OI Jin, Albert/0000-0003-3826-1081 FU National Cancer Institute of the National Institutes of Heath FX This work was supported by the Intramural Research Program of the National Cancer Institute of the National Institutes of Heath. The authors would like to acknowledge Ulrich Baxa for his work with TEM imaging and for intellectual conversations. NR 28 TC 55 Z9 55 U1 12 U2 99 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 SEP 28 PY 2011 VL 133 IS 38 BP 14975 EP 14977 DI 10.1021/ja206742m PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 829SK UT WOS:000295604400035 PM 21863803 ER PT J AU Cheng, N Cai, HB Belluscio, L AF Cheng, Ning Cai, Huaibin Belluscio, Leonardo TI In Vivo Olfactory Model of APP-Induced Neurodegeneration Reveals a Reversible Cell-Autonomous Function SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ALZHEIMERS-DISEASE; AMYLOID-BETA; A-BETA; TRANSGENIC MODEL; GENE-EXPRESSION; MOUSE; NEURONS; EPITHELIUM; APOPTOSIS; PLAQUES AB Amyloid precursor protein (APP) has long been linked to the neurodegeneration of Alzheimer's disease (AD), but the associated cell death has been difficult to capture in vivo, and the role of APP in effecting neuron loss is still unclear. Olfactory dysfunction is an early symptom of AD with amyloid pathology in the olfactory epithelium correlating well to the brain pathology of AD patients. As olfactory sensory neurons (OSNs) regenerate continuously with immature and mature OSNs coexisting in the same olfactory epithelium, we sought to use this unique system to study APP-induced neurodegeneration. Here we have developed an olfactory-based transgenic mouse model that overexpresses humanized APP containing familial AD mutations (hAPP) in either mature or immature OSNs, and found that despite the absence of extracellular plaques a striking number of apoptotic neurons were detected by 3 weeks of age. Importantly, apoptosis was restricted to the specific population overexpressing hAPP, either mature or immature OSNs, sparing those without hAPP. Interestingly, we observed that this widespread neurodegeneration could be rapidly rescued by reducing hAPP expression levels in immature neurons. Together, these data argue that overexpressing hAPP alone could induce cell-autonomous apoptosis in both mature and immature neurons, challenging the notion that amyloid plaques are necessary for neurodegeneration. Furthermore, we show that hAPP-induced neurodegeneration is reversible, suggesting that AD-related neural loss could potentially be rescued. Thus, we propose that this unique in vivo model will not only help determine the mechanisms underlying AD-related neurodegeneration but also serve as a platform to test possible treatments. C1 [Cheng, Ning; Belluscio, Leonardo] Natl Inst Neurol Disorders & Stroke, Dev Neural Plast Unit, NIH, Bethesda, MD 20892 USA. [Cai, Huaibin] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Belluscio, L (reprint author), Natl Inst Neurol Disorders & Stroke, Dev Neural Plast Unit, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM belluscl@ninds.nih.gov RI Cai, Huaibin/H-3359-2013 OI Cai, Huaibin/0000-0002-8596-6108 FU NINDS [1ZIANS003116-01] FX This work was supported by the NINDS intramural program, project number 1ZIANS003116-01. We thank Li Bai and Rini Singh for assistance with genotyping and immunohistochemistry. We thank the members of the Belluscio laboratory for constructive comments on this work. We thank the NINDS EM facility for assistance with the electron microscopy studies. NR 37 TC 15 Z9 15 U1 0 U2 3 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 SEP 28 PY 2011 VL 31 IS 39 BP 13699 EP 13704 DI 10.1523/JNEUROSCI.1714-11.2011 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 826OP UT WOS:000295363800002 PM 21957232 ER PT J AU Nasr, S Liu, N Devaney, KJ Yue, XM Rajimehr, R Ungerleider, LG Tootell, RBH AF Nasr, Shahin Liu, Ning Devaney, Kathryn J. Yue, Xiaomin Rajimehr, Reza Ungerleider, Leslie G. Tootell, Roger B. H. TI Scene-Selective Cortical Regions in Human and Nonhuman Primates SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HUMAN VISUAL-CORTEX; FUSIFORM FACE AREA; PARAHIPPOCAMPAL PLACE AREA; HUMAN EXTRASTRIATE CORTEX; INFERIOR TEMPORAL CORTEX; FUNCTIONAL MRI; CEREBRAL-CORTEX; VISUOTOPIC ORGANIZATION; RETROSPLENIAL CORTEX; OBJECT PERCEPTION AB fMRI studies have revealed three scene-selective regions in human visual cortex [the parahippocampal place area (PPA), transverse occipital sulcus (TOS), and retrosplenial cortex (RSC)], which have been linked to higher-order functions such as navigation, scene perception/recognition, and contextual association. Here, we document corresponding (presumptively homologous) scene-selective regions in the awake macaque monkey, based on direct comparison to human maps, using identical stimuli and largely overlapping fMRI procedures. In humans, our results showed that the three scene-selective regions are centered near-but distinct from-the gyri/sulci for which they were originally named. In addition, all these regions are located within or adjacent to known retinotopic areas. Human RSC and PPA are located adjacent to the peripheral representation of primary and secondary visual cortex, respectively. Human TOS is located immediately anterior/ventral to retinotopic area V3A, within retinotopic regions LO-1, V3B, and/or V7. Mirroring the arrangement of human regions fusiform face area (FFA) and PPA (which are adjacent to each other in cortex), the presumptive monkey homolog of human PPA is located adjacent to the monkey homolog of human FFA, near the posterior superior temporal sulcus. Monkey TOS includes the region predicted from the human maps (macaque V4d), extending into retinotopically defined V3A. A possible monkey homolog of human RSC lies in the medial bank, near peripheral V1. Overall, our findings suggest a homologous neural architecture for scene-selective regions in visual cortex of humans and nonhuman primates, analogous to the face-selective regions demonstrated earlier in these two species. C1 [Nasr, Shahin; Devaney, Kathryn J.; Yue, Xiaomin; Rajimehr, Reza; Tootell, Roger B. H.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Liu, Ning; Ungerleider, Leslie G.; Tootell, Roger B. H.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Nasr, S (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM shahin@nmr.mgh.harvard.edu FU NIH [R01 MH67529, R01 EY017081]; Martinos Center for Biomedical Imaging; NCRR; MIND Institute [1S10RR023401, 1S10RR019, 1S10RR023043]; NIMH FX This work was supported by NIH Grants R01 MH67529 and R01 EY017081 ( R. B. H. T.), the Martinos Center for Biomedical Imaging, the NCRR, the MIND Institute, Shared Instrumentation Grants 1S10RR023401, 1S10RR019, and 1S10RR023043, and the NIMH Intramural Research Program. NR 89 TC 81 Z9 82 U1 0 U2 11 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 SEP 28 PY 2011 VL 31 IS 39 BP 13771 EP 13785 DI 10.1523/JNEUROSCI.2792-11.2011 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 826OP UT WOS:000295363800010 PM 21957240 ER PT J AU He, BYJ AF He, Biyu J. TI Scale-Free Properties of the Functional Magnetic Resonance Imaging Signal during Rest and Task SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HUMAN BRAIN; NEURONAL-ACTIVITY; DEFAULT MODE; TIME-SERIES; CORTEX; NETWORKS; BEHAVIOR; NOISE; CONNECTIVITY; FLUCTUATIONS AB It has been shown recently that a significant portion of brain electrical field potentials consists of scale-free dynamics. These scale-free brain dynamics contain complex spatiotemporal structures and are modulated by task performance. Here we show that the fMRI signal recorded from the human brain is also scale free; its power-law exponent differentiates between brain networks and correlates with fMRI signal variance and brain glucose metabolism. Importantly, in parallel to brain electrical field potentials, the variance and power-law exponent of the fMRI signal decrease during task activation, suggesting that the signal contains more long-range memory during rest and conversely is more efficient at online information processing during task. Remarkably, similar changes also occurred in task-deactivated brain regions, revealing the presence of an optimal dynamic range in the fMRI signal. The scale-free properties of the fMRI signal and brain electrical field potentials bespeak their respective stationarity and nonstationarity. This suggests that neurovascular coupling mechanism is likely to contain a transformation from nonstationarity to stationarity. In summary, our results demonstrate the functional relevance of scale-free properties of the fMRI signal and impose constraints on future models of neurovascular coupling. C1 Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP He, BYJ (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. EM biyu.jade.he@gmail.com OI He, Biyu/0000-0003-1549-1351 FU NIH/NINDS FX This research was supported by the Intramural Research Program of the NIH/NINDS. I am grateful to Marc Raichle for sharing the data used in this study, past teachings of brain metabolism, and comments on a previous draft of this manuscript and to Patrice Abry and Philippe Ciuciu for sharing methods used in synthesizing fractional Gaussian noise. NR 70 TC 82 Z9 85 U1 5 U2 14 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 SEP 28 PY 2011 VL 31 IS 39 BP 13786 EP 13795 DI 10.1523/JNEUROSCI.2111-11.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 826OP UT WOS:000295363800011 PM 21957241 ER PT J AU Javitt, DC Schoepp, D Kalivas, PW Volkow, ND Zarate, C Merchant, K Bear, MF Umbricht, D Hajos, M Potter, WZ Lee, CM AF Javitt, Daniel C. Schoepp, Darryle Kalivas, Peter W. Volkow, Nora D. Zarate, Carlos Merchant, Kalpana Bear, Mark F. Umbricht, Daniel Hajos, Mihaly Potter, William Z. Lee, Chi-Ming TI Translating Glutamate: From Pathophysiology to Treatment SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material ID D-ASPARTATE ANTAGONIST; AMINO-ACID OXIDASE; MISMATCH NEGATIVITY GENERATION; GLYCINE TRANSPORTER TYPE-1; RECEPTOR AGONIST LY354740; RAPID ANTIDEPRESSANT RESPONSE; EVENT-RELATED POTENTIALS; FRAGILE-X-SYNDROME; PROOF-OF-CONCEPT; DOUBLE-BLIND PET AB The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders-including schizophrenia, drug abuse and addiction, autism, and depression-that were until recently poorly understood. Nevertheless, improvements in basic information regarding these disorders have yet to translate into Food and Drug Administration-approved treatments. Barriers to translation include the need not only for improved compounds but also for improved biomarkers sensitive to both structural and functional target engagement and for improved translational models. Overcoming these barriers will require unique collaborative arrangements between pharma, government, and academia. Here, we review a recent Institute of Medicine-sponsored meeting, highlighting advances in glutamatergic theories of neuropsychiatric illness as well as remaining barriers to treatment development. C1 [Javitt, Daniel C.] Columbia Univ Coll Phys & Surg, Nathan Kline Inst, Translat Schizophrenia Res Ctr, New York, NY 10032 USA. [Schoepp, Darryle] Neurosci Merck & Co Inc, N Wales, PA 19454 USA. [Kalivas, Peter W.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29464 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. [Zarate, Carlos] NIMH, Mood & Anxiety Disorders Res Unit, Bethesda, MD 20892 USA. [Merchant, Kalpana] Eli Lilly & Co, Translat Sci, Indianapolis, IN 46285 USA. [Bear, Mark F.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Umbricht, Daniel] F Hoffmann La Roche Ltd, Cent Nervous Syst, Neurosci Pharma Res & Early Dev, CH-4070 Basel, Switzerland. [Hajos, Mihaly] Pfizer Global Res & Dev, CNS Discovery, Dept Neurosci, Groton, CT 06340 USA. [Potter, William Z.] Hlth Biomarkers Consortium, Fdn Natl Inst, Bethesda, MD 20814 USA. [Lee, Chi-Ming] AstraZeneca, Sodertalje R&D, SE-15185 Sodertalje, Sweden. RP Javitt, DC (reprint author), Columbia Univ Coll Phys & Surg, Nathan Kline Inst, Translat Schizophrenia Res Ctr, 630 W 168th St, New York, NY 10032 USA. EM javitt@nki.rfmh.org FU National Institute of Mental Health; NIH; Howard Hughes Medical Institute; Howard Hughes Medical Institute, FRAXA; Simons Foundation Autism Research Initiative; Pfizer; Roche; Jazz; Promentis Pharmaceuticals Inc.; [R37MH49334]; [R01DA03383]; [P50MH086385] FX Manuscript preparation funded in part by grants R37MH49334, R01DA03383, and P50MH086385 to D.C.J. Supported by the Intramural Research Program at the National Institute of Mental Health. M. F. B. acknowledges support from NIH, Howard Hughes Medical Institute, FRAXA, and Simons Foundation Autism Research Initiative.; D.C.J. holds intellectual property rights for use of NMDA modulators in treatment of mental disorders including schizophrenia and depression. He holds equity interest in Glytech Inc. He has served as a paid consultant to Schering-Plough, Takeda, NPS, Solvay, Sepracor, AstraZeneca, Pfizer, Cypress, Merck, Sunovion Eli Lilly, and BMS. He has received research grants from Pfizer, Roche, and Jazz and serves on the advisory board for Glytech and Promentis Pharmaceuticals. P. W. K. is listed as co-inventor on a patent application for the combined use of mGluR5-negative allosteric modulators and N-acetylcysteine in the treatment of addiction. P. W. K. has financial interest in Promentis Pharmaceuticals Inc., which is developing compounds to modulate the cystine-glutamate exchanger for treating schizophrenia. C.Z. is listed as a co-inventor on a patent application for the use of ketamine in major depression. C.Z. has assigned his rights in the patent to the U. S. government but will share a percentage of any royalties that may be received by the government. M. F. B. holds equity in, and is a paid consultant for, Seaside Therapeutics Inc. W.Z.P. is a paid consultant to AgeneBio, Amgen, AstraZeneca, BMS, InVivo, Orasi, Pfizer, and Theravance. Hoffmann-La Roche holds the patents for the compound RG1678 referred to in the paper. The other authors declare that they have no competing interests. NR 155 TC 37 Z9 37 U1 4 U2 19 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD SEP 28 PY 2011 VL 3 IS 102 AR 102mr2 DI 10.1126/scitranslmed.3002804 PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 826AH UT WOS:000295323200010 PM 21957170 ER PT J AU Barry, MJ Meleth, S Lee, JY Kreder, KJ Avins, AL Nickel, JC Roehrborn, CG Crawford, ED Foster, HE Kaplan, SA McCullough, A Andriole, GL Naslund, MJ Williams, OD Kusek, JW Meyers, CM Betz, JM Cantor, A McVary, KT AF Barry, Michael J. Meleth, Sreelatha Lee, Jeannette Y. Kreder, Karl J. Avins, Andrew L. Nickel, J. Curtis Roehrborn, Claus G. Crawford, E. David Foster, Harris E., Jr. Kaplan, Steven A. McCullough, Andrew Andriole, Gerald L. Naslund, Michael J. Williams, O. Dale Kusek, John W. Meyers, Catherine M. Betz, Joseph M. Cantor, Alan McVary, Kevin T. CA Complementary Alternative Med Urol TI Effect of Increasing Doses of Saw Palmetto Extract on Lower Urinary Tract Symptoms A Randomized Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BENIGN PROSTATIC HYPERPLASIA; CLINICAL-RESEARCH; HEALTH-STATUS; IMPACT INDEX; SCALE; MEN; QUESTIONNAIRE; PHYTOTHERAPY; DYSFUNCTION; VALIDATION AB Context Saw palmetto fruit extracts are widely used for treating lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH); however, recent clinical trials have questioned their efficacy, at least at standard doses (320 mg/d). Objective To determine the effect of saw palmetto extract (Serenoa repens, from saw palmetto berries) at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH. Design, Setting, and Participants A double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites conducted between June 5, 2008, and October 10, 2010, of 369 men aged 45 years or older, with a peak urinary flow rate of at least 4 mL/s, an American Urological Association Symptom Index (AUASI) score of between 8 and 24 at 2 screening visits, and no exclusions. Interventions One, 2, and then 3 doses (320 mg/d) of saw palmetto extract or placebo, with dose increases at 24 and 48 weeks. Main Outcome Measures Difference in AUASI score between baseline and 72 weeks. Secondary outcomes included measures of urinary bother, nocturia, peak uroflow, post-void residual volume, prostate-specific antigen level, participants' global assessments, and indices of sexual function, continence, sleep quality, and prostatitis symptoms. Results Between baseline and 72 weeks, mean AUASI scores decreased from 14.42 to 12.22 points (-2.20 points; 95% CI, -3.04 to -0.36) with saw palmetto extract and from 14.69 to 11.70 points (-2.99 points; 95% CI, -3.81 to -2.17) with placebo. The group mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points favoring placebo (upper bound of the 1-sided 95% CI most favorable to saw palmetto extract was 1.77 points, 1-sided P=.91). Saw palmetto extract was no more effective than placebo for any secondary outcome. No clearly attributable adverse effects were identified. Conclusion Increasing doses of a saw palmetto fruit extract did not reduce lower urinary tract symptoms more than placebo. C1 [Barry, Michael J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Meleth, Sreelatha; Williams, O. Dale; Cantor, Alan] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Lee, Jeannette Y.] Univ Arkansas Med Sci, Dept Biostat, Little Rock, AR 72205 USA. [Kreder, Karl J.] Univ Iowa, Dept Urol, Iowa City, IA 52242 USA. [Avins, Andrew L.] No Calif Kaiser Permanente, Div Res, Oakland, CA USA. [Nickel, J. Curtis] Queens Univ, Dept Urol, Kingston, ON, Canada. [Roehrborn, Claus G.] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. [Crawford, E. David] Univ Colorado, Sect Urol Oncol, Denver, CO 80202 USA. [Foster, Harris E., Jr.] Yale Univ, Sch Med, Urol Sect, New Haven, CT USA. [Kaplan, Steven A.] Weill Cornell Med Coll, Dept Urol, New York, NY USA. [McCullough, Andrew] NYU, Urol Associates, New York, NY USA. [Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Naslund, Michael J.] Univ Maryland, Maryland Prostate Ctr, Baltimore, MD 21201 USA. [Kusek, John W.] NIDDK, Bethesda, MD USA. [Meyers, Catherine M.] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [McVary, Kevin T.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Barry, MJ (reprint author), Massachusetts Gen Hosp, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM mbarry@partners.org FU GlaxoSmithKline; Pfizer; Watson; Astellas; Ferring; Taris; Triton; Farr Labs; Trillium; Cernelle; Johnson Johnson; Amgen; Bayer; Caris; France Foundation; GenProbe; Steba Biotech; Ortho-Clinical Diagnostics; Ferring Pharmaceuticals; Lilly/ICOS; Allergan; National Institute of Diabetes and Digestive and Kidney Diseases; Watson Pharm; Neotract; National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK63795, U01 DK63797, U01 DK63825, U01 DK63835, U01 DK63866, U01 DK63833, U01 DK63862, U01 DK63840, U01 DK63883, U01 DK63831, U01 DK63778, U01 DK63788]; National Center for Complementary and Alternative Medicine; Office of Dietary Supplements, NIH FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Barry reported serving on the board of and receiving salary support as president of the not-for-profit (501[3]c) Foundation for Informed Medical Decision Making (http://www.fimdm.org), which develops content for patient education programs. The foundation has an arrangement with a for-profit company, Health Dialog, to coproduce and market these programs to health care organizations. Dr Lee reported that funds were paid to her institution for consultancy to Merck. Dr Nickel reported receiving consultation funds from GlaxoSmithKline, Pfizer, Watson, Astellas, Ferring, Taris, Triton, Farr Labs, Trillium, Cernelle, and Johnson & Johnson; having provided expert testimony for GlaxoSmithKline; and having received payment for development of educational presentations from the Canadian Urological Association. Dr Crawford reported receiving payment for lectures from Ferring Pharmaceuticals and GlaxoSmithKline. Dr Andriole reported receiving consultation funds from Amgen, Bayer, Caris, France Foundation, GenProbe, GlaxoSmithKline, Steba Biotech, Ortho-Clinical Diagnostics, and Ferring Pharmaceuticals; having received royalties from Up to Date; receiving payment for development of educational presentations from Amgen; having stock and/or stock options in Envisioneering Medical, Viking Medical, Augmenix, and Cambridge Endo; and receiving travel, accommodations, and meeting expenses from Amgen, Augmenix, Bayer, Cambridge Endo, Caris, France Foundation, GenProbe, Myriad Genetics, Steba Biotech, and Ortho Clinical Diagnostics. Dr Naslund reported receiving payment for lectures from GlaxoSmithKline and sanofi-aventis, as well as payment for development of educational presentations for France Foundation. Dr McVary reported receiving consultancy funds from Lilly/ICOS, Allergan, National Institute of Diabetes and Digestive and Kidney Diseases, Watson Pharm, and Neotract, as well as payment for lectures from GlaxoSmithKline. No other disclosures were reported.; This study was funded by cooperative agreements U01 DK63795, U01 DK63797, U01 DK63825, U01 DK63835, U01 DK63866, U01 DK63833, U01 DK63862, U01 DK63840, U01 DK63883, U01 DK63831, U01 DK63778, and U01 DK63788 from the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases. Support was also provided by the National Center for Complementary and Alternative Medicine and the Office of Dietary Supplements, NIH. Saw palmetto fruit extract and matching placebo were donated by Rottapharm/Madaus, Cologne, Germany. This study was conducted under an Investigational New Drug Application from the US Food and Drug Administration. NR 28 TC 55 Z9 55 U1 1 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 28 PY 2011 VL 306 IS 12 BP 1344 EP 1351 DI 10.1001/jama.2011.1364 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 825FQ UT WOS:000295257000023 PM 21954478 ER PT J AU Kalil, K Li, L Hutchins, BI AF Kalil, Katherine Li, Li Hutchins, B. Ian TI Signaling mechanisms in cortical axon growth, guidance, and branching SO FRONTIERS IN NEUROANATOMY LA English DT Review DE axon outgrowth; axon guidance; axon branching; calcium signaling; Wnt5a; CaMKII; corpus callosum; microtubules ID PROTEIN-KINASE-II; VERTEBRATE NERVOUS-SYSTEM; HUMAN FETAL-BRAIN; CORPUS-CALLOSUM; NEURITE OUTGROWTH; CYCLIC-AMP; IN-VIVO; STRUCTURAL PLASTICITY; MICROTUBULE DYNAMICS; HIPPOCAMPAL-NEURONS AB Precise wiring of cortical circuits during development depends upon axon extension, guidance, and branching to appropriate targets. Motile growth cones at axon tips navigate through the nervous system by responding to molecular cues, which modulate signaling pathways within axonal growth cones. Intracellular calcium signaling has emerged as a major transducer of guidance cues but exactly how calcium signaling pathways modify the actin and microtubule cytoskeleton to evoke growth cone behaviors and axon branching is still mysterious. Axons must often pause their extension in tracts while their branches extend into targets. Some evidence suggests a competition between growth of axons and branches but the mechanisms are poorly understood. Since it is difficult to study growing axons deep within the mammalian brain, much of what we know about signaling pathways and cytoskeletal dynamics of growth cones comes from tissue culture studies, in many cases, of non-mammalian species. Consequently it is not well understood how guidance cues relevant to mammalian neural development in vivo signal to the growth cone cytoskeleton during axon outgrowth and guidance. In this review we describe our recent work in dissociated cultures of developing rodent sensorimotor cortex in the context of the current literature on molecular guidance cues, calcium signaling pathways, and cytoskeletal dynamics that regulate growth cone behaviors. A major challenge is to relate findings in tissue culture to mechanisms of cortical development in vivo.Toward this goal, we describe our recent work in cortical slices, which preserve the complex cellular and molecular environment of the mammalian brain but allow direct visualization of growth cone behaviors and calcium signaling. Findings from this work suggest that mechanisms regulating axon growth and guidance in dissociated culture neurons also underlie development of cortical connectivity in vivo. C1 [Kalil, Katherine] Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA. [Kalil, Katherine; Li, Li; Hutchins, B. Ian] Univ Wisconsin, Neurosci Training Program, Madison, WI 53706 USA. [Li, Li] Pfizer Inc, Groton, CT 06340 USA. [Hutchins, B. Ian] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Kalil, K (reprint author), Univ Wisconsin, Dept Neurosci, 1300 Univ Ave, Madison, WI 53706 USA. EM kakalil@facstaff.wisc.edu RI Hutchins, Ian/A-5713-2009; Kalil, Katherine/B-4413-2009 OI Hutchins, Ian/0000-0001-7657-552X; FU National Institutes of Health [NSO14428]; Whitehall Foundation; University of Wisconsin Graduate School; National Research Service Award [GM801642]; NINDS; NIGMS FX The work from our laboratory was funded by National Institutes of Health Grant NSO14428 and grants from the Whitehall Foundation and the University of Wisconsin Graduate School (to Katherine Kalil), a Herman Shapiro fellowship (to Li Li), and National Research Service Award GM801642 (to Bruce Ian Hutchins). Bruce Ian Hutchins is currently supported by the Intramural Research Program of NINDS and the Pharmacology Research Associate Program of NIGMS. NR 106 TC 22 Z9 23 U1 3 U2 29 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5129 J9 FRONT NEUROANAT JI Front. Neuroanat. PD SEP 28 PY 2011 VL 5 AR 62 DI 10.3389/fnana.2011.00062 PG 15 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA 886RS UT WOS:000299872200001 PM 22046148 ER PT J AU Hines, CS Liow, JS Zanotti-Fregonara, P Hirvonen, J Morse, C Pike, VW Innis, RB AF Hines, Christina S. Liow, Jeih-San Zanotti-Fregonara, Paolo Hirvonen, Jussi Morse, Cheryl Pike, Victor W. Innis, Robert B. TI Human Biodistribution and Dosimetry of C-11-CUMI-101, an Agonist Radioligand for Serotonin-1A Receptors in Brain SO PLOS ONE LA English DT Article ID D-2 DOPAMINE-RECEPTOR; ANTERIOR-PITUITARY; RADIOTRACER; BINDING; PET AB As a reported agonist, C-11-CUMI-101 is believed to selectively bind the G-protein-coupled state of the serotonin-1A (5-HT1A) receptor, thereby providing a measure of the active subset of all 5-HT1A receptors in brain. Although C-11-CUMI-101 has been successfully used to quantify 5-HT1A receptors in human and monkey brain, its radiation exposure has not previously been reported. The purpose of this study was to calculate the radiation exposure to organs of the body based on serial whole-body imaging with positron emission tomography (PET) in human subjects. Methods: Nine healthy volunteers were injected with 428 +/- 84 MBq (mean +/- SD) C-11-CUMI-101 and then imaged with a PET-only device for two hours from head to mid-thigh. Eleven source organs (brain, heart, liver, pancreas, stomach, spleen, lungs, kidneys, lumbar spine L1-5, thyroid, and urinary bladder) were identified on whole body images and used to calculate radiation doses using the software program OLINDA/EXM 1.1. To confirm that we had correctly identified the pancreas, a tenth subject was imaged on a PET/CT device. Results: Brain had high uptake (similar to 11% of injected activity (IA)) at 10 min. Although liver had the highest uptake (similar to 35% IA at 120 min), excretion of this activity was not visible in gall bladder or intestine during the scanning session. Organs which received the highest doses (microSv/MBq) were pancreas (32.0), liver (18.4), and spleen (14.5). The effective dose of 11-CCUMI-101 was 5.3 +/- 0.5 microSv/MBq. Conclusion: The peak brain uptake (similar to 11% IA) of C-11-CUMI-101 is the highest among more than twenty C-11-labeled ligands reported in the literature and provides good counting statistics from relatively low injected activities. Similar to that of other C-11-labeled ligands for brain imaging, the effective dose of C-11-CUMI-101 is 5.3 +/- 0.5 microSv/MBq, a value that can now be used to estimate the radiation risks in future research studies. C1 [Hines, Christina S.; Liow, Jeih-San; Zanotti-Fregonara, Paolo; Hirvonen, Jussi; Morse, Cheryl; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Hines, CS (reprint author), NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. EM robert.innis@nih.gov NR 11 TC 9 Z9 9 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 SEP 27 PY 2011 VL 6 IS 9 AR e25309 DI 10.1371/journal.pone.0025309 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834BW UT WOS:000295933700026 PM 21980419 ER PT J AU Arbyn, M Roelens, J Martin-Hirsch, P Leeson, S Wentzensen, N AF Arbyn, M. Roelens, J. Martin-Hirsch, P. Leeson, S. Wentzensen, N. TI Use of HC2 to triage women with borderline and mild dyskaryosis in the UK SO BRITISH JOURNAL OF CANCER LA English DT Editorial Material ID ATYPICAL SQUAMOUS-CELLS; CERVICAL CYTOLOGY; GRADE; ALTS C1 [Arbyn, M.; Roelens, J.] Sci Inst Publ Hlth, Canc Epidemiol Unit, Brussels, Belgium. [Martin-Hirsch, P.] Cent Lancashire Teaching Hosp, Dept Obstet & Gynaecol, Preston, Lancs, England. [Leeson, S.] Betsi Cadwaladr Univ, Dept Obstet & Gynaecol, Hlth Board, N Wales, PA USA. [Wentzensen, N.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. RP Arbyn, M (reprint author), Sci Inst Publ Hlth, Canc Epidemiol Unit, Brussels, Belgium. EM marc.arbyn@wiv-isp.be NR 13 TC 8 Z9 8 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 SEP 27 PY 2011 VL 105 IS 7 BP 877 EP 880 DI 10.1038/bjc.2011.351 PG 4 WC Oncology SC Oncology GA 826MI UT WOS:000295357900001 PM 21952649 ER PT J AU De Luca, A Lamura, L Strizzi, L Roma, C D'Antonio, A Margaryan, N Pirozzi, G Hsu, MY Botti, G Mari, E Hendrix, MJC Salomon, DS Normanno, N AF De Luca, A. Lamura, L. Strizzi, L. Roma, C. D'Antonio, A. Margaryan, N. Pirozzi, G. Hsu, M-Y Botti, G. Mari, E. Hendrix, M. J. C. Salomon, D. S. Normanno, N. TI Expression and functional role of CRIPTO-1 in cutaneous melanoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE CRIPTO-1; melanoma; invasion; therapy; saracatinib ID TUMOR-CELL GROWTH; HUMAN-MALIGNANT MELANOMA; EGF-RELATED PEPTIDES; BREAST-CANCER CELLS; SRC FAMILY KINASES; C-SRC; SIGNALING PATHWAY; TRANSGENIC MICE; OVEREXPRESSION; INHIBITION AB BACKGROUND: CRIPTO-1 (CR-1) is involved in the pathogenesis and progression of human carcinoma of different histological origin. In this study we addressed the expression and the functional role of CR-1 in cutaneous melanoma. METHODS: Expression of CR-1 protein in melanomas and melanoma cell lines was assessed by immunohistochemistry, western blotting and/or flow cytometry. Levels of mRNA were evaluated by real-time PCR. Invasion assays were performed in Matrigel-coated modified Boyden chambers. RESULTS: Expression of CR-1 protein and/or mRNA was found in 16 out of 37 primary human cutaneous melanomas and in 12 out of 21 melanoma cell lines. Recombinant CR-1 protein activated in melanoma cells c-Src and, at lesser extent, Smad signalling. In addition, CR-1 significantly increased the invasive ability of melanoma cells that was prevented by treatment with either the ALK4 inhibitor SB-431542 or the c-Src inhibitor saracatinib (AZD0530). Anti-CR-1 siRNAs produced a significant inhibition of the growth and the invasive ability of melanoma cells. Finally, a close correlation was found in melanoma cells between the levels of expression of CR-1 and the effects of saracatinib on cell growth. CONCLUSION: These data indicate that a significant fraction of cutaneous melanoma expresses CR-1 and that this growth factor is involved in the invasion and proliferation of melanoma cells. British Journal of Cancer (2011) 105, 1030-1038. doi:10.1038/bjc.2011.324 www.bjcancer.com Published online 23 August 2011 (C) 2011 Cancer Research UK C1 [De Luca, A.; Lamura, L.; Pirozzi, G.; Normanno, N.] INT Fdn Pascale, Cell Biol & Biotherapy Unit, Res Dept, I-80131 Naples, Italy. [Strizzi, L.; Margaryan, N.; Hendrix, M. J. C.] Northwestern Univ, Childrens Mem Res Ctr, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60614 USA. [Roma, C.] CROM, Lab Pharmacogenom, I-83013 Mercogliano, AV, Italy. [D'Antonio, A.] S Giovanni Dio E Ruggi Aragona Hosp, Pathol Unit, I-84100 Salerno, Italy. [Hsu, M-Y] Boston Univ, Dept Dermatol, Sch Med, Boston, MA 02118 USA. [Botti, G.] INT Fdn Pascale, Pathol Unit, I-80131 Naples, Italy. [Mari, E.] AstraZeneca, I-20080 Basiglio, MI, Italy. [Salomon, D. S.] NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Normanno, N (reprint author), INT Fdn Pascale, Cell Biol & Biotherapy Unit, Res Dept, I-80131 Naples, Italy. EM nicnorm@yahoo.com RI De Luca, Antonella/J-8737-2016; OI De Luca, Antonella/0000-0001-5762-447X; roma, cristin/0000-0001-8164-1704; Normanno, Nicola/0000-0002-7158-2605 FU Associazione Italiana per la Ricerca sul Cancro (AIRC); Italian Department of Health; National Cancer Institute (NCI) [CA121205] FX We thank Giuseppina Liguori (Pathology Unit, INT-Fondazione Pascale, Naples, Italy) and Michele Grassi (Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Naples, Italy) for technical support, Alessandra Trocino for bibliographic assistance. This work was in part supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) and from the Italian Department of Health to N Normanno, and from the National Cancer Institute (NCI) to MJC Hendrix (grant CA121205). NR 43 TC 13 Z9 13 U1 0 U2 3 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 SEP 27 PY 2011 VL 105 IS 7 BP 1030 EP 1038 DI 10.1038/bjc.2011.324 PG 9 WC Oncology SC Oncology GA 826MI UT WOS:000295357900023 PM 21863025 ER PT J AU Daniel, CR Schwartz, KL Colt, JS Dong, LM Ruterbusch, JJ Purdue, MP Cross, AJ Rothman, N Davis, FG Wacholder, S Graubard, BI Chow, WH Sinha, R AF Daniel, C. R. Schwartz, K. L. Colt, J. S. Dong, L. M. Ruterbusch, J. J. Purdue, M. P. Cross, A. J. Rothman, N. Davis, F. G. Wacholder, S. Graubard, B. I. Chow, W. H. Sinha, R. TI Meat-cooking mutagens and risk of renal cell carcinoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE benzo(a)pyrene; heterocyclic amines; meat intake; African Americans; smoking; kidney cancer ID POLYCYCLIC AROMATIC-HYDROCARBONS; FOOD FREQUENCY QUESTIONNAIRES; PAH-DNA-ADDUCTS; CANCER-RISK; HETEROCYCLIC AMINES; RED MEAT; PANCREATIC-CANCER; BREAST-CANCER; COLORECTAL ADENOMA; AFRICAN-AMERICANS AB BACKGROUND: High-temperature cooked meat contains two families of carcinogens, heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). Given the kidneys' role in metabolism and urinary excretion of these compounds, we investigated meat-derived mutagens, as well as meat intake and cooking methods, in a population-based case-control study conducted in metropolitan Detroit and Chicago. METHODS: Newly diagnosed, histologically confirmed adenocarcinoma of the renal parenchyma (renal cell carcinoma (RCC)) cases (n = 1192) were frequency matched on age, sex, and race to controls (n = 1175). The interviewer-administered Diet History Questionnaire (DHQ) included queries for meat-cooking methods and doneness with photographic aids. Levels of meat mutagens were estimated using the DHQ in conjunction with the CHARRED database. RESULTS: The risk of RCC increased with intake of barbecued meat (P(trend) = 0.04) and the PAH, benzo(a) pyrene (BaP) (multivariable-adjusted odds ratio and 95% confidence interval, highest vs lowest quartile: 1.50 (1.14, 1.95), P(trend) = 0.001). With increasing BaP intake, the risk of RCC was more than twofold in African Americans and current smokers (P(interaction) <0.05). We found no association for HCAs or overall meat intake. CONCLUSION: BaP intake, a PAH in barbecued meat, was positively associated with RCC. These biologically plausible findings advocate further epidemiological investigation into dietary intake of BaP and risk of RCC. British Journal of Cancer (2011) 105, 1096-1104. doi:10.1038/bjc.2011.343 www.bjcancer.com Published online 6 September 2011 (C) 2011 Cancer Research UK C1 [Daniel, C. R.; Colt, J. S.; Dong, L. M.; Purdue, M. P.; Cross, A. J.; Rothman, N.; Wacholder, S.; Graubard, B. I.; Chow, W. H.; Sinha, R.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Schwartz, K. L.; Ruterbusch, J. J.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. [Davis, F. G.] Univ Illinois, Sch Publ Hlth, Dept Epidemiol & Biostat, Chicago, IL 60612 USA. [Schwartz, K. L.] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI 48201 USA. RP Daniel, CR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd, Rockville, MD 20852 USA. EM Carrie.Daniel@nih.hhs.gov RI Sinha, Rashmi/G-7446-2015; Purdue, Mark/C-9228-2016 OI Sinha, Rashmi/0000-0002-2466-7462; Purdue, Mark/0000-0003-1177-3108 FU NIH, National Cancer Institute FX We would like to thank Gloria Gridley, formerly of NCI's Division of Cancer Epidemiology and Genetics, for her substantial contributions to the design of the dietary questionnaire and development of the nutrient variables, and Adam Risch of Information Management Services Inc. for his technical support in computing the dietary nutrient variables. We wish to express our deep gratitude to the residents of Chicago and Detroit who participated in this study. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 77 TC 8 Z9 9 U1 5 U2 16 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 SEP 27 PY 2011 VL 105 IS 7 BP 1096 EP 1104 DI 10.1038/bjc.2011.343 PG 9 WC Oncology SC Oncology GA 826MI UT WOS:000295357900033 PM 21897389 ER PT J AU Sachdev, V Kato, GJ Gibbs, JSR Barst, RJ Machado, RF Nouraie, M Hassell, KL Little, JA Schraufnagel, DE Krishnamurti, L Novelli, EM Girgis, RE Morris, CR Rosenzweig, EB Badesch, DB Lanzkron, S Castro, OL Taylor, JG Hannoush, H Goldsmith, JC Gladwin, MT Gordeuk, VR AF Sachdev, Vandana Kato, Gregory J. Gibbs, J. Simon R. Barst, Robyn J. Machado, Roberto F. Nouraie, Mehdi Hassell, Kathryn L. Little, Jane A. Schraufnagel, Dean E. Krishnamurti, Lakshmanan Novelli, Enrico M. Girgis, Reda E. Morris, Claudia R. Rosenzweig, Erika Berman Badesch, David B. Lanzkron, Sophie Castro, Oswaldo L. Taylor, James G. Hannoush, Hwaida Goldsmith, Jonathan C. Gladwin, Mark T. Gordeuk, Victor R. CA Walk-PHASST Investigators TI Echocardiographic Markers of Elevated Pulmonary Pressure and Left Ventricular Diastolic Dysfunction Are Associated With Exercise Intolerance in Adults and Adolescents With Homozygous Sickle Cell Anemia in the United States and United Kingdom SO CIRCULATION LA English DT Article DE anemia, sickle cell; diastole; echocardiography; hypertension, pulmonary; exercise ID NITRIC-OXIDE BIOAVAILABILITY; ENDOTHELIAL PROGENITOR CELLS; DOPPLER-ECHOCARDIOGRAPHY; CARDIAC-CATHETERIZATION; FILLING PRESSURES; COR-PULMONALE; RISK-FACTOR; HYPERTENSION; DISEASE; ERYTHROPOIETIN AB Background-Noninvasively assessed pulmonary pressure elevations and left ventricular (LV) diastolic dysfunction are associated with increased mortality in adults with sickle cell disease, but their relationship to exercise intolerance has not been evaluated prospectively. Methods and Results-Echocardiography, 6-minute walk distance, hemolytic rate, and serum concentrations of ferritin and erythropoietin were evaluated in a cohort of 483 subjects with homozygous hemoglobin S in the US and UK Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) study. Tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure, was 2.7 to <3.0 m/s (mean +/- SD, 2.8 +/- 0.1) in 26% of the subjects and >3.0 m/s (mean +/- SD, 3.4 +/- 0.4) in 11%. The LV lateral E/e' ratio, which has been shown to reflect LV filling pressure in other conditions but has not been studied in sickle cell disease, was significantly higher in the groups with tricuspid regurgitation velocity >= 2.7 m/s. Increased hemolysis (P < 0.0001), LV lateral E/e' ratio (P = 0.0001), blood urea nitrogen (P = 0.0002), and erythropoietin (P = 0.002) were independently associated with an increased tricuspid regurgitation velocity. Furthermore, female sex (P < 0.0001), older age (P < 0.0001), LV lateral E/e' ratio (P = 0.014), and tricuspid regurgitation velocity (P = 0.019) were independent predictors of a shorter 6-minute walk distance. Conclusions-Echocardiography-estimated elevated pulmonary artery systolic pressure and LV lateral E/e' ratio were independently associated with poor exercise capacity in a large cohort of patients with sickle cell anemia. Controlled trials investigating whether strategies to prevent or delay pulmonary hypertension and/or LV diastolic dysfunction will improve exercise capacity and long-term outcomes in sickle cell anemia should be considered. C1 [Nouraie, Mehdi; Castro, Oswaldo L.; Gordeuk, Victor R.] Howard Univ, Washington, DC 20001 USA. [Sachdev, Vandana; Kato, Gregory J.; Taylor, James G.; Hannoush, Hwaida] NHLBI, Cardiovasc & Pulm Med Branch, Bethesda, MD 20892 USA. [Gibbs, J. Simon R.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Barst, Robyn J.; Rosenzweig, Erika Berman] Columbia Univ, New York, NY USA. [Machado, Roberto F.; Schraufnagel, Dean E.] Univ Illinois, Chicago, IL USA. [Hassell, Kathryn L.; Badesch, David B.] Univ Colorado HSC, Denver, CO USA. [Little, Jane A.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Krishnamurti, Lakshmanan] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Girgis, Reda E.; Lanzkron, Sophie] Johns Hopkins Univ, Baltimore, MD USA. [Morris, Claudia R.] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA. [Goldsmith, Jonathan C.] NHLBI, NIH, Bethesda, MD 20892 USA. [Gladwin, Mark T.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Novelli, Enrico M.; Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. RP Gordeuk, VR (reprint author), Howard Univ, Res Bldg 1,1840 7th St NW,Room 201, Washington, DC 20001 USA. EM vgordeuk@howard.edu RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Schraufnagel, Dean/0000-0003-0063-7223; Taylor, James/0000-0002-4421-1809 FU NHLBI, NIH, Department of Health and Human Services [HHSN268200617182C]; NIH CTSA [UL1 RR024131]; NHLBI [2 R25 HL003679-08, 1 R01 HL079912-02, HB-06-06, K23HL083089-03]; Howard University GCRC from NCRR, NIH [2MOI RR10284-10]; NIH [R01HL098032, RO1HL096973, RC1DK085852]; Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania; NIHR Biomedical Research Centre; Actelion; Eli Lilly; Gilead; Glaxo Smith-Kline; Medtronics; Bayer; Ikaria; Pfizer; Novartis; United Therapeutics; Ikaria INO Therapeutics; Division of Intramural Research of the NIH; Biomarin; TRF-Pharma; Emmaus Pharmaceuticals; Lilly; ICOS; US government FX This project was funded by the NHLBI, NIH, Department of Health and Human Services under contract HHSN268200617182C (http://www.clinicaltrials.gov; unique identifier: NCT00492531). This work was supported in part by NIH CTSA grant UL1 RR024131 (to Dr Morris); grants 2 R25 HL003679-08 and 1 R01 HL079912-02 from NHLBI (to Dr Gordeuk); Howard University GCRC grant 2MOI RR10284-10 from NCRR, NIH; NIH grants R01HL098032, RO1HL096973, and RC1DK085852 to Dr Gladwin; the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania; the intramural research program of the NIH; and a grant from the NIHR Biomedical Research Centre (to Dr Gibbs).; Dr Barst has received support for research grants and/or consulting from Actelion, Eli Lilly, Gilead, Glaxo Smith-Kline, Medtronics, Bayer, Ikaria, Pfizer, Novartis, United Therapeutics, and NHLBI. Dr Kato has received research support from a cooperative research and development agreement between the NIH and Ikaria INO Therapeutics and from the Division of Intramural Research of the NIH. Dr Gordeuk has received research support from Biomarin, TRF-Pharma, and Emmaus Pharmaceuticals. Dr Gibbs has received research support from Actelion and Bayer and has served on advisory boards and/or received lecture fees from Actelion, Bayer, Glaxo SmithKline, Lilly, Pfizer, and United Therapeutics. Dr Krishnamurti has received research support from the NHLBI (HB-06-06). Dr Girgis has served as an advisory board member for Actelion, Gilead, and United Therapeutics and has received research support from Actelion, Gilead, United Therapeutics, Pfizer, and ICOS. Dr Rosenzweig has received research support from Pfizer. Dr Badesch has received research support from the NHLBI and has participated as a consultant or steering committee or advisory board member for Actelion/CoTherix, Gilead/Myogen, Encysive, Pfizer, Mondo-Biotech/Mondogen, Biogen IDEC, United Therapeutics/Lung Rx, GlaxoSmithKline, and Lilly/ICOS. Dr Lanzkron has received award K23HL083089-03 from the NHLBI. Dr Gladwin has received research support in the form of a collaborative research and development agreement between the US government and INO Therapeutics and is listed as a coinventor on a US government patent for the use of nitrite salts for cardiovascular indications. The views of Dr Goldsmith do not reflect those of the US government. The other authors report no conflicts. NR 49 TC 43 Z9 45 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 27 PY 2011 VL 124 IS 13 BP 1452 EP 1460 DI 10.1161/CIRCULATIONAHA.111.032920 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 824QV UT WOS:000295218000018 PM 21900080 ER PT J AU Mattison, DR Plant, TM Lin, HM Chen, HC Chen, JJ Twaddle, NC Doerge, D Slikker, W Patton, RE Hotchkiss, CE Callicott, RJ Schrader, SM Turner, TW Kesner, JS Vitiello, B Petibone, DM Morris, SM AF Mattison, Donald R. Plant, Tony M. Lin, Hui-Min Chen, Hung-Chia Chen, James J. Twaddle, Nathan C. Doerge, Daniel Slikker, William, Jr. Patton, Ralph E. Hotchkiss, Charlotte E. Callicott, Ralph J. Schrader, Steven M. Turner, Terry W. Kesner, James S. Vitiello, Benedetto Petibone, Dayton M. Morris, Suzanne M. TI Pubertal delay in male nonhuman primates (Macaca mulatta) treated with methylphenidate SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE attention deficit hyperactivity disorder; developmental delay; male puberty ID FOLLICLE-STIMULATING-HORMONE; INHIBIN-B; LUTEINIZING-HORMONE; GONADOTROPIN; TESTOSTERONE; SECRETION; RELEASE; SERTOLI; LEPTIN; RATS AB Juvenile male rhesus monkeys treated with methylphenidate hydrochloride (MPH) to evaluate genetic and behavioral toxicity were observed after 14 mo of treatment to have delayed pubertal progression with impaired testicular descent and reduced testicular volume. Further evaluation of animals dosed orally twice a day with (i) 0.5 mL/kg of vehicle (n = 10), (ii) 0.15 mg/kg of MPH increased to 2.5 mg/kg (low dose, n = 10), or (iii) 1.5 mg/kg of MPH increased to 12.5 mg/kg (high dose, n = 10) for a total of 40 mo revealed that testicular volume was significantly reduced (P < 0.05) at months 15 to 19 and month 27. Testicular descent was significantly delayed (P < 0.05) in the high-dose group. Significantly lower serum testosterone levels were detected in both the low-(P = 0.0017) and high-dose (P = 0.0011) animals through month 33 of treatment. Although serum inhibin B levels were increased overall in low-dose animals (P = 0.0328), differences between groups disappeared by the end of the study. Our findings indicate that MPH administration, beginning before puberty, and which produced clinically relevant blood levels of the drug, impaired pubertal testicular development until similar to 5 y of age. It was not possible to resolve whether MPH delayed the initiation of the onset of puberty or reduced the early tempo of the developmental process. Regardless, deficits in testicular volume and hormone secretion disappeared over the 40-mo observation period, suggesting that the impact of MPH on puberty is not permanent. C1 [Mattison, Donald R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. [Plant, Tony M.] Univ Pittsburgh, Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15213 USA. [Lin, Hui-Min; Chen, Hung-Chia; Chen, James J.; Twaddle, Nathan C.; Doerge, Daniel; Slikker, William, Jr.; Petibone, Dayton M.; Morris, Suzanne M.] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Patton, Ralph E.] Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Hotchkiss, Charlotte E.; Callicott, Ralph J.] Bionet Corp, Jefferson, AR 72079 USA. [Schrader, Steven M.; Turner, Terry W.; Kesner, James S.] NIOSH, Div Appl Res & Technol, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. RP Mattison, DR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. EM mattisod@mail.nih.gov RI Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 FU Eunice Kennedy Shriver National Institute for Child Health; Development/National Institutes of Health; National Center for Toxicological Research/Food and Drug Administration; National Center for Toxicological Research; National Institute for Occupational Safety and Health; Oak Ridge Institute for Science and Education; National Institute for Child Health and Human Development; National Institutes of Health [R01 HD 013254] FX This work was supported by an InterAgency Agreement between the Eunice Kennedy Shriver National Institute for Child Health and Development/National Institutes of Health and the National Center for Toxicological Research/Food and Drug Administration; an Interagency Agreement between the National Center for Toxicological Research and the National Institute for Occupational Safety and Health; an Interagency Agreement between the Oak Ridge Institute for Science and Education and the National Center for Toxicological Research/Food and Drug Administration (H.-M. L. and H.-C. C.); intramural funds from the National Institute for Child Health and Human Development (to D. R. M.); and National Institutes of Health Grant R01 HD 013254 (to T. M. P.). NR 21 TC 16 Z9 17 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 27 PY 2011 VL 108 IS 39 BP 16301 EP 16306 DI 10.1073/pnas.1102187108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825FB UT WOS:000295255300038 PM 21930929 ER PT J AU Sheng, ZM Chertow, DS Ambroggio, X McCall, S Przygodzki, RM Cunningham, RE Maximova, OA Kash, JC Morens, DM Taubenberger, JK AF Sheng, Zong-Mei Chertow, Daniel S. Ambroggio, Xavier McCall, Sherman Przygodzki, Ronald M. Cunningham, Robert E. Maximova, Olga A. Kash, John C. Morens, David M. Taubenberger, Jeffery K. TI Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE archaevirology; postmortem; immunohistochemistry ID ARMED-FORCES-INSTITUTE; VIRUS INFECTIONS; A VIRUSES; BINDING-SPECIFICITY; IMMUNE-RESPONSE; HOST IMMUNE; HEMAGGLUTININ; GENE; TRANSMISSION; PATHOGENESIS AB The 1918 to 1919 "Spanish" influenza pandemic virus killed up to 50 million people. We report here clinical, pathological, bacteriological, and virological findings in 68 fatal American influenza/pneumonia military patients dying between May and October of 1918, a period that includes similar to 4 mo before the 1918 pandemic was recognized, and 2 mo (September-October 1918) during which it appeared and peaked. The lung tissues of 37 of these cases were positive for influenza viral antigens or viral RNA, including four from the prepandemic period (May-August). The prepandemic and pandemic peak cases were indistinguishable clinically and pathologically. All 68 cases had histological evidence of bacterial pneumonia, and 94% showed abundant bacteria on Gram stain. Sequence analysis of the viral hemagglutinin receptor-binding domain performed on RNA from 13 cases suggested a trend from a more "avian-like" viral receptor specificity with G222 in prepandemic cases to a more "human-like" specificity associated with D222 in pandemic peak cases. Viral antigen distribution in the respiratory tree, however, was not apparently different between prepandemic and pandemic peak cases, or between infections with viruses bearing different receptor-binding polymorphisms. The 1918 pandemic virus was circulating for at least 4 mo in the United States before it was recognized epidemiologically in September 1918. The causes of the unusually high mortality in the 1918 pandemic were not explained by the pathological and virological parameters examined. These findings have important implications for understanding the origins and evolution of pandemic influenza viruses. C1 [Sheng, Zong-Mei; Chertow, Daniel S.; Kash, John C.; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Ambroggio, Xavier] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. [Maximova, Olga A.] NIAID, Off Chief, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Morens, David M.] NIAID, Off Director, NIH, Bethesda, MD 20892 USA. [McCall, Sherman] USA, Clin Pathol Lab, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Przygodzki, Ronald M.] Dept Vet Affairs, Washington, DC 20420 USA. [Cunningham, Robert E.] Armed Forces Inst Pathol, Dept Biophys, Rockville, MD 20850 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov OI Przygodzki, Ronald/0000-0002-1238-262X FU National Institutes of Health; National Institute of Allergy and Infectious Diseases FX We thank Frank Roberts and the repository staff of the Armed Forces Institute of Pathology for their help in locating 1918 case material, and Jen Hammock for assistance with the histological preparations. This work was supported by the intramural funds of the National Institutes of Health and the National Institute of Allergy and Infectious Diseases. NR 52 TC 54 Z9 55 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 SEP 27 PY 2011 VL 108 IS 39 BP 16416 EP 16421 DI 10.1073/pnas.1111179108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825FB UT WOS:000295255300058 PM 21930918 ER PT J AU Zhang, PS Casaday-Potts, R Precht, P Jiang, HY Liu, Y Pazin, MJ Mattson, MP AF Zhang, Peisu Casaday-Potts, Rebecca Precht, Patricia Jiang, Haiyang Liu, Yie Pazin, Michael J. Mattson, Mark P. TI Nontelomeric splice variant of telomere repeat-binding factor 2 maintains neuronal traits by sequestering repressor element 1-silencing transcription factor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE brain development; RE1 element; Cajal-Retzius cells; alternative splicing; proteasomal degradation ID TARGET GENES; STEM-CELLS; REST; PROTEIN; REST/NRSF; DIFFERENTIATION; NEUROGENESIS; ACTIVATION; EXPRESSION; MODULATE AB Telomere repeat-binding factor 2 (TRF2) is critical for telomere integrity in dividing stem and somatic cells, but its role in postmitotic neurons is unknown. Apart from protecting telomeres, nuclear TRF2 interacts with the master neuronal gene-silencer repressor element 1-silencing transcription factor (REST), and disruption of this interaction induces neuronal differentiation. Here we report a developmental switch from the expression of TRF2 in proliferating neural progenitor cells to expression of a unique short nontelomeric isoform of TRF2 (TRF2-S) as neurons establish a fully differentiated state. Unlike nuclear TRF2, which enhances REST-mediated gene repression, TRF2-S is located in the cytoplasm where it sequesters REST, thereby maintaining the expression of neuronal genes, including those encoding glutamate receptors, cell adhesion, and neurofilament proteins. In neurons, TRF2-S-mediated antagonism of REST nuclear activity is greatly attenuated by either overexpression of TRF2 or administration of the excitatory amino acid kainic acid. Overexpression of TRF2-S rescues kainic acid-induced REST nuclear accumulation and its gene-silencing effects. Thus, TRF2-S acts as part of a unique developmentally regulated molecular switch that plays critical roles in the maintenance and plasticity of neurons. C1 [Zhang, Peisu; Jiang, Haiyang; Mattson, Mark P.] Natl Inst Aging Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. [Casaday-Potts, Rebecca; Precht, Patricia; Pazin, Michael J.] Natl Inst Aging Intramural Res Program, Lab Cellular & Mol Biol, Baltimore, MD 21224 USA. [Liu, Yie] Natl Inst Aging Intramural Res Program, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Zhang, PS (reprint author), Natl Inst Aging Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. EM zhangpe@grc.nia.nih.gov; mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; OI Pazin, Michael/0000-0002-7561-3640 FU National Institute on Aging FX We thank C. D. Hu for VN173 and VC155 plasmids and Y. H. Chen, Yun Bai, M. R. Mughal, E. M. Kawamoto, P. Yao, and S. J. Texel for valuable comments on the manuscript and technical support. This research was supported by the National Institute on Aging Intramural Research Program. NR 38 TC 10 Z9 10 U1 1 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 SEP 27 PY 2011 VL 108 IS 39 BP 16434 EP 16439 DI 10.1073/pnas.1106906108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825FB UT WOS:000295255300061 PM 21903926 ER PT J AU Ribas, V Drew, BG Le, JA Soleymani, T Daraei, P Sitz, D Mohammad, L Henstridge, DC Febbraio, MA Hewitt, SC Korach, KS Bensinger, SJ Hevener, AL AF Ribas, Vicent Drew, Brian G. Le, Jamie A. Soleymani, Teo Daraei, Pedram Sitz, Daniel Mohammad, Laila Henstridge, Darren C. Febbraio, Mark A. Hewitt, Sylvia C. Korach, Kenneth S. Bensinger, Steven J. Hevener, Andrea L. TI Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE estrogen action; insulin sensitivity ID REVERSE CHOLESTEROL TRANSPORT; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; APOLIPOPROTEIN-E; GENE-EXPRESSION; MACROPHAGE RECRUITMENT; GENDER-DIFFERENCES; SKELETAL-MUSCLE; RISK-FACTOR; PPAR-GAMMA AB ER alpha is expressed in macrophages and other immune cells known to exert dramatic effects on glucose homeostasis. We investigated the impact of ER alpha expression on macrophage function to determine whether hematopoietic or myeloid-specific ER alpha deletion manifests obesity-induced insulin resistance in mice. Indeed, altered plasma adipokine and cytokine levels, glucose intolerance, insulin resistance, and increased adipose tissue mass were observed in animals harboring a hematopoietic or myeloid-specific deletion of ER alpha. A similar obese phenotype and increased atherosclerotic lesion area was displayed in LDL receptor-KO mice transplanted with ER alpha(-/)-bone marrow. In isolated macrophages, ER alpha was necessary for repression of inflammation, maintenance of oxidative metabolism, IL4-mediated induction of alternative activation, full phagocytic capacity in response to LPS, and oxidized LDL-induced expression of ApoE and Abca1. Furthermore, we identified ER alpha as a direct regulator of macrophage transglutaminase 2 expression, a multifunctional atheroprotective enzyme. Our findings suggest that diminished ER alpha expression in hematopoietic/myeloid cells promotes aspects of the metabolic syndrome and accelerates atherosclerosis in female mice. C1 [Ribas, Vicent; Drew, Brian G.; Le, Jamie A.; Soleymani, Teo; Daraei, Pedram; Sitz, Daniel; Mohammad, Laila; Henstridge, Darren C.; Hevener, Andrea L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA. [Henstridge, Darren C.; Febbraio, Mark A.] Baker IDI Heart & Diabet Inst, Cellular & Mol Metab Lab, Melbourne, Vic 8008, Australia. [Hewitt, Sylvia C.; Korach, Kenneth S.] Natl Inst Environm Hlth Sci, Receptor Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. [Bensinger, Steven J.] Univ Calif Los Angeles, Inst Mol Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. RP Hevener, AL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA. EM ahevener@mednet.ucla.edu RI Ribas, Vicent/K-1390-2014; OI Ribas, Vicent/0000-0003-3380-2256; Korach, Kenneth/0000-0002-7765-418X FU National Institutes of Health [DK060484, DK073227, DK063491]; Intramural Research Program; National Institute of Environmental Health Sciences [Z01ES70065]; UCLA Department of Medicine; UCLA Iris Cantor Women's Health Center Foundation; Australian National Health and Medical Research Council; Instituto de Salud Carlos III (Ministerio de Ciencia e Innovacion, Spain) FX We thank Peter Tontonoz, Jerrold Olefsky, Pinchas Cohen, Chris Glass, and the University of California at San Diego (UCSD)-University of California, Los Angeles (UCLA) Diabetes and Endocrinology Research Center (DERC), as well as Pamela Berryhill, Brandi Hutchinson, Tonishia Boyle, and Virginia Ducanes for continued support of our work and assistance with the preparation of this manuscript; Rima Boyadjian from the UCLA DERC Inflammation Core for assistance with Lincoplex analyses performed on mouse plasma; Diana Becerra under the direction of Rajendra Tangirala from the UCLA DERC Mouse Phenotyping Core for assessment of atherosclerotic lesions; Tammy Phung for assistance with FACS analyses; Laarni Gupta under the direction of Dr. Nissi Varki from the Histology Core Facility and UCSD Moore's Cancer Center for assistance with adipose tissue histochemistry. These studies were supported in part by National Institutes of Health Grants DK060484, DK073227, and DK063491 (to A.L.H.); Intramural Research Program, National Institute of Environmental Health Sciences Project Z01ES70065 (to S.C.H. and K.S.K.), and research grants from UCLA Department of Medicine, and UCLA Iris Cantor Women's Health Center Foundation. B.G.D. is supported by an Australian National Health and Medical Research Council postdoctoral research fellowship. V.R. is supported by a postdoctoral fellowship from the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovacion, Spain). NR 55 TC 59 Z9 61 U1 0 U2 5 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 SEP 27 PY 2011 VL 108 IS 39 BP 16457 EP 16462 DI 10.1073/pnas.1104533108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825FB UT WOS:000295255300065 PM 21900603 ER PT J AU Maciejewski, M Tjandra, N Barlow, PN AF Maciejewski, Mateusz Tjandra, Nico Barlow, Paul N. TI Estimation of Interdomain Flexibility of N-Terminus of Factor H Using Residual Dipolar Couplings SO BIOCHEMISTRY LA English DT Article ID COMPLEMENT CONTROL PROTEIN; MODEL-FREE APPROACH; MOLECULAR-STRUCTURE DETERMINATION; NUCLEAR-MAGNETIC-RESONANCE; RECEPTOR-TYPE 1; BIOLOGICAL MACROMOLECULES; MULTIDOMAIN PROTEINS; CONFORMATIONAL SPACE; NMR-SPECTROSCOPY; XPLOR-NIH AB Characterization of segmental flexibility is needed to understand the biological mechanisms of the very large category of functionally diverse proteins, exemplified by the regulators of complement activation, that consist of numerous compact modules or domains linked by short, potentially flexible, sequences of amino acid residues. The use of NMR-derived residual dipolar couplings (RDCs), in magnetically aligned media, to evaluate interdomain motion is established but only for two-domain proteins. We focused on the three N-terminal domains (called CCPs or SCRs) of the important complement regulator, human factor H (i.e., FH1-3). These domains cooperate to facilitate cleavage of the key complement activation-specific protein fragment, C3b, forming iC3b that no longer participates in the complement cascade. We refined a three-dimensional solution structure of recombinant FH1-3 based on nuclear Overhauser effects and RDCs. We then employed a rudimentary series of RDC data sets, collected in media containing magnetically aligned bicelles (disklike particles formed from phospholipids) under three different conditions, to estimate interdomain motions. This circumvents a requirement of previous approaches for technically difficult collection of five independent RDC data sets. More than 80% of conformers of this predominantly extended three-domain molecule exhibit flexions of <40 degrees Such segmental flexibility (together with the local dynamics of the hypervariable loop within domain 3) could facilitate recognition of C3b via initial anchoring and eventual reorganization of modules to the conformation captured in the previously solved crystal structure of a C3b:FH1-4 complex. C1 [Maciejewski, Mateusz; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Maciejewski, Mateusz; Barlow, Paul N.] Univ Edinburgh, Sch Chem, Edinburgh EH9 3JJ, Midlothian, Scotland. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, 50 Ctr Dr, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov; paul.barlow@ed.ac.uk RI Barlow, Paul/G-2853-2011 FU NIH, NHLBI; Wellcome Trust/NIH FX This work was supported by the Intramural Research Program of the NIH, NHLBI, to N.T. and a Wellcome Trust/NIH PhD studentship to M.M. NR 59 TC 17 Z9 17 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 27 PY 2011 VL 50 IS 38 BP 8138 EP 8149 DI 10.1021/bi200575b PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 822OT UT WOS:000295058700005 PM 21793561 ER PT J AU Venkatraman, VK Aizenstein, HJ Newman, AB Yaffe, K Harris, T Kritchevsky, S Ayonayon, HN Rosano, C AF Venkatraman, Vijay K. Aizenstein, Howard J. Newman, Anne B. Yaffe, Kristine Harris, Tamara Kritchevsky, Stephen Ayonayon, Hilsa N. Rosano, Caterina TI Lower digit symbol substitution score in the oldest old is related to magnetization transfer and diffusion tensor imaging of the white matter SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Article DE digit symbol substitution score; oldest old; magnetization transfer; diffusion tensor imaging; white matter ID COGNITIVE DECLINE; SPATIAL STATISTICS; PROCESSING-SPEED; GRAY-MATTER; HUMAN BRAIN; MR-IMAGES; AGE; ADULTS; ANISOTROPY; HYPERINTENSITIES AB Background: Slowing information processing is common among community-dwelling elderly and it predicts greater mortality and disability risk. Slowing information processing is related to brain macro-structural abnormalities. Specifically, greater global atrophy and greater small vessel disease of the white matter (WM) have been associated with slower processing speed. However, community-dwelling elderly with such macro-structural abnormalities can maintain processing speed. The roles of brain micro-structure for slow processing in very old adults living in the community is uncertain, as epidemiological studies relating these brain markers to cognition and in the context of other health characteristics are sparse. Hypothesis: Information processing is cross-sectionally associated with WM micro-structure independent of overt macro-structural abnormalities and also independent of health related characteristics. Methods: Imaging indices of micro-structure diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI), macro-structure white matter hyperintensities (WMH), gray matter (GM) volume, digit symbol substitution test (DSST), and health characteristics were measured in 272 elderly (mean age 83 years old, 43% men, 40% black) living in the community. Results: The DTI- and MTI-indices of micro-structure from the normal appearing WM and not from the normal appearing GM were associated with DSST score independent of WMH and GM volumes. Associations were also independent of age, race, gender, mini-mental score, systolic blood pressure, and prevalent myocardial infarction. Interpretation: DTI and MTI-indices of normal appearing WM are indicators of information processing speed in this cohort of very old adults living in the community. Since processing slowing is a potent index of mortality and disability, these indices may serves as biomarkers in prevention or treatment trials of disability. C1 [Aizenstein, Howard J.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Venkatraman, Vijay K.; Aizenstein, Howard J.] Univ Pittsburgh, Dept Bioengn, Swanson Sch Engn, Pittsburgh, PA 15213 USA. [Newman, Anne B.; Rosano, Caterina] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. [Yaffe, Kristine; Ayonayon, Hilsa N.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Harris, Tamara] NIH, Bethesda, MD 20892 USA. [Kritchevsky, Stephen] Wake Forest Univ, Winston Salem, NC 27109 USA. RP Aizenstein, HJ (reprint author), Univ Pittsburgh, Dept Psychiat, 3811 Ohara St, Pittsburgh, PA 15213 USA. EM aizen@pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Kritchevsky, Stephen/0000-0003-3336-6781 FU Intramural Research Program of the NIH, National Institute on Aging [K23 AG 028966, R01 AG 029232]; [N01-AG-6-2101]; [N01-AG-6-2103]; [N01-AG-6-2106] FX N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. K23 AG 028966, R01 AG 029232. NR 45 TC 15 Z9 15 U1 1 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD SEP 27 PY 2011 VL 3 AR 11 DI 10.3389/fnagi.2011.00011 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 054IK UT WOS:000312337000001 PM 21991255 ER PT J AU Finckbeiner, S Ko, PJ Carrington, B Sood, R Gross, K Dolnick, B Sufrin, J Liu, P AF Finckbeiner, Steve Ko, Pin-Joe Carrington, Blake Sood, Raman Gross, Kenneth Dolnick, Bruce Sufrin, Janice Liu, Paul TI Transient knockdown and overexpression reveal a developmental role for the zebrafish enosf1b gene SO CELL AND BIOSCIENCE LA English DT Article ID 5-FLUOROURACIL RESISTANCE MARKER; THYMIDYLATE SYNTHASE INHIBITORS; MULTIPLE SEQUENCE ALIGNMENT; D-GLUCARATE DEHYDRATASE; ENOLASE SUPERFAMILY; ENZYMATIC-ACTIVITIES; ESCHERICHIA-COLI; (D)-GLUCARATE DEHYDRATASE; PROTEIN SUPERFAMILIES; PSEUDOMONAS-PUTIDA AB Background: Despite detailed in vivo knowledge of glycolytic enolases and many bacterial non-enolase members of the superfamily, little is known about the in vivo function of vertebrate non-enolase enolase superfamily members (ENOSF1s). Results of previous studies suggest involvement of the beta splice form of ENOSF1 in breast and colon cancers. This study used the zebrafish (Danio rerio) as a vertebrate model of ENOSF1 beta function. Results: Whole mount in situ hybridization (WISH) showed that zebrafish ENOSF1 beta (enosf1b) is zygotic and expressed ubiquitously through the first 24 hours post fertilization (hpf). After 24 hpf, enosf1b expression is restricted to the notochord. Embryos injected with enosf1b-EGFP mRNA grew slower than EGFP mRNA-injected embryos but caught up to the EGFP-injected embryos by 48 hpf. Embryos injected with ATG or exon 10 enosf1b mRNA-targeting morpholinos had kinked notochords, shortened anterior-posterior axes, and circulatory edema. WISH for ntl or pax2a expression showed that embryos injected with either morpholino have deformed notochord and pronephros. TUNEL staining revealed increased apoptosis in the peri notochord region. Conclusions: This study is the first report of ENOSF1 function in a vertebrate and shows that ENOSF1 is required for embryonic development. Increased apoptosis following enosf1b knockdown suggests a potential survival advantage for increased ENOSF1 beta expression in human cancers. C1 [Finckbeiner, Steve; Ko, Pin-Joe; Sood, Raman; Liu, Paul] NHGRI, Oncogenesis & Dev Sect, Bethesda, MD 20892 USA. [Finckbeiner, Steve] SUNY Buffalo, Program Mol Pharmacol & Canc Therapeut, Roswell Pk Grad Div, Buffalo, NY USA. [Carrington, Blake; Sood, Raman] NHGRI, Zebrafish Core, Bethesda, MD 20892 USA. [Gross, Kenneth] Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA. [Dolnick, Bruce; Sufrin, Janice] Roswell Pk Canc Inst, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA. RP Liu, P (reprint author), NHGRI, Oncogenesis & Dev Sect, 49 Convent Dr, Bethesda, MD 20892 USA. EM pliu@mail.nih.gov RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU Intramural Program of the National Human Genome Research Institute, NIH FX Barbara Foster, Mike Moser, Jason Kirk, and Avinash Srivatsan provided critical evaluation at multiple points during the conception and development stages of this study. We also thank Colleen Kane, Kevin Bishop, and other members of the Dolnick, Sufrin, and Liu Labs for helpful discussions. This work was supported in part by The Intramural Program of the National Human Genome Research Institute, NIH. NR 76 TC 4 Z9 4 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD SEP 26 PY 2011 VL 1 AR 32 DI 10.1186/2045-3701-1-32 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982PR UT WOS:000307058400001 PM 21943404 ER PT J AU Fung, SJ Joshi, D Allen, KM Sivagnanasundaram, S Rothmond, DA Saunders, R Noble, PL Webster, MJ Weickert, CS AF Fung, Samantha J. Joshi, Dipesh Allen, Katherine M. Sivagnanasundaram, Sinthuja Rothmond, Debora A. Saunders, Richard Noble, Pamela L. Webster, Maree J. Weickert, Cynthia Shannon TI Developmental Patterns of Doublecortin Expression and White Matter Neuron Density in the Postnatal Primate Prefrontal Cortex and Schizophrenia SO PLOS ONE LA English DT Article ID MICROTUBULE-ASSOCIATED PROTEIN; NEWLY GENERATED NEURONS; CELL-ADHESION MOLECULE; PSA-NCAM EXPRESSION; CEREBRAL-CORTEX; HUMAN BRAIN; CORTICAL DEVELOPMENT; SUBVENTRICULAR ZONE; ADULT NEUROGENESIS; GABAERGIC NEURONS AB Postnatal neurogenesis occurs in the subventricular zone and dentate gyrus, and evidence suggests that new neurons may be present in additional regions of the mature primate brain, including the prefrontal cortex (PFC). Addition of new neurons to the PFC implies local generation of neurons or migration from areas such as the subventricular zone. We examined the putative contribution of new, migrating neurons to postnatal cortical development by determining the density of neurons in white matter subjacent to the cortex and measuring expression of doublecortin (DCX), a microtubule-associated protein involved in neuronal migration, in humans and rhesus macaques. We found a striking decline in DCX expression (human and macaque) and density of white matter neurons (humans) during infancy, consistent with the arrival of new neurons in the early postnatal cortex. Considering the expansion of the brain during this time, the decline in white matter neuron density does not necessarily indicate reduced total numbers of white matter neurons in early postnatal life. Furthermore, numerous cells in the white matter and deep grey matter were positive for the migration-associated glycoprotein polysialiated-neuronal cell adhesion molecule and GAD65/67, suggesting that immature migrating neurons in the adult may be GABAergic. We also examined DCX mRNA in the PFC of adult schizophrenia patients (n = 37) and matched controls (n = 37) and did not find any difference in DCX mRNA expression. However, we report a negative correlation between DCX mRNA expression and white matter neuron density in adult schizophrenia patients, in contrast to a positive correlation in human development where DCX mRNA and white matter neuron density are higher earlier in life. Accumulation of neurons in the white matter in schizophrenia would be congruent with a negative correlation between DCX mRNA and white matter neuron density and support the hypothesis of a migration deficit in schizophrenia. C1 [Fung, Samantha J.; Joshi, Dipesh; Allen, Katherine M.; Sivagnanasundaram, Sinthuja; Rothmond, Debora A.; Weickert, Cynthia Shannon] Schizophrenia Res Inst, Sydney, NSW, Australia. [Fung, Samantha J.; Joshi, Dipesh; Allen, Katherine M.; Sivagnanasundaram, Sinthuja; Rothmond, Debora A.; Weickert, Cynthia Shannon] Neurosci Res Australia, Sydney, NSW, Australia. [Fung, Samantha J.] Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia. [Allen, Katherine M.; Weickert, Cynthia Shannon] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Saunders, Richard] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Noble, Pamela L.] Natl Inst Mental Hlth NIMH IRP Nonhuman Primate C, Poolesville, MD USA. [Webster, Maree J.] Stanley Med Res Inst, Rockville, MD USA. RP Fung, SJ (reprint author), Schizophrenia Res Inst, Sydney, NSW, Australia. EM s.fung@neura.edu.au RI Fung, Samantha/C-9660-2011; Shannon Weickert, Cynthia/G-3171-2011; Joshi, Dipesh/I-2918-2012 FU Schizophrenia Research Institute; NSW Health; Macquarie Group Foundation; Neuroscience Research Australia; University of New South Wales; National Health and Medical Research Council of Australia [630452]; University of Sydney; National Institute of Alcohol Abuse and Alcoholism [R24AA012725]; NSW Department of Health FX This work was supported by the Schizophrenia Research Institute, utilizing funding from NSW Health and the Macquarie Group Foundation; Neuroscience Research Australia; the University of New South Wales; and National Health and Medical Research Council of Australia (grant number 630452). Tissues were received from the Australian Brain Donor Programs NSW Tissue Resource Centre, which is supported by the University of Sydney, National Health and Medical Research Council of Australia, Schizophrenia Research Institute, National Institute of Alcohol Abuse and Alcoholism (grant number R24AA012725) and NSW Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 84 TC 19 Z9 20 U1 1 U2 1 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 SEP 26 PY 2011 VL 6 IS 9 AR e25194 DI 10.1371/journal.pone.0025194 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834BK UT WOS:000295932100023 PM 21966452 ER PT J AU Nair, S Bayer, W Ploquin, MJY Kassiotis, G Hasenkrug, KJ Dittmer, U AF Nair, Savita Bayer, Wibke Ploquin, Mickael J. Y. Kassiotis, George Hasenkrug, Kim J. Dittmer, Ulf TI Distinct roles of CD4(+) T cell subpopulations in retroviral immunity: lessons from the Friend virus mouse model SO RETROVIROLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHRONIC VIRAL-INFECTION; HERPES-SIMPLEX-VIRUS; IN-VITRO PROLIFERATION; MURINE LEUKEMIA-VIRUS; FBL-3 TUMOR-CELLS; HIV-INFECTION; GAMMA-INTERFERON; LYMPHOID-TISSUE; HELPER-CELLS AB It is well established that CD4(+) T cells play an important role in immunity to infections with retroviruses such as HIV. However, in recent years CD4(+) T cells have been subdivided into several distinct populations that are differentially regulated and perform widely varying functions. Thus, it is important to delineate the separate roles of these subsets, which range from direct antiviral activities to potent immunosuppression. In this review, we discuss contributions from the major CD4(+) T cell subpopulations to retroviral immunity. Fundamental concepts obtained from studies on numerous viral infections are presented along with a more detailed analysis of studies on murine Friend virus. The relevance of these studies to HIV immunology and immunotherapy is reviewed. C1 [Nair, Savita; Bayer, Wibke; Dittmer, Ulf] Univ Duisburg Essen, Univ Clin Essen, Inst Virol, D-45122 Essen, Germany. [Hasenkrug, Kim J.; Dittmer, Ulf] NIAID, Lab Persistent Viral Dis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Ploquin, Mickael J. Y.; Kassiotis, George] Natl Inst Med Res, MRC, Div Immunoregulat, London NW7 1AA, England. [Nair, Savita] Fox Chase Canc Ctr, Immune Cell Dev & Host Def Program, Philadelphia, PA 19111 USA. RP Dittmer, U (reprint author), Univ Duisburg Essen, Univ Clin Essen, Inst Virol, Hufelandstr 55, D-45122 Essen, Germany. EM ulf.dittmer@uni-due.de FU Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, NIH FX This work was supported by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, NIH. NR 143 TC 12 Z9 13 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 SEP 26 PY 2011 VL 8 AR 76 DI 10.1186/1742-4690-8-76 PG 12 WC Virology SC Virology GA 834OA UT WOS:000295970100002 PM 21943070 ER PT J AU Viatour, P Ehmer, U Saddic, LA Dorrell, C Andersen, JB Lin, CW Zmoos, AF Mazur, PK Schaffer, BE Ostermeier, A Vogel, H Sylvester, KG Thorgeirsson, SS Grompe, M Sage, J AF Viatour, Patrick Ehmer, Ursula Saddic, Louis A. Dorrell, Craig Andersen, Jesper B. Lin, Chenwei Zmoos, Anne-Flore Mazur, Pawel K. Schaffer, Bethany E. Ostermeier, Austin Vogel, Hannes Sylvester, Karl G. Thorgeirsson, Snorri S. Grompe, Markus Sage, Julien TI Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HEPATIC PROGENITOR CELLS; RETINOBLASTOMA TUMOR-SUPPRESSOR; BILE-DUCT DEVELOPMENT; STEM-CELLS; IN-VIVO; FUNCTIONAL GENOMICS; ALAGILLE-SYNDROME; EPITHELIAL-CELLS; GENE-EXPRESSION; HUMAN LIVER AB Hepatocellular carcinoma (HCC) is the third cancer killer worldwide with >600,000 deaths every year. Although the major risk factors are known, therapeutic options in patients remain limited in part because of our incomplete understanding of the cellular and molecular mechanisms influencing HCC development. Evidence indicates that the retinoblastoma (RB) pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms. To investigate the functional relevance of this observation, we inactivated the RB pathway in the liver of adult mice by deleting the three members of the Rb (Rb1) gene family: Rb, p107, and p130. Rb family triple knockout mice develop liver tumors with histopathological features and gene expression profiles similar to human HCC. In this mouse model, cancer initiation is associated with the specific expansion of populations of liver stem/progenitor cells, indicating that the RB pathway may prevent HCC development by maintaining the quiescence of adult liver progenitor cells. In addition, we show that during tumor progression, activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanism to slow HCC growth. The level of Notch activity is also able to predict survival of HCC patients, suggesting novel means to diagnose and treat HCC. C1 [Viatour, Patrick; Ehmer, Ursula; Saddic, Louis A.; Lin, Chenwei; Zmoos, Anne-Flore; Mazur, Pawel K.; Schaffer, Bethany E.; Ostermeier, Austin; Sage, Julien] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Viatour, Patrick; Ehmer, Ursula; Saddic, Louis A.; Lin, Chenwei; Zmoos, Anne-Flore; Mazur, Pawel K.; Schaffer, Bethany E.; Ostermeier, Austin; Sage, Julien] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. [Vogel, Hannes] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Sylvester, Karl G.] Stanford Univ, Dept Surg, Stanford, CA 94305 USA. [Dorrell, Craig; Grompe, Markus] Oregon Hlth & Sci Univ, Oregon Stem Cell Ctr, Portland, OR 97239 USA. [Viatour, Patrick] Univ Liege, Dept Med Chem, B-4000 Liege, Belgium. [Andersen, Jesper B.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Sage, J (reprint author), Stanford Univ, Dept Genet, Stanford, CA 94305 USA. EM julsage@stanford.edu OI Vogel, Otto Hannes/0000-0002-0960-3508; Andersen , Jesper B/0000-0003-1760-5244; Mazur, Pawel/0000-0002-5820-8344 FU Lucile Packard Foundation for Children's Health; Damon Runyon Cancer Research Foundation; National Institutes of Health-National Cancer Institute [R01 CA114102]; Human Frontier Science Program; European Molecular Biology Organization; Fonds de la Recherche Scientifique; Leon Fredericq Foundation; Deutsche Krebshilfe FX This work was supported by the Lucile Packard Foundation for Children's Health, the Damon Runyon Cancer Research Foundation, and National Institutes of Health-National Cancer Institute grant R01 CA114102 (to J. Sage), as well as fellowships from Human Frontier Science Program, European Molecular Biology Organization, the Fonds de la Recherche Scientifique, and the Leon Fredericq Foundation (to P. Viatour) and a Dr. Mildred Scheel fellowship from the Deutsche Krebshilfe (to U. Ehmer). NR 83 TC 83 Z9 85 U1 0 U2 18 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 26 PY 2011 VL 208 IS 10 BP 1963 EP 1976 DI 10.1084/jem.20110198 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 825YS UT WOS:000295318900005 PM 21875955 ER PT J AU Ali, MA Dale, JK Kozak, CA Goldbach-Mansky, R Miller, FW Straus, SE Cohen, JI AF Ali, Mir A. Dale, Janet K. Kozak, Christine A. Goldbach-Mansky, Raphaela Miller, Frederick W. Straus, Stephen E. Cohen, Jeffrey I. TI Xenotropic murine leukemia virus-related virus is not associated with chronic fatigue syndrome in patients from different areas of the us in the 1990s SO VIROLOGY JOURNAL LA English DT Article DE chronic fatigue syndrome; xenotropic murine leukemia virus-related virus; murine leukemia virus ID UNITED-STATES; PROSTATE-CANCER; NO ASSOCIATION; XMRV; CONTAMINATION; RETROVIRUS; SEQUENCES; ABSENCE; PREVALENCE; FAILURE AB Background: In 2009, xenotropic murine leukemia virus-related virus (XMRV) was reported in 67% of patients with chronic fatigue syndrome (CFS) compared to 4% of controls. Since then numerous reports failed to detect XMRV in other cohorts of CFS patients, and some studies suggested that XMRV sequences in human samples might be due to contamination of these samples with mouse DNA. Results: We determined the prevalence of XMRV in patients with CFS from similar areas in the United States as the original 2009 study, along with patients with chronic inflammatory disorders and healthy persons. Using quantitative PCR, we initially detected very low level signals for XMRV DNA in 15% of patients with CFS; however, the frequency of PCR positivity was no different between patients with CFS and controls. Repeated attempts to isolate PCR products from these reactions were unsuccessful. These findings were supported by our observations that PHA and IL-2 stimulation of peripheral blood mononuclear cells from patients with apparently low levels of XMRV, which induced virus replication in the 2009 report, resulted in the disappearance of the signal for XMRV DNA in the cells. Immunoprecipitation of XMRV-infected cell lysates using serum from patients from whom we initially detected low levels of XMRV DNA followed by immunoblotting with antibodies to XMRV gp70 protein failed to detect antibody in the patients, although one control had a weak level of reactivity. Diverse murine leukemia virus (MLV) sequences were obtained by nested PCR with a similar frequency in CFS patients and controls. Finally, we did not detect XMRV sequences in patients with several chronic inflammatory disorders including rheumatoid arthritis, Bechet's disease, and systemic lupus erythematosus. Conclusions: We found no definitive evidence for XMRV DNA sequences or antibody in our cohort of CFS patients, which like the original 2009 study, included patients from diverse regions of the United States. In addition, XMRV was not detected in a cohort of patients with chronic inflammatory disorders. C1 [Ali, Mir A.; Dale, Janet K.; Straus, Stephen E.; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Kozak, Christine A.] NIAID, Viral Biol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Goldbach-Mansky, Raphaela] NIAMSD, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. [Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, NIH, Bethesda, MD USA. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov OI Miller, Frederick/0000-0003-2831-9593 FU National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute of Environmental Health Sciences. We thank Francis Ruscetti for XMRV VP62 plasmid and Jing Qin for performing statistics and Terrance O'Hanlon for technical assistance. NR 27 TC 6 Z9 7 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD SEP 24 PY 2011 VL 8 AR 450 DI 10.1186/1743-422X-8-450 PG 8 WC Virology SC Virology GA 844IN UT WOS:000296741000001 PM 21943244 ER PT J AU Sheng, WW Zong, YJ Mohammad, A Ajit, D Cui, JK Han, DD Hamilton, JL Simonyi, A Sun, AY Gu, ZZ Hong, JS Weisman, GA Sun, GY AF Sheng, Wenwen Zong, Yijia Mohammad, Arwa Ajit, Deepa Cui, Jiankun Han, Dongdong Hamilton, Jennifer L. Simonyi, Agnes Sun, Albert Y. Gu, Zezong Hong, Jau-Shyong Weisman, Gary A. Sun, Grace Y. TI Pro-inflammatory cytokines and lipopolysaccharide induce changes in cell morphology, and upregulation of ERK1/2, iNOS and sPLA(2)-IIA expression in astrocytes and microglia SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE BV-2; HAPI; DITNC; primary astrocytes; primary microglial cells; sPLA2-IIA; iNOS; ERK1/2; filopodia ID NITRIC-OXIDE SYNTHASE; SECRETORY PHOSPHOLIPASE A(2); FOCAL CEREBRAL-ISCHEMIA; IFN-GAMMA; NEURODEGENERATIVE DISEASES; PROINFLAMMATORY CYTOKINES; SIGNALING PATHWAYS; GENE-EXPRESSION; RAT-BRAIN; LPS AB Background: Activation of glial cells, including astrocytes and microglia, has been implicated in the inflammatory responses underlying brain injury and neurodegenerative diseases including Alzheimer's and Parkinson's diseases. Although cultured astrocytes and microglia are capable of responding to pro-inflammatory cytokines and lipopolysaccharide (LPS) in the induction and release of inflammatory factors, no detailed analysis has been carried out to compare the induction of iNOS and sPLA2-IIA. In this study, we investigated the effects of cytokines (TNFalpha, IL-1beta, and IFN-gamma) and LPS + IFN-gamma to induce temporal changes in cell morphology and induction of p-ERK1/2, iNOS and sPLA(2)-IIA expression in immortalized rat (HAPI) and mouse (BV-2) microglial cells, immortalized rat astrocytes (DITNC), and primary microglia and astrocytes. Methods/Results: Cytokines (TNF-alpha, IL-1beta, and IFN-gamma) and LPS + IFN-gamma induced a time-dependent increase in fine processes (filopodia) in microglial cells but not in astrocytes. Filopodia production was attributed to IFN-gamma and was dependent on ERK1/2 activation. Cytokines induced an early (15 min) and a delayed phase (1 similar to 4 h) increase in p-ERK1/2 expression in microglial cells, and the delayed phase increase corresponded to the increase in filopodia production. In general, microglial cells are more active in responding to cytokines and LPS than astrocytes in the induction of NO. Although IFN-gamma and LPS could individually induce NO, additive production was observed when IFN-gamma was added together with LPS. On the other hand, while TNF-alpha, IL-1beta, and LPS could individually induce sPLA(2)-IIA mRNA and protein expression, this induction process does not require IFN-gamma. Interestingly, neither rat immortalized nor primary microglial cells were capable of responding to cytokines and LPS in the induction of sPLA2-IIA expression. Conclusion: These results demonstrated the utility of BV-2 and HAPI cells as models for investigation on cytokine and LPS induction of iNOS, and DITNC astrocytes for induction of sPLA2-IIA. In addition, results further demonstrated that cytokine-induced sPLA2-IIA is attributed mainly to astrocytes and not microglial cells. C1 [Sheng, Wenwen; Ajit, Deepa; Han, Dongdong; Hamilton, Jennifer L.; Simonyi, Agnes; Weisman, Gary A.; Sun, Grace Y.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. [Zong, Yijia; Sun, Grace Y.] Univ Missouri, Interdisciplinary Neurosci Program, Columbia, MO 65211 USA. [Mohammad, Arwa] Univ Missouri, Dept Biol Sci, Columbia, MO 65211 USA. [Ajit, Deepa; Hamilton, Jennifer L.; Weisman, Gary A.] Univ Missouri, Christopher S Bond Life Sci Ctr, Columbia, MO 65211 USA. [Cui, Jiankun; Sun, Albert Y.; Gu, Zezong; Sun, Grace Y.] Univ Missouri, Sch Med, Dept Pathol & Anat Sci, Columbia, MO 65212 USA. [Cui, Jiankun; Simonyi, Agnes; Sun, Albert Y.; Gu, Zezong; Sun, Grace Y.] Univ Missouri, Sch Med, Ctr Translat Neurosci, Columbia, MO 65212 USA. [Hong, Jau-Shyong] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Sun, GY (reprint author), Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. EM sung@missouri.edu FU NIH/NIEHS; [2P01 AG018357]; [1P50 AT006273] FX This research was supported in part by the Intramural Research Program of the NIH/NIEHS, and 2P01 AG018357 (GYS) and 1P50 AT006273 (Dennis Lubahn/GYS). Reading and editing of the manuscript by Mr. D. Reith is acknowledged. NR 36 TC 47 Z9 48 U1 1 U2 12 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 SEP 24 PY 2011 VL 8 AR 121 DI 10.1186/1742-2094-8-121 PG 15 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 841PY UT WOS:000296526000001 PM 21943492 ER PT J AU Piwowar-Manning, E Fiamma, A Laeyendecker, O Kulich, M Donnell, D Szekeres, G Robins-Morris, L Mullis, CE Vallari, A Hackett, J Mastro, TD Gray, G Richter, L Alexandre, MW Chariyalertsak, S Chingono, A Sweat, M Coates, T Eshleman, SH AF Piwowar-Manning, Estelle Fiamma, Agnes Laeyendecker, Oliver Kulich, Michal Donnell, Deborah Szekeres, Greg Robins-Morris, Laura Mullis, Caroline E. Vallari, Ana Hackett, John, Jr. Mastro, Timothy D. Gray, Glenda Richter, Linda Alexandre, Michel W. Chariyalertsak, Suwat Chingono, Alfred Sweat, Michael Coates, Thomas Eshleman, Susan H. TI HIV Surveillance in a Large, Community-Based Study: Results from the Pilot Study of Project Accept (HIV Prevention Trials Network 043) SO BMC INFECTIOUS DISEASES LA English DT Article ID NORTHERN THAILAND; INFECTION; AFRICA; IMMUNOASSAYS; ALGORITHMS; ZIMBABWE; ANTIBODY; RISK AB Background: Project Accept is a community randomized, controlled trial to evaluate the efficacy of community mobilization, mobile testing, same-day results, and post-test support for the prevention of HIV infection in Thailand, Tanzania, Zimbabwe, and South Africa. We evaluated the accuracy of in-country HIV rapid testing and determined HIV prevalence in the Project Accept pilot study. Methods: Two HIV rapid tests were performed in parallel in local laboratories. If the first two rapid tests were discordant (one reactive, one non-reactive), a third HIV rapid test or enzyme immunoassay was performed. Samples were designated HIV NEG if the first two tests were non-reactive, HIV DISC if the first two tests were discordant, and HIV POS if the first two tests were reactive. Samples were re-analyzed in the United States using a panel of laboratory tests. Results: HIV infection status was correctly determined based on-in country testing for 2,236 (99.5%) of 2,247 participants [7 (0.37%) of 1,907 HIV NEG samples were HIV-positive; 2 (0.63%) of 317 HIV POS samples were HIV-negative; 2 (8.3%) of 24 HIV DISC samples were incorrectly identified as HIV-positive based on the in-country tie-breaker test]. HIV prevalence was: Thailand: 0.6%, Tanzania: 5.0%, Zimbabwe 14.7%, Soweto South Africa: 19.4%, Vulindlela, South Africa: 24.4%, (overall prevalence: 14.4%). Conclusions: In-country testing based on two HIV rapid tests correctly identified the HIV infection status for 99.5% of study participants; most participants with discordant HIV rapid tests were not infected. HIV prevalence varied considerably across the study sites (range: 0.6% to 24.4%). C1 [Piwowar-Manning, Estelle; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Fiamma, Agnes; Szekeres, Greg; Coates, Thomas] Univ Calif Los Angeles, Program Global Hlth, Los Angeles, CA USA. [Laeyendecker, Oliver; Mullis, Caroline E.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Laeyendecker, Oliver] NIAID, Lab Immunoregulat, NIH, Baltimore, MD USA. [Kulich, Michal] Charles Univ Prague, Fac Math & Phys, Dept Probabil & Stat, Prague, Czech Republic. [Donnell, Deborah; Robins-Morris, Laura] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Vallari, Ana; Hackett, John, Jr.] Abbott Diagnost, Infect Dis Res, Abbott Pk, IL USA. [Mastro, Timothy D.] FHI 360, Durham, NC USA. [Gray, Glenda] Univ Witwatersrand, Chris Hani Baragwanath Hosp, Perinatal HIV Res Unit, Johannesburg, South Africa. [Richter, Linda] Human Sci Res Council, Durban, South Africa. [Alexandre, Michel W.] Muhimbili Univ Hlth & Allied Sci, Dept Microbiol & Immunol, Dar Es Salaam, Tanzania. [Chariyalertsak, Suwat] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai 50000, Thailand. [Chingono, Alfred] Univ Zimbabwe, Sch Med, Dept Psychiat, Harare, Zimbabwe. [Sweat, Michael] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. RP Eshleman, SH (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; Kulich, Michal/B-1483-2013 OI Laeyendecker, Oliver/0000-0002-6429-4760; Donnell, Deborah/0000-0002-0587-7480; Kulich, Michal/0000-0002-2812-8968 FU HIV Prevention Trials Network (HPTN); National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Office of AIDS Research, of the National Institutes of Health (NIH), Dept. of Health and Human Services (DHHS), through HPTN Network Laboratory [U01AI068613/UM1AI068613]; HPTN Statistical and Data Management Center [U01AI068617]; HPTN Core and Operations Center [U01AI068619]; NIMH, through Johns Hopkins University [U01MH066687]; Medical University of South Carolina [U01MH066688]; University of California, Los Angeles [U01MH066701]; University of California, San Francisco [U01MH066702]; Division of Intramural Research, NIAID, NIH FX This project was supported by the following awards: (1) The HIV Prevention Trials Network (HPTN) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the Office of AIDS Research, of the National Institutes of Health (NIH), Dept. of Health and Human Services (DHHS), through U01AI068613/UM1AI068613 (HPTN Network Laboratory Susan Eshleman, PI), U01AI068617 (HPTN Statistical and Data Management Center - Deborah Donnell, PI), and U01AI068619 (HPTN Core and Operations Center - Sten Vermund, PI). (2) A cooperative agreement from the NIMH, through contracts U01MH066687 (Johns Hopkins University - David Celentano, PI), U01MH066688 (Medical University of South Carolina - Michael Sweat, PI), U01MH066701 (University of California, Los Angeles - Thomas Coates, PI), and U01MH066702 (University of California, San Francisco - Stephen Morin, PI). (3) Additional support was provided by the Division of Intramural Research, NIAID, NIH. NR 18 TC 7 Z9 7 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD SEP 24 PY 2011 VL 11 AR 251 DI 10.1186/1471-2334-11-251 PG 8 WC Infectious Diseases SC Infectious Diseases GA 839FC UT WOS:000296349800001 PM 21943026 ER PT J AU Cheng-Mayer, C Huang, YX Gettie, A Tsai, L Ren, WZ Shakirzyanova, M Sina, ST Trunova, N Blanchard, J Jenkins, LMM Lo, YT Schito, ML Appella, E AF Cheng-Mayer, Cecilia Huang, Yaoxing Gettie, Agegnehu Tsai, Lily Ren, Wuze Shakirzyanova, Madina Sina, Silvana T. Trunova, Nataliya Blanchard, James Jenkins, Lisa M. Miller Lo, Yungtai Schito, Marco L. Appella, Ettore TI Delay of simian human immunodeficiency virus infection and control of viral replication in vaccinated macaques challenged in the presence of a topical microbicide SO AIDS LA English DT Article DE HIV; nucleocapsid inhibitor; prevention; topical microbicide; vaccine ID NUCLEOCAPSID PROTEIN; HIV-1 INFECTION; MUCOSAL TRANSMISSION; RHESUS-MONKEYS; ZINC FINGERS; AIDS VACCINE; COITAL ACT; T-CELLS; TYPE-1; INHIBITORS AB Objective: Development of an effective vaccine or topical compound to prevent HIV transmission remains a major goal for control of the AIDS pandemic. Using a nonhuman primate model of heterosexual HIV-1 transmission, we tested whether a topical microbicide that reduces viral infectivity can potentiate the efficacy of a T-cell-based HIV vaccine. Design: A DNA prime and rAd5 virus boost vaccination strategy was employed, and a topical microbicide against the HIV nucleocapsid protein was used. To rigorously test the combination hypothesis, the vaccine constructs contained only two transgenes and the topical microbicide inhibitor was used at a suboptimal dose. Vaccinees were exposed in the absence and presence of the topical microbicide to repeated vaginal R5 simian human immunodeficiency virus (SHIV)(SF162P3) challenge at an escalating dose to more closely mimic high-risk exposure of women to HIV. Methods: Infection status was determined by PCR. Antiviral immune responses were evaluated by gp120 ELISA and intracellular cytokine staining. Results: A significant delay in SHIV acquisition (log-rank test; P = 0.0416) was seen only in vaccinated macaques that were repeatedly challenged in the presence of the topical microbicide. Peak acute viremia was lower (Mann-Whitney test; P = 0.0387) and viral burden was also reduced (Mann-Whitney test; P = 0.0252) in the combination-treated animals. Conclusion: The combined use of a topical microbicide to lower the initial viral seeding/spread and a T-cell-based vaccine to immunologically contain the early virological events of mucosal transmission holds promise as a preventive approach to control the spread of the AIDS epidemic. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Cheng-Mayer, Cecilia; Huang, Yaoxing; Gettie, Agegnehu; Tsai, Lily; Ren, Wuze; Shakirzyanova, Madina; Sina, Silvana T.; Trunova, Nataliya] Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. [Blanchard, James] Tulane Univ, Med Ctr, Tulane Natl Primate Res Ctr, Covington, LA USA. [Jenkins, Lisa M. Miller; Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Lo, Yungtai] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY USA. [Schito, Marco L.] NIAID, Henry M Jackson Fdn Adv Mil Med, Div AIDS, NIH, Bethesda, MD 20892 USA. RP Cheng-Mayer, C (reprint author), Aaron Diamond AIDS Res Ctr, 455 1st Ave,7th Floor, New York, NY 10016 USA. EM cmayer@adarc.org FU NIH [AI069991]; Tulane National Primate Research Center [RR00164] FX The present work was supported in part by the NIH Intramural AIDS Targeted Antiretroviral Program (IATAP) (E.A.), the Tulane National Primate Research Center Base grant RR00164, and NIH grant AI069991 (C.C.M.). The authors declare no competing financial interests or conflicts of interest. NR 40 TC 13 Z9 13 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 24 PY 2011 VL 25 IS 15 BP 1833 EP 1841 DI 10.1097/QAD.0b013e32834a1d94 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 821AP UT WOS:000294947500004 PM 21750420 ER PT J AU Revell, AD Wang, DC Boyd, MA Emery, S Pozniak, AL De Wolf, F Harrigan, R Montaner, JSG Lane, C Larder, BA AF Revell, Andrew D. Wang, Dechao Boyd, Mark A. Emery, Sean Pozniak, Anton L. De Wolf, Frank Harrigan, Richard Montaner, Julio S. G. Lane, Clifford Larder, Brendan A. CA RDI Study Grp TI The development of an expert system to predict virological response to HIV therapy as part of an online treatment support tool SO AIDS LA English DT Article DE antiretroviral therapy; computer models; HIV drug resistance; predictions; treatment outcome ID SOCIETY-USA PANEL; DRUG-RESISTANCE; ANTIRETROVIRAL TREATMENT; VIRTUAL PHENOTYPE; GENOTYPE; RECOMMENDATIONS; INFECTION AB Objective: The optimum selection and sequencing of combination antiretroviral therapy to maintain viral suppression can be challenging. The HIV Resistance Response Database Initiative has pioneered the development of computational models that predict the virological response to drug combinations. Here we describe the development and testing of random forest models to power an online treatment selection tool. Methods: Five thousand, seven hundred and fifty-two treatment change episodes were selected to train a committee of 10 models to predict the probability of virological response to a new regimen. The input variables were antiretroviral treatment history, baseline CD4 cell count, viral load and genotype, drugs in the new regimen, time from treatment change to follow-up and follow-up viral load values. The models were assessed during cross-validation and with an independent set of 50 treatment change episodes by plotting receiver-operator characteristic curves and their performance compared with genotypic sensitivity scores from rules-based genotype interpretation systems. Results: The models achieved an area under the curve during cross-validation of 0.77-0.87 (mean = 0.82), accuracy of 72-81% (mean = 77%), sensitivity of 62-80% (mean = 67%) and specificity of 75-89% (mean = 81%). When tested with the 50 test cases, the area under the curve was 0.70-0.88, accuracy 64-82%, sensitivity 62-80% and specificity 68-95%. The genotypic sensitivity scores achieved an area under the curve of 0.51-0.52, overall accuracy of 54-56%, sensitivity of 43-64% and specificity of 41-73%. Conclusion: The models achieved a consistent, high level of accuracy in predicting treatment responses, which was markedly superior to that of genotypic sensitivity scores. The models are being used to power an experimental system now available via the Internet. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Revell, Andrew D.; Wang, Dechao; Larder, Brendan A.] RDI, London, England. [Boyd, Mark A.; Emery, Sean] Univ New S Wales, Kirby Inst, Sydney, NSW, Australia. [Boyd, Mark A.] St Vincents Hosp, Sydney, NSW 2010, Australia. [Pozniak, Anton L.] Chelsea & Westminster Hosp, London, England. [De Wolf, Frank] Netherlands HIV Monitoring Fdn, Amsterdam, Netherlands. [Harrigan, Richard; Montaner, Julio S. G.] BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Lane, Clifford] NIAID, Bethesda, MD 20892 USA. RP Revell, AD (reprint author), 14 Union Sq, London N1 7DH, England. EM andrewrevell@hivrdi.org RI Marconi, Vincent/N-3210-2014; Emery, Sean/H-4920-2013; OI Marconi, Vincent/0000-0001-8409-4689; Emery, Sean/0000-0001-6072-8309; Zazzi, Maurizio/0000-0002-0344-6281 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported by the National Institute of Allergy and Infectious Diseases. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 25 TC 13 Z9 13 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 24 PY 2011 VL 25 IS 15 BP 1855 EP 1863 DI 10.1097/QAD.0b013e328349a9c2 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 821AP UT WOS:000294947500006 PM 21785323 ER PT J AU Maifeld, SV MacKinnon, AL Garrison, JL Sharma, A Kunkel, EJ Hegde, RS Taunton, J AF Maifeld, Sarah V. MacKinnon, Andrew L. Garrison, Jennifer L. Sharma, Ajay Kunkel, Eric J. Hegde, Ramanujan S. Taunton, Jack TI Secretory Protein Profiling Reveals TNF-alpha Inactivation by Selective and Promiscuous Sec61 Modulators SO CHEMISTRY & BIOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; SIGNAL RECOGNITION PARTICLE; CELL-ADHESION MOLECULE-1; ENDOPLASMIC-RETICULUM; COTRANSLATIONAL TRANSLOCATION; RICH ELEMENTS; INHIBITOR; BIOSYNTHESIS; SEQUENCES; MEMBRANES AB Cotransins are cyclic heptadepsipeptides that bind the Sec61 translocon to inhibit cotranslational translocation of a subset of secreted and type I transmembrane proteins. The few known cotransin-sensitive substrates are all targeted to the translocon by a cleavable signal sequence, previously shown to be a critical determinant of cotransin sensitivity. By profiling two cotransin variants against a panel of secreted and transmembrane proteins, we demonstrate that cotransin side-chain differences profoundly affect substrate selectivity. Among the most sensitive substrates we identified is the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). Like all type II transmembrane proteins, TNF-alpha is targeted to the translocon by its membrane-spanning domain, indicating that a cleavable signal sequence is not strictly required for cotransin sensitivity. Our results thus reveal an unanticipated breadth of translocon substrates whose expression is inhibited by Sec61 modulators. C1 [Maifeld, Sarah V.; MacKinnon, Andrew L.; Garrison, Jennifer L.; Taunton, Jack] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Sharma, Ajay; Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Kunkel, Eric J.] Bioseek Inc, Burlingame, CA 94010 USA. [Taunton, Jack] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA. RP Taunton, J (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. EM taunton@cmp.ucsf.edu FU U.S. National Institutes of Health [GM081644, 5F32GM080945]; National Institute of Child Health and Human Development FX This work was supported by the U.S. National Institutes of Health (GM081644 to J.T.; 5F32GM080945 to S.V.M) and the Intramural Research Program of the National Institute of Child Health and Human Development (R.S.H.). NR 26 TC 17 Z9 17 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD SEP 23 PY 2011 VL 18 IS 9 BP 1082 EP 1088 DI 10.1016/j.chembiol.2011.06.015 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 833QN UT WOS:000295900100007 PM 21944747 ER PT J AU Durbin, AP Kirkpatrick, BD Pierce, KK Schmidt, AC Whitehead, SS AF Durbin, Anna P. Kirkpatrick, Beth D. Pierce, Kristen K. Schmidt, Alexander C. Whitehead, Stephen S. TI Development and clinical evaluation of multiple investigational monovalent DENV vaccines to identify components for inclusion in a live attenuated tetravalent DENV vaccine SO VACCINE LA English DT Review DE Dengue; Vaccine development; Clinical trial ID DENGUE-VIRUS TYPE-4; ANTIBODY-DEPENDENT ENHANCEMENT; HEALTHY ADULT VOLUNTEERS; FLAVIVIRUS-NAIVE ADULTS; 3' UNTRANSLATED REGION; RHESUS-MONKEYS; 3'-UNTRANSLATED REGION; HEMORRHAGIC-FEVER; VERO CELLS; CANDIDATE AB The Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health has been engaged in an effort to develop a safe, efficacious, and affordable live attenuated tetravalent dengue vaccine (LATV) for more than ten years. Numerous recombinant monovalent DENV vaccine candidates have been evaluated in the SCID-HuH-7 mouse and in rhesus macaques to identify those candidates with a suitable attenuation phenotype. In addition, the ability of these candidates to infect and disseminate in Aedes mosquitoes had also been determined. Those candidates that were suitably attenuated in SCID-HuH-7 mice, rhesus macaques, and mosquitoes were selected for further evaluation in humans. This review will describe the generation of multiple candidate vaccines directed against each DENV serotype, the preclinical and clinical evaluation of these candidates, and the process of selecting suitable candidates for inclusion in a LAW dengue vaccine. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD 21205 USA. [Kirkpatrick, Beth D.; Pierce, Kristen K.] Univ Vermont, Coll Med, Vaccine Testing Ctr, Burlington, VT USA. [Kirkpatrick, Beth D.; Pierce, Kristen K.] Univ Vermont, Coll Med, Infect Dis Unit, Burlington, VT USA. [Kirkpatrick, Beth D.; Pierce, Kristen K.] Univ Vermont, Coll Med, Div Infect Dis, Burlington, VT USA. [Schmidt, Alexander C.; Whitehead, Stephen S.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Durbin, AP (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD 21205 USA. EM adurbin@jhsph.edu FU NIAID Division of Intramural Research at the NIH; NIAID Division of Clinical Research FX This vaccine development project was supported by the NIAID Division of Intramural Research at the NIH. Oversight of the clinical trials was provided by the Laboratory of Infectious Diseases with the NIAID Division of Clinical Research serving as the IND sponsor. NR 46 TC 48 Z9 50 U1 0 U2 5 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 SEP 23 PY 2011 VL 29 IS 42 SI SI BP 7242 EP 7250 DI 10.1016/j.vaccine.2011.07.023 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 830NA UT WOS:000295662500004 PM 21781997 ER PT J AU Amit, M Collins, MT FitzGibbon, EJ Butman, JA Fliss, DM Gil, Z AF Amit, Moran Collins, Michael T. FitzGibbon, Edmond J. Butman, John A. Fliss, Dan M. Gil, Ziv TI Surgery versus Watchful Waiting in Patients with Craniofacial Fibrous Dysplasia - a Meta-Analysis SO PLOS ONE LA English DT Article ID OPTIC-NERVE DECOMPRESSION; MCCUNE-ALBRIGHT-SYNDROME; STIMULATORY G-PROTEIN; OF-THE-LITERATURE; SURGICAL-TREATMENT; PRECOCIOUS PUBERTY; VISUAL-LOSS; SKULL BASE; ORBIT; VISION AB Background: Fibrous dysplasia (FD) is a benign bone tumor which most commonly involves the craniofacial skeleton. The most devastating consequence of craniofacial FD (CFD) is loss of vision due to optic nerve compression (ONC). Radiological evidence of ONC is common, however the management of this condition is not well established. Our objective was to compare the long-term outcome of patients with optic nerve compression (ONC) due to craniofacial fibrous dysplasia (CFD) who either underwent surgery or were managed expectantly. Methodology/Principal Findings: We performed a meta-analysis of 27 studies along with analysis of the records of a cohort of patients enrolled in National Institutes of Health (NIH) protocol 98-D-0145, entitled Screening and Natural History of Fibrous Dysplasia, with a diagnosis of CFD. The study group consisted of 241 patients; 122 were enrolled in the NIH study and 119 were extracted from cases published in the literature. The median follow-up period was 54 months (range, 6-228 months). A total of 368 optic nerves were investigated. All clinically impaired optic nerves (n = 86, 23.3%) underwent therapeutic decompression. Of the 282 clinically intact nerves, 41 (15%) were surgically decompressed and 241 (85%) were followed expectantly. Improvement in visual function was reported in fifty-eight (67.4%) of the clinically impaired nerves after surgery. In the intact nerves group, long-term stable vision was achieved in 31/45 (75.6%) of the operated nerves, compared to 229/241 (95.1%) of the non-operated ones (p = 0.0003). Surgery in asymptomatic patients was associated with visual deterioration (RR 4.89; 95% CI 2.26-10.59). Conclusions: Most patients with CFD will remain asymptomatic during long-term follow-up. Expectant management is recommended in asymptomatic patients even in the presence of radiological evidence of ONC. C1 [Amit, Moran; Fliss, Dan M.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Sackler Fac Med, Dept Otolaryngol Head & Neck Surg, IL-69978 Tel Aviv, Israel. [Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [FitzGibbon, Edmond J.] NEI, NIH, Bethesda, MD 20892 USA. [Butman, John A.] NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Gil, Ziv] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Sackler Fac Med, Head & Neck Surg Unit, IL-69978 Tel Aviv, Israel. [Gil, Ziv] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Sackler Fac Med, Lab Appl Canc Res, IL-69978 Tel Aviv, Israel. RP Amit, M (reprint author), Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Sackler Fac Med, Dept Otolaryngol Head & Neck Surg, IL-69978 Tel Aviv, Israel. EM mc247k@nih.gov; ziv@baseofskull.org RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU Israel Science Foundation [1680/08]; Israel Cancer Association [20090068]; Israeli Ministry of Health [3-7355]; Weizmann Institute - Sourasky Medical Center; Tel Aviv Sourasky Intramural Grant; US-Israel Binational Science Foundation [2007312]; Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA FX This research was supported by the Legacy Heritage Biomedical Science Partnership Program of the Israel Science Foundation (No. 1680/08), the Israel Cancer Association (grant donated by Ellan and Emanuel Kronitz in memory of Dr Leon Kronitz No. 20090068), the Israeli Ministry of Health (No. 3-7355), the Weizmann Institute - Sourasky Medical Center Joint Grant, the Tel Aviv Sourasky Intramural Grant (all to Z.G.) and by a grant from the US-Israel Binational Science Foundation (No. 2007312) to Z.G., R.J.W. and Y.F. This work was supported in part by funding from the Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 17 Z9 18 U1 0 U2 9 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 SEP 23 PY 2011 VL 6 IS 9 AR e25179 DI 10.1371/journal.pone.0025179 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IZ UT WOS:000295267100025 PM 21966448 ER PT J AU Dronamraju, R Mason, JM AF Dronamraju, Raghuvar Mason, James M. TI MU2 and HP1a Regulate the Recognition of Double Strand Breaks in Drosophila melanogaster SO PLOS ONE LA English DT Article ID DNA-DAMAGE RESPONSE; HETEROCHROMATIN PROTEIN-1; CHROMATIN-STRUCTURE; GAMMA-H2AX FOCI; CELL-CYCLE; IONIZING-RADIATION; GENE; ATM; TRANSCRIPTION; MITOSIS AB Chromatin structure regulates the dynamics of the recognition and repair of DNA double strand breaks; open chromatin enhances the recruitment of DNA damage response factors, while compact chromatin is refractory to the assembly of radiation-induced repair foci. MU2, an orthologue of human MDC1, a scaffold for ionizing radiation-induced repair foci, is a widely distributed chromosomal protein in Drosophila melanogaster that moves to DNA repair foci after irradiation. Here we show using yeast 2 hybrid screens and co-immunoprecipitation that MU2 binds the chromoshadow domain of the heterochromatin protein HP1 in untreated cells. We asked what role HP1 plays in the formation of repair foci and cell cycle control in response to DNA damage. After irradiation repair foci form in heterochromatin but are shunted to the edge of heterochromatic regions an HP1-dependent manner, suggesting compartmentalized repair. Hydroxyurea-induced repair foci that form at collapsed replication forks, however, remain in the heterochromatic compartment. HP1a depletion in irradiated imaginal disc cells increases apoptosis and disrupts G2/M arrest. Further, cells irradiated in mitosis produced more and brighter repair foci than to cells irradiated during interphase. Thus, the interplay between MU2 and HP1a is dynamic and may be different in euchromatin and heterochromatin during DNA break recognition and repair. C1 [Dronamraju, Raghuvar; Mason, James M.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Dronamraju, R (reprint author), Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. EM masonj@niehs.nih.gov FU National Institutes of Health, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 7 Z9 8 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 23 PY 2011 VL 6 IS 9 AR e25439 DI 10.1371/journal.pone.0025439 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IZ UT WOS:000295267100061 PM 21966530 ER PT J AU Liu, Q Fan, JJ Niu, C Wang, DC Wang, JP Wang, X Villaruz, AE Li, M Otto, M Gao, Q AF Liu, Qian Fan, Jiajia Niu, Chen Wang, Decheng Wang, Jianping Wang, Xing Villaruz, Amer E. Li, Min Otto, Michael Gao, Qian TI The Eukaryotic-Type Serine/Threonine Protein Kinase Stk Is Required for Biofilm Formation and Virulence in Staphylococcus epidermidis SO PLOS ONE LA English DT Article ID POLYSACCHARIDE INTERCELLULAR ADHESIN; SERINE THREONINE KINASE; STREPTOCOCCUS-PNEUMONIAE; SER/THR KINASE; BINDING PROTEIN; SENSING SYSTEM; AUREUS; GENE; IDENTIFICATION; PHOSPHATASE AB Background: Serine/threonine kinases are involved in gene regulation and signal transduction in prokaryotes and eukaryotes. Here, we investigated the role of the serine/threonine kinase Stk in the opportunistic pathogen Staphylococcus epidermidis. Methodology/Principal Findings: We constructed an isogenic stk mutant of a biofilm-forming clinical S. epidermidis isolate. Presence of stk was important for biofilm formation in vitro and virulence in a murine subcutaneous foreign body infection model. Furthermore, the stk mutant exhibited phenotypes indicating an impact of stk on metabolic pathways. Using different constructs for the genetic complementation of the stk mutant strain with full-length Stk or specific Stk domains, we determined that the Stk intracellular kinase domain is important for biofilm formation and regulation of purine metabolism. Site-specific inactivation of the Stk kinase domain led to defective biofilm formation, in further support of the notion that the kinase activity of Stk regulates biofilm formation of S. epidermidis. According to immunological detection of the biofilm exopolysaccharide PIA and real-time PCR of the PIA biosynthesis genes, the impact of stk on biofilm formation is mediated, at least in part, by a strong influence on PIA expression. Conclusions: Our study identifies Stk as an important regulator of biofilm formation and virulence of S. epidermidis, with additional involvement in purine metabolism and the bacterial stress response. C1 [Liu, Qian; Fan, Jiajia; Niu, Chen; Wang, Decheng; Wang, Jianping; Wang, Xing; Gao, Qian] Fudan Univ, Key Lab Med Mol Virol, Inst Biomed Sci, Shanghai 200433, Peoples R China. [Liu, Qian; Fan, Jiajia; Niu, Chen; Wang, Decheng; Wang, Jianping; Wang, Xing; Gao, Qian] Fudan Univ, Inst Med Microbiol, Shanghai 200433, Peoples R China. [Villaruz, Amer E.; Otto, Michael] NIAID, NIH, Bethesda, MD 20892 USA. [Li, Min] Fudan Univ, Dept Lab Med, Huashan Hosp, Shanghai Med Coll, Shanghai 200433, Peoples R China. RP Liu, Q (reprint author), Fudan Univ, Key Lab Med Mol Virol, Inst Biomed Sci, Shanghai 200433, Peoples R China. EM qgao99@yahoo.com OI Otto, Michael/0000-0002-2222-4115 FU National Natural Science Foundation of China [30670108, J0730860]; National Institute of Allergy and Infectious Diseases, The National Institutes of Health, USA FX This study was supported by National Natural Science Foundation of China 30670108 and J0730860, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, The National Institutes of Health, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 10 Z9 10 U1 1 U2 9 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 SEP 23 PY 2011 VL 6 IS 9 AR e25380 DI 10.1371/journal.pone.0025380 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IZ UT WOS:000295267100051 PM 21966513 ER PT J AU Mukherjee, AB Zhang, ZJ AF Mukherjee, Anil B. Zhang, Zhongjian TI Allergic Asthma: Influence of Genetic and Environmental Factors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID DUST-MITE EXPOSURE; AIRWAY INFLAMMATION; SUSCEPTIBILITY GENES; ATOPIC-DERMATITIS; DENDRITIC CELLS; IMMUNE-RESPONSES; CHILDHOOD ASTHMA; TH2 RESPONSES; SERUM IGE; MAST-CELL AB Allergic asthma is a chronic airway inflammatory disease in which exposure to allergens causes intermittent attacks of breathlessness, airway hyper-reactivity, wheezing, and coughing. Allergic asthma has been called a "syndrome" resulting from a complex interplay between genetic and environmental factors. Worldwide, > 300 million individuals are affected by this disease, and in the United States alone, it is estimated that > 35 million people, mostly children, suffer from asthma. Although animal models, linkage analyses, and genome-wide association studies have identified numerous candidate genes, a solid definition of allergic asthma has not yet emerged; however, such studies have contributed to our understanding of the multiple pathways to this syndrome. In contrast with animal models, in which T-helper 2 (T(H)2) cell response is the dominant feature, in human asthma, an initial exposure to allergen results in T(H)2 cell-dependent stimulation of the immune response that mediates the production of IgE and cytokines. Re-exposure to allergen then activates mast cells, which release mediators such as histamines and leukotrienes that recruit other cells, including T(H)2 cells, which mediate the inflammatory response in the lungs. In this minireview, we discuss the current understanding of how associated genetic and environmental factors increase the complexity of allergic asthma and the challenges allergic asthma poses for the development of novel approaches to effective treatment and prevention. C1 [Mukherjee, Anil B.; Zhang, Zhongjian] Eunice Kennedy Shriver NICHD, Sect Dev Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Mukherjee, AB (reprint author), Eunice Kennedy Shriver NICHD, Sect Dev Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov FU National Institutes of Health Intramural Research Program of Eunice Kennedy Shriver NICHD FX This work was supported by the National Institutes of Health Intramural Research Program of Eunice Kennedy Shriver NICHD. This is the second article in the Thematic Minireview Series on Molecular Bases of Disease: Asthma. This minireview will be reprinted in the 2011 Minireview Compendium, which will be available in January, 2012. NR 94 TC 49 Z9 52 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 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 23 PY 2011 VL 286 IS 38 BP 32883 EP 32889 DI 10.1074/jbc.R110.197046 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 821IR UT WOS:000294968800006 PM 21799018 ER PT J AU Kasaikina, MV Fomenko, DE Labunskyy, VM Lachke, SA Qiu, WY Moncaster, JA Zhang, J Wojnarowicz, MW Natarajan, SK Malinouski, M Schweizer, U Tsuji, PA Carlson, BA Maas, RL Lou, MF Goldstein, LE Hatfield, DL Gladyshev, VN AF Kasaikina, Marina V. Fomenko, Dmitri E. Labunskyy, Vyacheslav M. Lachke, Salil A. Qiu, Wenya Moncaster, Juliet A. Zhang, Jie Wojnarowicz, Mark W., Jr. Natarajan, Sathish Kumar Malinouski, Mikalai Schweizer, Ulrich Tsuji, Petra A. Carlson, Bradley A. Maas, Richard L. Lou, Marjorie F. Goldstein, Lee E. Hatfield, Dolph L. Gladyshev, Vadim N. TI Roles of the 15-kDa Selenoprotein (Sep15) in Redox Homeostasis and Cataract Development Revealed by the Analysis of Sep 15 Knockout Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM; CELL-DEATH; SELENIUM; EXPRESSION; MUTATIONS; DISEASE; GENE; POLYMORPHISMS; SYSTEMS AB The 15-kDa selenoprotein (Sep15) is a thioredoxin-like, endoplasmic reticulum-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose: glycoprotein glucosyltransferase. Expression of Sep15 is regulated by dietary selenium and the unfolded protein response, but its specific function is not known. In this study, we developed and characterized Sep15 KO mice by targeted removal of exon 2 of the Sep15 gene coding for the cysteine-rich UDP-glucose: glycoprotein glucosyltransferase-binding domain. These KO mice synthesized a mutant mRNA, but the shortened protein product could be detected neither in tissues nor in Sep15 KO embryonic fibroblasts. Sep15 KO mice were viable and fertile, showed normal brain morphology, and did not activate endoplasmic reticulum stress pathways. However, parameters of oxidative stress were elevated in the livers of these mice. We found that Sep15 mRNA was enriched during lens development. Further phenotypic characterization of Sep15 KO mice revealed a prominent nuclear cataract that developed at an early age. These cataracts did not appear to be associated with severe oxidative stress or glucose dysregulation. We suggest that the cataracts resulted from an improper folding status of lens proteins caused by Sep15 deficiency. C1 [Kasaikina, Marina V.; Labunskyy, Vyacheslav M.; Lachke, Salil A.; Malinouski, Mikalai; Maas, Richard L.; Gladyshev, Vadim N.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Kasaikina, Marina V.; Labunskyy, Vyacheslav M.; Lachke, Salil A.; Malinouski, Mikalai; Maas, Richard L.; Gladyshev, Vadim N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kasaikina, Marina V.; Fomenko, Dmitri E.; Natarajan, Sathish Kumar; Malinouski, Mikalai] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Kasaikina, Marina V.; Fomenko, Dmitri E.; Natarajan, Sathish Kumar; Malinouski, Mikalai] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. [Lachke, Salil A.] Univ Delaware, Dept Biol Sci, Newark, DE 19716 USA. [Qiu, Wenya; Lou, Marjorie F.] Univ Nebraska, Sch Vet Med & Biomed Sci, Lincoln, NE 68583 USA. [Moncaster, Juliet A.; Wojnarowicz, Mark W., Jr.; Goldstein, Lee E.] Boston Univ, Sch Med, Mol Aging & Dev Lab, Boston, MA 02118 USA. [Zhang, Jie; Schweizer, Ulrich] Charite Univ Med Berlin, Inst Expt Endokrinol, D-13353 Berlin, Germany. [Tsuji, Petra A.; Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Brigham & Womens Hosp, Dept Med, Div Genet, New Res Bldg,Room 435,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM vgladyshev@rics.bwh.harvard.edu RI Gladyshev, Vadim/A-9894-2013; Schweizer, Ulrich/E-8105-2013; OI Moncaster, Juliet/0000-0002-7849-4325; Schweizer, Ulrich/0000-0003-1380-4780; Goldstein, Lee/0000-0001-8419-9800 FU National Institutes of Health [CA080946]; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This study was supported, in whole or in part, by National Institutes of Health Grant CA080946 (to V. N. G.) and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (to D. L. H.). NR 39 TC 30 Z9 34 U1 1 U2 11 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 SEP 23 PY 2011 VL 286 IS 38 BP 33203 EP 33212 DI 10.1074/jbc.M111.259218 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 821IR UT WOS:000294968800039 PM 21768092 ER PT J AU Drwal, MN Agama, K Wakelin, LPG Pommier, Y Griffith, R AF Drwal, Malgorzata N. Agama, Keli Wakelin, Laurence P. G. Pommier, Yves Griffith, Renate TI Exploring DNA Topoisomerase I Ligand Space in Search of Novel Anticancer Agents SO PLOS ONE LA English DT Article ID PLANT ANTITUMOR AGENTS; DRUG DISCOVERY; CAMPTOTHECIN RESISTANCE; MEDICINAL CHEMISTRY; COVALENT COMPLEX; INHIBITORS; DESIGN; NORINDENOISOQUINOLINE; DERIVATIVES; MECHANISM AB DNA topoisomerase I (Top1) is over-expressed in tumour cells and is an important target in cancer chemotherapy. It relaxes DNA torsional strain generated during DNA processing by introducing transient single-strand breaks and allowing the broken strand to rotate around the intermediate Top1 -DNA covalent complex. This complex can be trapped by a group of anticancer agents interacting with the DNA bases and the enzyme at the cleavage site, preventing further topoisomerase activity. Here we have identified novel Top1 inhibitors as potential anticancer agents by using a combination of structure- and ligand-based molecular modelling methods. Pharmacophore models have been developed based on the molecular characteristics of derivatives of the alkaloid camptothecin (CPT), which represent potent antitumour agents and the main group of Top1 inhibitors. The models generated were used for in silico screening of the National Cancer Institute (NCI, USA) compound database, leading to the identification of a set of structurally diverse molecules. The strategy is validated by the observation that amongst these molecules are several known Top1 inhibitors and agents cytotoxic against human tumour cell lines. The potential of the untested hits to inhibit Top1 activity was further evaluated by docking into the binding site of a Top1 -DNA complex, resulting in a selection of 10 compounds for biological testing. Limited by the compound availability, 7 compounds have been tested in vitro for their Top1 inhibitory activity, 5 of which display mild to moderate Top1 inhibition. A further compound, found by similarity search to the active compounds, also shows mild activity. Although the tested compounds display only low in vitro antitumour activity, our approach has been successful in the identification of structurally novel Top1 inhibitors worthy of further investigation as potential anticancer agents. C1 [Drwal, Malgorzata N.; Wakelin, Laurence P. G.; Griffith, Renate] Univ New S Wales, Dept Pharmacol, Sch Med Sci, Sydney, NSW, Australia. [Agama, Keli; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Drwal, MN (reprint author), Univ New S Wales, Dept Pharmacol, Sch Med Sci, Sydney, NSW, Australia. EM r.griffith@unsw.edu.au RI Griffith, Renate/A-3584-2015; Drwal, Malgorzata/B-6461-2015 OI Griffith, Renate/0000-0001-7739-5686; FU University of New South Wales; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Support for the computer-aided design work was provided by internal University of New South Wales funding (Faculty grant to RG, scholarship to MD). The biological assays were supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 16 Z9 16 U1 0 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 SEP 22 PY 2011 VL 6 IS 9 AR e25150 DI 10.1371/journal.pone.0025150 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IJ UT WOS:000295265100068 PM 21966440 ER PT J AU Glunt, KD Thomas, MB Read, AF AF Glunt, Katey D. Thomas, Matthew B. Read, Andrew F. TI The Effects of Age, Exposure History and Malaria Infection on the Susceptibility of Anopheles Mosquitoes to Low Concentrations of Pyrethroid SO PLOS ONE LA English DT Article ID INSECTICIDE RESISTANCE; PLASMODIUM-FALCIPARUM; VECTOR CONTROL; SOUTH-AFRICA; MANAGEMENT; GAMBIAE; EVOLUTION; FIELD; NETS; ARABIENSIS AB Chemical insecticides are critical components of malaria control programs. Their ability to eliminate huge numbers of mosquitoes allows them to swiftly interrupt disease transmission, but that lethality also imposes immense selection for insecticide resistance. Targeting control at the small portion of the mosquito population actually responsible for transmitting malaria parasites to humans would reduce selection for resistance, yet maintain effective malaria control. Here, we ask whether simply lowering the concentration of the active ingredient in insecticide formulations could preferentially kill mosquitoes infected with malaria and/or those that are potentially infectious, namely, old mosquitoes. Using modified WHO resistance-monitoring assays, we exposed uninfected Anopheles stephensi females to low concentrations of the pyrethroid permethrin at days 4, 8, 12, and 16 days post-emergence and monitored survival for at least 30 days to evaluate the immediate and long-term effects of repeated exposure as mosquitoes aged. We also exposed Plasmodium chabaudi- and P. yoelii-infected An. stephensi females. Permethrin exposure did not consistently increase mosquito susceptibility to subsequent insecticide exposure, though older mosquitoes were more susceptible. A blood meal slightly improved survival after insecticide exposure; malaria infection did not detectably increase insecticide susceptibility. Exposure to low concentrations over successive feeding cycles substantially altered cohort age-structure. Our data suggest the possibility that, where high insecticide coverage can be achieved, low concentration formulations have the capacity to reduce disease transmission without the massive selection for resistance imposed by current practice. C1 [Glunt, Katey D.; Thomas, Matthew B.; Read, Andrew F.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Glunt, Katey D.; Read, Andrew F.] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Thomas, Matthew B.; Read, Andrew F.] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Glunt, KD (reprint author), Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM kdglunt@gmail.com FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [R21 AIO88094] FX This work was supported by grant number R21 AIO88094 from the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 17 Z9 17 U1 6 U2 24 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2011 VL 6 IS 9 AR e24968 DI 10.1371/journal.pone.0024968 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IJ UT WOS:000295265100036 PM 21966392 ER PT J AU Huang, Y Cai, ML Clore, GM Craigie, R AF Huang, Ying Cai, Mengli Clore, G. Marius Craigie, Robert TI No Interaction of Barrier-to-Autointegration Factor (BAF) with HIV-1 MA, Cone-Rod Homeobox (Crx) or MAN1-C in Absence of DNA SO PLOS ONE LA English DT Article ID NUCLEAR-ENVELOPE; STRUCTURAL BASIS; RETROVIRAL DNA; IN-VITRO; BINDING; PROTEIN; COMPLEX; MATRIX; DOMAIN AB Barrier-to-autointegration factor is a cellular protein that protects retroviral DNA from autointegration. Its cellular role is not well understood, but genetic studies show that it is essential and depletion or knockout results in lethal nuclear defects. In addition to binding DNA, BAF interacts with the LEM domain, a domain shared among a family of lamin-associated polypeptides. BAF has also been reported to interact with several other viral and cellular proteins suggesting that these interactions may be functionally relevant. We find that, contrary to previous reports, BAF does not interact with HIV-1 MA, cone-rod homeobox (Crx) or MAN1-C. The reported interactions can be explained by indirect association through DNA binding and are unlikely to be biologically relevant. A mutation that causes a premature aging syndrome lies on the previously reported MAN1-C binding surface of BAF. The absence of direct binding of BAF to MAN1-C eliminates disruption of this interaction as the cause of the premature aging phenotype. C1 [Huang, Ying; Craigie, Robert] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Cai, Mengli; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Huang, Y (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM bobc@helix.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU NIDDK, National Institutes of Health (NIH); Office of the Director of the NIH FX This work was supported by the Intramural Program of NIDDK, National Institutes of Health (NIH), and by the AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to GMC and RC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 8 Z9 8 U1 0 U2 1 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 SEP 22 PY 2011 VL 6 IS 9 AR e25123 DI 10.1371/journal.pone.0025123 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IJ UT WOS:000295265100061 PM 21966431 ER PT J AU Sun, W Maffie, JK Lin, L Petralia, RS Rudy, B Hoffman, DA AF Sun, Wei Maffie, Jon K. Lin, Lin Petralia, Ronald S. Rudy, Bernardo Hoffman, Dax A. TI DPP6 Establishes the A-Type K+ Current Gradient Critical for the Regulation of Dendritic Excitability in CA1 Hippocampal Neurons SO NEURON LA English DT Article ID PYRAMIDAL NEURONS; POTASSIUM CHANNELS; ACTION-POTENTIALS; APICAL DENDRITES; DOWN-REGULATION; ALPHA-SUBUNITS; KV4.2 CHANNELS; PROTEIN DPPX; RAT-BRAIN; MODULATION AB Subthreshold-activating A-type K+ currents are essential for the proper functioning of the brain, where they act to delay excitation and regulate firing frequency. In CA1 hippocampal pyramidal neuron dendrites, the density of A-type K+ current increases with distance from the soma, playing an important role in synaptic integration and plasticity. The mechanism underlying this gradient has, however, remained elusive. Here, dendritic recordings from mice lacking the Kv4 transmembrane auxiliary subunit DPP6 revealed that this protein is critical for generating the A-current gradient. Loss of DPP6 led to a decrease in A-type current, specifically in distal dendrites. Decreased current density was accompanied by a depolarizing shift in the voltage dependence of channel activation. Together these changes resulted in hyperexcitable dendrites with enhanced dendritic AP back-propagation, calcium electrogenesis, and induction of synaptic long-term potentiation. Despite enhanced dendritic excitability, firing behavior evoked by somatic current injection was mainly unaffected in DPP6-KO recordings, indicating compartmentalized regulation of neuronal excitability. C1 [Sun, Wei; Lin, Lin; Hoffman, Dax A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Unit, NIH, Bethesda, MD 20892 USA. [Sun, Wei] Peking Univ, Hlth Sci Ctr, Neurosci Res Inst, Beijing 01082801114, Peoples R China. [Sun, Wei] Peking Univ, Hlth Sci Ctr, Dept Neurobiol, Beijing 01082801114, Peoples R China. [Maffie, Jon K.; Rudy, Bernardo] NYU, Sch Med, Dept Physiol & Neurosci, New York, NY 10016 USA. [Maffie, Jon K.; Rudy, Bernardo] NYU, Sch Med, Smilow Neurosci Program, New York, NY 10016 USA. [Petralia, Ronald S.] Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Hoffman, DA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurophysiol & Biophys Unit, NIH, Bethesda, MD 20892 USA. EM hoffmand@mail.nih.gov RI Hoffman, Dax/E-5155-2011; OI Hoffman, Dax/0000-0001-6999-2157; Rudy, Bernardo/0000-0001-5748-6900 FU NICHD; NIDCD; NINDS [NS045217]; NIH [5F30NS071660] FX This work was supported by the NICHD and NIDCD Intramural Research Programs and by NINDS grant NS045217 (B.R.) and NIH 5F30NS071660 (J.K.M.). We thank Dr. Ya-Xian Wang for help with the immunogold study and Begum Choudhury for excellent technical assistance. NR 49 TC 37 Z9 37 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 22 PY 2011 VL 71 IS 6 BP 1102 EP 1115 DI 10.1016/j.neuron.2011.08.008 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 829DM UT WOS:000295556500014 PM 21943606 ER PT J AU Hodge, JN Srinivasula, S Hu, ZH Read, SW Porter, BO Kim, I Mican, JM Paik, C DeGrange, P Di Mascio, M Sereti, I AF Hodge, Jessica N. Srinivasula, Sharat Hu, Zonghui Read, Sarah W. Porter, Brian O. Kim, Insook Mican, Joann M. Paik, Chang DeGrange, Paula Di Mascio, Michele Sereti, Irini TI Decreases in IL-7 levels during antiretroviral treatment of HIV infection suggest a primary mechanism of receptor-mediated clearance SO BLOOD LA English DT Article ID T-CELL HOMEOSTASIS; VIRUS TYPE-1 INFECTION; INTERLEUKIN-7 RECEPTOR; MONOCLONAL-ANTIBODIES; IMMUNE RECONSTITUTION; NONHUMAN-PRIMATES; CD127 EXPRESSION; CD4 CELLS; THERAPY; ACTIVATION AB IL-7 is essential for T-cell homeostasis. Elevated serum IL-7 levels in lymphopenic states, including HIV infection, are thought to be due to increased production by homeostatic feedback, decreased receptor-mediated clearance, or both. The goal of this study was to understand how immune reconstitution through antiretroviral therapy (ART) in HIV(+) patients affects IL-7 serum levels, expression of the IL-7 receptor (CD127), and T-cell cycling. Immunophenotypic analysis of T cells from 29 HIV(-) controls and 43 untreated HIV(+) patients (30 of whom were followed longitudinally for <= 24 months on ART) was performed. Restoration of both CD4(+) and CD8(+) T cells was driven by increases in CD127(+) naive and central memory T cells. CD4(+) T-cell subsets were not fully restored after 2 years of ART, whereas serum IL-7 levels normalized by 1 year of ART. Mathematical modeling indicated that changes in serum IL-7 levels could be accounted for by changes in the receptor concentration. These data suggest that T-cell restoration after ART in HIV infection is driven predominantly by CD127(+) cells and that decreases of serum IL-7 can be largely explained by improved CD127-mediated clearance. (Blood. 2011;118(12):3244-3253) C1 [Sereti, Irini] NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH,Div Intramural Res, Bethesda, MD 20892 USA. [Srinivasula, Sharat] SAIC Frederick Inc, Biostat Res Branch, NCI Frederick, Frederick, MD USA. [Hu, Zonghui] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Read, Sarah W.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Kim, Insook] SAIC Frederick Inc, Appl Dev Res Directorate, Frederick, MD USA. [Mican, Joann M.] NIAID, Div Clin Res, Bethesda, MD 20892 USA. [Paik, Chang] Ctr Clin, Radiopharmaceut Lab, Bethesda, MD USA. [DeGrange, Paula] NIAID Frederick, Battelle Charles River Integrated Res Facil, NIH, Bethesda, MD USA. RP Sereti, I (reprint author), NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH,Div Intramural Res, 10 Ctr Dr,Bldg 10,Rm 11B07A, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov FU NIAID/NIH FX This work was supported in part by the Intramural Research Program of NIAID/NIH. NR 50 TC 20 Z9 21 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 22 PY 2011 VL 118 IS 12 BP 3244 EP 3253 DI 10.1182/blood-2010-12-323600 PG 10 WC Hematology SC Hematology GA 823KK UT WOS:000295120900011 PM 21778338 ER PT J AU Jirmanova, L Torchia, MLG Sarma, ND Mittelstadt, PR Ashwell, JD AF Jirmanova, Ludmila Torchia, Maria Letizia Giardino Sarma, Nandakumara D. Mittelstadt, Paul R. Ashwell, Jonathan D. TI Lack of the T cell-specific alternative p38 activation pathway reduces autoimmunity and inflammation SO BLOOD LA English DT Article ID GENE-TARGETED MICE; PROTEIN-KINASE; MAPK INHIBITOR; ARTHRITIS; P38-ALPHA; GAMMA; ALPHA; TH1; ENCEPHALOMYELITIS; PHOSPHORYLATION AB Stimulation via the T-cell receptor (TCR) activates p38 alpha and p38 beta by phosphorylation of p38 Tyr-323 (p38(Y323)). Here we characterize knockin mice in which p38 alpha and/or beta Tyr-323 has been replaced with Phe. We find that p38 alpha accounts for two-thirds and p38 beta the remainder of TCR-induced p38 activation. T cells from double knockin mice (p38 alpha beta(Y323F)) had defects in TCR-mediated proliferation and Th1 and Th17 skewing, the former corresponding with an inability to sustain T-bet expression. Introduction of p38 alpha(Y323F) into Gadd45 alpha-deficient mice, in which the alternative p38 pathway is constitutively active, reversed T-cell hyperproliferation and autoimmunity. Furthermore, p38 alpha beta(Y323F) mice had delayed onset and reduced severity of the inflammatory autoimmune diseases collagen-induced arthritis and experimental autoimmune encephalomyelitis. Thus, T cell-specific alternative activation of p38 is an important pathway in T-cell proliferation, Th skewing, and inflammatory autoimmunity, and may be an attractive tissue-specific target for intervention in these processes. (Blood. 2011;118(12):3280-3289) C1 [Jirmanova, Ludmila; Torchia, Maria Letizia Giardino; Sarma, Nandakumara D.; Mittelstadt, Paul R.; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Rm 3002, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 45 TC 27 Z9 28 U1 2 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 22 PY 2011 VL 118 IS 12 BP 3280 EP 3289 DI 10.1182/blood-2011-01-333039 PG 10 WC Hematology SC Hematology GA 823KK UT WOS:000295120900015 PM 21715315 ER PT J AU Faraday, N Yanek, LR Yang, XP Mathias, R Herrera-Galeano, JE Suktitipat, B Qayyum, R Johnson, AD Chen, MH Tofler, GH Ruczinski, I Friedman, AD Gylfason, A Thorsteinsdottir, U Bray, PF O'Donnell, CJ Becker, DM Becker, LC AF Faraday, Nauder Yanek, Lisa R. Yang, Xiao Ping Mathias, Rasika Herrera-Galeano, J. Enrique Suktitipat, Bhoom Qayyum, Rehan Johnson, Andrew D. Chen, Ming-Huei Tofler, Geoffrey H. Ruczinski, Ingo Friedman, Alan D. Gylfason, Arnaldur Thorsteinsdottir, Unnur Bray, Paul F. O'Donnell, Christopher J. Becker, Diane M. Becker, Lewis C. TI Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression SO BLOOD LA English DT Article ID GENOME-WIDE ASSOCIATION; ASPIRIN RESISTANCE; CARDIOVASCULAR EVENTS; AGGREGATION; HERITABILITY; METAANALYSIS; ACTIVATION; PATHWAYS; HISTORY; DISEASE AB Genetic variation is thought to contribute to variability in platelet function; however, the specific variants and mechanisms that contribute to altered platelet function are poorly defined. With the use of a combination of fine mapping and sequencing of the platelet endothelial aggregation receptor 1 (PEAR1) gene we identified a common variant (rs12041331) in intron 1 that accounts for <= 15% of total phenotypic variation in platelet function. Association findings were robust in 1241 persons of European ancestry (P = 2.22 x 10(-8)) and were replicated down to the variant and nucleotide level in 835 persons of African ancestry (P = 2.31 x 10(-27)) and in an independent sample of 2755 persons of European descent (P = 1.64 x 10(-5)). Sequencing confirmed that variation at rs12041331 accounted most strongly (P = 2.07 x 10(-6)) for the relation between the PEAR1 gene and platelet function phenotype. A dose-response relation between the number of G alleles at rs12041331 and expression of PEAR1 protein in human platelets was confirmed by Western blotting and ELISA. Similarly, the Gallele was associated with greater protein expression in a luciferase reporter assay. These experiments identify the precise genetic variant in PEAR1 associated with altered platelet function and provide a plausible biologic mechanism to explain the association between variation in the PEAR1 gene and platelet function phenotype. (Blood. 2011;118(12):3367-3375) C1 [Faraday, Nauder] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Yanek, Lisa R.; Yang, Xiao Ping; Mathias, Rasika; Herrera-Galeano, J. Enrique; Suktitipat, Bhoom; Qayyum, Rehan; Becker, Diane M.; Becker, Lewis C.] Johns Hopkins Univ, Sch Med, GeneSTAR Res Program, Dept Med, Baltimore, MD 21205 USA. [Johnson, Andrew D.; Chen, Ming-Huei; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Ming-Huei] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Tofler, Geoffrey H.] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia. [Ruczinski, Ingo] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Friedman, Alan D.] Johns Hopkins Univ, Sch Med, Div Pediat Oncol, Baltimore, MD USA. [Gylfason, Arnaldur; Thorsteinsdottir, Unnur] deCODE Genet, Reykjavik, Iceland. [Bray, Paul F.] Thomas Jefferson Sch Med, Dept Med, Div Hematol, Philadelphia, PA USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA USA. RP Faraday, N (reprint author), Johns Hopkins Univ Hosp, 298 Meyer Bldg,600 N Wolfe St, Baltimore, MD 21287 USA. EM nfaraday@jhmi.edu RI Johnson, Andrew/G-6520-2013; OI Qayyum, Rehan/0000-0003-3086-8014; Suktitipat, Bhoom/0000-0001-8034-7757 FU National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI [U01 HL72518]; STAMPEED consortia [R01 HL087698-01]; Johns Hopkins General Clinical Research Center; National Center for Research Resources [M01-RR000052]; NHLBI [N01-HC-25195]; Affymetrix Inc [N02-HL-6-4278]; Department of Medicine at Boston University School of Medicine; Boston Medical Center; [R01-HL-48157] FX This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI (U01 HL72518) and STAMPEED (R01 HL087698-01) consortia and by grant R01-HL-48157. A portion of this work was supported by resources of the Johns Hopkins General Clinical Research Center, funded through the National Center for Research Resources (grant M01-RR000052). This work was also supported by the NHLBI's Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix Inc for genotyping services (contract no. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. NR 20 TC 32 Z9 34 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 22 PY 2011 VL 118 IS 12 BP 3367 EP 3375 DI 10.1182/blood-2010-11-320788 PG 9 WC Hematology SC Hematology GA 823KK UT WOS:000295120900025 PM 21791418 ER PT J AU Dondorp, AM Fairhurst, RM Slutsker, L MacArthur, JR Breman, JG Guerin, PJ Wellems, TE Ringwald, P Newman, RD Plowe, CV AF Dondorp, Arjen M. Fairhurst, Rick M. Slutsker, Laurence MacArthur, John R. Breman, Joel G. Guerin, Philippe J. Wellems, Thomas E. Ringwald, Pascal Newman, Robert D. Plowe, Christopher V. TI The Threat of Artemisinin-Resistant Malaria SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PLASMODIUM-FALCIPARUM; CAMBODIA C1 [Dondorp, Arjen M.] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand. [Fairhurst, Rick M.; Wellems, Thomas E.] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Slutsker, Laurence; MacArthur, John R.] Ctr Dis Control & Prevent, Malaria Branch, Atlanta, GA USA. [Breman, Joel G.] NIH, Fogarty Int Ctr, Bethesda, MD USA. [Guerin, Philippe J.] Univ Oxford, Worldwide Antimalarial Resistance Network, Ctr Trop Med, Oxford, England. [Ringwald, Pascal; Newman, Robert D.] World Hlth Org, Global Malaria Program, Geneva, Switzerland. [Plowe, Christopher V.] Univ Maryland, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21201 USA. [Plowe, Christopher V.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. RP Dondorp, AM (reprint author), Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand. FU Intramural NIH HHS [ZIA AI001000-06] NR 5 TC 126 Z9 130 U1 0 U2 13 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 SEP 22 PY 2011 VL 365 IS 12 BP 1073 EP 1075 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 822WR UT WOS:000295081600005 PM 21992120 ER PT J AU Emanuel, EJ Menikoff, J AF Emanuel, Ezekiel J. Menikoff, Jerry TI Reforming the Regulations Governing Research with Human Subjects SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID STANDARDS C1 [Emanuel, Ezekiel J.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Menikoff, Jerry] Dept Hlth & Human Serv, Off Human Res Protect, Rockville, MD USA. RP Emanuel, EJ (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. NR 14 TC 61 Z9 62 U1 0 U2 5 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 SEP 22 PY 2011 VL 365 IS 12 BP 1145 EP 1150 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 822WR UT WOS:000295081600016 PM 21787202 ER PT J AU Stamelou, M Edwards, MJ Espay, AJ Fung, VSC Hallett, M Lang, AE Tijssen, MAJ Bhatia, KP AF Stamelou, Maria Edwards, Mark J. Espay, Alberto J. Fung, Victor S. C. Hallett, Mark Lang, Anthony E. Tijssen, Marina A. J. Bhatia, Kailash P. TI Movement Disorders on YouTube - Caveat Spectator SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Stamelou, Maria; Edwards, Mark J.; Bhatia, Kailash P.] UCL, London, England. [Espay, Alberto J.] Univ Cincinnati, Cincinnati, OH USA. [Fung, Victor S. C.] Sydney Med Sch, Sydney, NSW, Australia. [Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. [Lang, Anthony E.] Univ Toronto, Toronto, ON, Canada. [Tijssen, Marina A. J.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. RP Bhatia, KP (reprint author), UCL, London, England. EM k.bhatia@ion.ucl.ac.uk RI Edwards, Mark/F-1052-2012; OI Espay, Alberto/0000-0002-3389-136X FU Intramural NIH HHS [Z99 NS999999] NR 2 TC 18 Z9 18 U1 0 U2 0 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 SEP 22 PY 2011 VL 365 IS 12 BP 1160 EP 1161 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 822WR UT WOS:000295081600031 PM 21992142 ER PT J AU Xiao, JB Marugan, JJ Zheng, W Titus, S Southall, N Cherry, JJ Evans, M Androphy, EJ Austin, CP AF Xiao, Jingbo Marugan, Juan J. Zheng, Wei Titus, Steve Southall, Noel Cherry, Jonathan J. Evans, Matthew Androphy, Elliot J. Austin, Christopher P. TI Discovery, Synthesis, and Biological Evaluation of Novel SMN Protein Modulators SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SPINAL MUSCULAR-ATROPHY; VALPROIC ACID INCREASES; MOTOR-NEURON PROTEIN; MOUSE MODEL; SINGLE NUCLEOTIDE; POTENTIAL THERAPY; IN-VITRO; GENE; CELLS; EXPRESSION AB Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting the expression or function of survival motor neuron protein (SMN) due to the homozygous deletion or rare point mutations in the survival motor neuron gene 1 (SMN1). The human genome includes a second nearly identical gene called SMN2 that is retained in SMA. SMN2 transcripts undergo alternative splicing with reduced levels of SMN, Up-regulation of SMN2 expression, modification of its splicing, or inhibition of proteolysis of the truncated protein derived from SMN2 have been discussed as potential therapeutic strategies for SMA. In this manuscript, we detail the discovery of a series of arylpiperidines as novel modulators of SMN protein. Systematic hit-to-lead efforts significantly improved potency and efficacy of the series in the primary and orthogonal assays. Structure-property relationships including microsomal stability, cell permeability, and in vivo pharmacokinetics (PK) studies were also investigated. We anticipate that a lead candidate chosen from this series may serve as a useful probe for exploring the therapeutic benefits of SMN protein up-regulation in SMA animal models and a starting point for clinical development. C1 [Xiao, Jingbo; Marugan, Juan J.; Zheng, Wei; Titus, Steve; Southall, Noel; Austin, Christopher P.] NHGRI, NIH Chem Genom Ctr, NIH, Rockville, MD 20850 USA. [Cherry, Jonathan J.; Evans, Matthew; Androphy, Elliot J.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. RP Marugan, JJ (reprint author), NHGRI, NIH Chem Genom Ctr, NIH, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM xiaoj@mail.nih.gov; maruganj@mail.nih.gov RI Southall, Noel/H-8991-2012; Zheng, Wei/J-8889-2014; OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757; Androphy, Elliot/0000-0002-8104-0703 FU National Institutes of Health Roadmap for Medical Research [U54MH084681]; National Human Genome Research Institute, National Institutes of Health [R03MH084179-01] FX We thank William Leister, Jim Bougie, Chris LeClair, Paul Shinn, Danielle van Leer, Thomas Daniel, and Jeremy Smith for assistance with compound purification and management. We thank Dr. Marc Ferrer for helpful suggestions and Allison Mandich for critical review of the manuscript. This research was supported by the Molecular Libraries Program of the National Institutes of Health Roadmap for Medical Research (U54MH084681), the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, and R03MH084179-01 to E.J.A. NR 56 TC 21 Z9 21 U1 2 U2 9 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 SEP 22 PY 2011 VL 54 IS 18 BP 6215 EP 6233 DI 10.1021/jm200497t PG 19 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 819ZN UT WOS:000294875300007 PM 21819082 ER PT J AU Beauchamp, MS Beurlot, MR Fava, E Nath, AR Parikh, NA Saad, ZS Bortfeld, H Oghalai, JS AF Beauchamp, Michael S. Beurlot, Michelle R. Fava, Eswen Nath, Audrey R. Parikh, Nehal A. Saad, Ziad S. Bortfeld, Heather Oghalai, John S. TI The Developmental Trajectory of Brain-Scalp Distance from Birth through Childhood: Implications for Functional Neuroimaging SO PLOS ONE LA English DT Article ID NEAR-INFRARED SPECTROSCOPY; VERBAL-FLUENCY TASK; TRANSCRANIAL MAGNETIC STIMULATION; VAULT REDUCTION CRANIOPLASTY; CEREBRAL BLOOD OXYGENATION; SOURCE-DETECTOR DISTANCE; OPTICAL TOPOGRAPHY; HEMODYNAMIC-CHANGES; VISUAL-STIMULATION; PREFRONTAL CORTEX AB Measurements of human brain function in children are of increasing interest in cognitive neuroscience. Many techniques for brain mapping used in children, including functional near-infrared spectroscopy (fNIRS), electroencephalography (EEG), magnetoencephalography (MEG) and transcranial magnetic stimulation (TMS), use probes placed on or near the scalp. The distance between the scalp and the brain is a key variable for these techniques because optical, electrical and magnetic signals are attenuated by distance. However, little is known about how scalp-brain distance differs between different cortical regions in children or how it changes with development. We investigated scalp-brain distance in 71 children, from newborn to age 12 years, using structural T1-weighted MRI scans of the whole head. Three-dimensional reconstructions were created from the scalp surface to allow for accurate calculation of brain-scalp distance. Nine brain landmarks in different cortical regions were manually selected in each subject based on the published fNIRS literature. Significant effects were found for age, cortical region and hemisphere. Brain-scalp distances were lowest in young children, and increased with age to up to double the newborn distance. There were also dramatic differences between brain regions, with up to 50% differences between landmarks. In frontal and temporal regions, scalp-brain distances were significantly greater in the right hemisphere than in the left hemisphere. The largest contributors to developmental changes in brain-scalp distance were increases in the corticospinal fluid (CSF) and inner table of the cranium. These results have important implications for functional imaging studies of children: age and brain-region related differences in fNIRS signals could be due to the confounding factor of brain-scalp distance and not true differences in brain activity. C1 [Beauchamp, Michael S.; Beurlot, Michelle R.; Fava, Eswen; Nath, Audrey R.] Univ Texas Hlth Sci Ctr, Dept Neurobiol & Anat, Houston, TX 77030 USA. [Fava, Eswen] Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. [Parikh, Nehal A.] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. [Parikh, Nehal A.] Nationwide Childrens Hosp, Res Inst, Ctr Perinatal Res, Columbus, OH USA. [Saad, Ziad S.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Bortfeld, Heather] Univ Connecticut, Dept Psychol, Storrs, CT USA. [Oghalai, John S.] Stanford Univ, Dept Otolaryngol Head & Neck Surg, Palo Alto, CA 94304 USA. RP Beauchamp, MS (reprint author), Univ Texas Hlth Sci Ctr, Dept Neurobiol & Anat, Houston, TX 77030 USA. EM Michael.S.Beauchamp@uth.tmc.edu OI Beauchamp, Michael/0000-0002-7599-9934; Bortfeld, Heather/0000-0002-3545-5449 FU National Science Foundation Cognitive Neuroscience Initiative [0642532]; National Institutes of Health (NIH) NINDS [NS065395]; NIH NICHD/NCRR [RR024148]; NIH NIDCD [DC010164]; Dana Foundation; National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke [N01-HD02-3343, N01-MH09-0002, N01-NS-9-2314, N01-NS-9-2315, N01-NS-9-2316, N01-NS-9-2317, N01-NS-9-2319, N01-NS-9-2320] FX This research was supported by National Science Foundation Cognitive Neuroscience Initiative Research Grants 0642532 and National Institutes of Health (NIH) NINDS NS065395 to Dr. Beauchamp, NIH NICHD/NCRR RR024148 (support to Dr. Parikh), NIH NIDCD DC010164 and DC010164 to Dr. Oghalai, and The Dana Foundation to Dr. Oghalai and Dr. Bortfeld. Certain data used in the preparation of this article were obtained from the NIH Pediatric MRI Data Repository created by the NIH MRI Study of Normal Brain Development, a project supported by the National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke (Contract #s N01-HD02-3343, N01-MH09-0002, and N01-NS-9-2314, -2315, -2316, -2317, -2319 and -2320. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 114 TC 25 Z9 25 U1 3 U2 17 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 SEP 21 PY 2011 VL 6 IS 9 AR e24981 DI 10.1371/journal.pone.0024981 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825HM UT WOS:000295262100029 PM 21957470 ER PT J AU Meschia, JF Singleton, A Nalls, MA Rich, SS Sharma, P Ferrucci, L Matarin, M Hernandez, DG Pearce, K Brott, TG Brown, RD Hardy, J Worrall, BB AF Meschia, James F. Singleton, Andrew Nalls, Michael A. Rich, Stephen S. Sharma, Pankaj Ferrucci, Luigi Matarin, Mar Hernandez, Dena G. Pearce, Kerra Brott, Thomas G. Brown, Robert D., Jr. Hardy, John Worrall, Bradford B. TI Genomic Risk Profiling of Ischemic Stroke: Results of an International Genome-Wide Association Meta-Analysis SO PLOS ONE LA English DT Article ID ATRIAL-FIBRILLATION; POPULATION; CLASSIFICATION; VARIANTS; SEQUENCE; SUBTYPES AB Introduction: Familial aggregation of ischemic stroke derives from shared genetic and environmental factors. We present a meta-analysis of genome-wide association scans (GWAS) from 3 cohorts to identify the contribution of common variants to ischemic stroke risk. Methods: This study involved 1464 ischemic stroke cases and 1932 controls. Cases were genotyped using the Illumina 610 or 660 genotyping arrays; controls, with Illumina HumanHap 550Kv1 or 550Kv3 genotyping arrays. Imputation was performed with the 1000 Genomes European ancestry haplotypes (August 2010 release) as a reference. A total of 5,156,597 single-nucleotide polymorphisms (SNPs) were incorporated into the fixed effects meta-analysis. All SNPs associated with ischemic stroke (P < 1 x 10(-5)) were incorporated into a multivariate risk profile model. Results: No SNP reached genome-wide significance for ischemic stroke (P < 5 x 10(-8)). Secondary analysis identified a significant cumulative effect for age at onset of stroke (first versus fifth quintile of cumulative profiles based on SNPs associated with late onset, beta = 14.77 [10.85, 18.68], P = 5.5 x 10(-12)), as well as a strong effect showing increased risk across samples with a high propensity for stroke among samples with enriched counts of suggestive risk alleles (P < 5 x 10(-6)). Risk profile scores based only on genomic information offered little incremental prediction. Discussion: There is little evidence of a common genetic variant contributing to moderate risk of ischemic stroke. Quintiles based on genetic loading of alleles associated with a younger age at onset of ischemic stroke revealed a significant difference in age at onset between those in the upper and lower quintiles. Using common variants from GWAS and imputation, genomic profiling remains inferior to family history of stroke for defining risk. Inclusion of genomic (rare variant) information may be required to improve clinical risk profiling. C1 [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Brown, Robert D., Jr.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Hardy, John] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Singleton, Andrew; Nalls, Michael A.; Ferrucci, Luigi; Hernandez, Dena G.] NIA, Bethesda, MD 20892 USA. [Rich, Stephen S.; Worrall, Bradford B.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Sharma, Pankaj] Univ London Imperial Coll Sci Technol & Med, ICCRU, London, England. [Sharma, Pankaj] Hammersmith Hosp, London, England. [Matarin, Mar] UCL, Inst Neurol, Dept Clin & Expt Epilepsy, London, England. [Pearce, Kerra] Univ Coll London Genom, London, England. [Pearce, Kerra] Inst Child Hlth, London, England. [Worrall, Bradford B.] Univ Virginia, Dept Neurol, Charlottesville, VA USA. RP Meschia, JF (reprint author), Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. EM meschia.james@mayo.edu RI Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; Matarin, Mar/F-1771-2016 OI Matarin, Mar/0000-0002-4717-5735 FU National Institutes of Health [SWISS (NS39987), ISGS (NS42733)]; Department of Health (UK); Henry Smith Charity; British Council (UK-India Education Research Initiative, UKIERI) FX SWISS, ISGS, and BRAINS were supported by non-industry grants. SWISS (NS39987) and ISGS (NS42733) were funded by the National Institutes of Health. BRAINS was suported by a Department of Health (UK) senior fellowship to PS and also by grants from the Henry Smith Charity and the British Council (UK-India Education Research Initiative, UKIERI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 10 Z9 10 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 SEP 21 PY 2011 VL 6 IS 9 AR e23161 DI 10.1371/journal.pone.0023161 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825HM UT WOS:000295262100001 PM 21957438 ER PT J AU Wong-Goodrich, SJE Tognoni, CM Mellott, TJ Glenn, MJ Blusztajn, JK Williams, CL AF Wong-Goodrich, Sarah J. E. Tognoni, Christina M. Mellott, Tiffany J. Glenn, Melissa J. Blusztajn, Jan K. Williams, Christina L. TI Prenatal choline deficiency does not enhance hippocampal vulnerability after kainic acid-induced seizures in adulthood SO BRAIN RESEARCH LA English DT Article DE Choline; Glial fibrillary acidic protein; Glutamic acid decarboxylase; Growth factor; Hippocampus; Seizure ID TEMPORAL-LOBE EPILEPSY; GROWTH-FACTOR-I; ATTENUATES BEHAVIORAL ALTERATIONS; PILOCARPINE-INDUCED SEIZURES; SPONTANEOUS MOTOR SEIZURES; INDUCED MEMORY IMPAIRMENT; LONG-TERM POTENTIATION; ECTOPIC GRANULE CELLS; NEURAL-TUBE DEFECTS; STATUS EPILEPTICUS AB Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12-17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury. (C) 2011 Elsevier B.V. All rights reserved. C1 [Wong-Goodrich, Sarah J. E.; Tognoni, Christina M.; Williams, Christina L.] Duke Univ, Dept Psychol & Neurosci, Durham, NC 27708 USA. [Wong-Goodrich, Sarah J. E.] NIMH, Unit Neuroplast, NIH, Bethesda, MD 20892 USA. [Mellott, Tiffany J.; Blusztajn, Jan K.] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. [Glenn, Melissa J.] Colby Coll, Dept Psychol, Waterville, ME 04901 USA. RP Williams, CL (reprint author), Duke Univ, Dept Psychol & Neurosci, 572 Res Dr,Box 91050,GSRB 2, Durham, NC 27708 USA. EM williams@psych.duke.edu FU [AG009525] FX We would like to thank Aynara Chavez for assistance with data collection. This work was supported by AG009525 to J.K.B. and C.L.W. NR 89 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 21 PY 2011 VL 1413 BP 84 EP 97 DI 10.1016/j.brainres.2011.07.042 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 825QM UT WOS:000295297200009 PM 21840511 ER PT J AU Varmus, H Trimble, EL AF Varmus, Harold Trimble, Edward L. TI Integrating Cancer Control into Global Health SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NONCOMMUNICABLE DISEASES; GRAND CHALLENGES AB Many in the global health community have recently proposed that current efforts be expanded to include diseases typically associated with advanced economies, such as heart disease, mental health disorders, diabetes, and cancers. Here, we discuss ways in which the National Cancer Institute's newly formed Center for Global Health plans to stem the rising cancer burden in developing countries. C1 [Varmus, Harold; Trimble, Edward L.] NCI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Varmus, H (reprint author), NCI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM harold.varmus@nih.gov NR 11 TC 3 Z9 4 U1 1 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD SEP 21 PY 2011 VL 3 IS 101 AR 101cm28 DI 10.1126/scitranslmed.3002321 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 822VW UT WOS:000295079300002 PM 21937755 ER PT J AU Bolton, EE Chen, J Kim, S Han, LY He, SQ Shi, WY Simonyan, V Sun, Y Thiessen, PA Wang, JY Yu, B Zhang, J Bryant, SH AF Bolton, Evan E. Chen, Jie Kim, Sunghwan Han, Lianyi He, Siqian Shi, Wenyao Simonyan, Vahan Sun, Yan Thiessen, Paul A. Wang, Jiyao Yu, Bo Zhang, Jian Bryant, Stephen H. TI PubChem3D: a new resource for scientists SO JOURNAL OF CHEMINFORMATICS LA English DT Article ID MOLECULAR-FORCE FIELD; DRUG DESIGN; CONFORMER GENERATION; GAUSSIAN DESCRIPTION; SHAPE; INFORMATION; STRATEGIES; DISCOVERY; MMFF94 AB Background: PubChem is an open repository for small molecules and their experimental biological activity. PubChem integrates and provides search, retrieval, visualization, analysis, and programmatic access tools in an effort to maximize the utility of contributed information. There are many diverse chemical structures with similar biological efficacies against targets available in PubChem that are difficult to interrelate using traditional 2-D similarity methods. A new layer called PubChem3D is added to PubChem to assist in this analysis. Description: PubChem generates a 3-D conformer model description for 92.3% of all records in the PubChem Compound database (when considering the parent compound of salts). Each of these conformer models is sampled to remove redundancy, guaranteeing a minimum (non-hydrogen atom pair-wise) RMSD between conformers. A diverse conformer ordering gives a maximal description of the conformational diversity of a molecule when only a subset of available conformers is used. A pre-computed search per compound record gives immediate access to a set of 3-D similar compounds (called "Similar Conformers") in PubChem and their respective superpositions. Systematic augmentation of PubChem resources to include a 3-D layer provides users with new capabilities to search, subset, visualize, analyze, and download data. A series of retrospective studies help to demonstrate important connections between chemical structures and their biological function that are not obvious using 2-D similarity but are readily apparent by 3-D similarity. Conclusions: The addition of PubChem3D to the existing contents of PubChem is a considerable achievement, given the scope, scale, and the fact that the resource is publicly accessible and free. With the ability to uncover latent structure-activity relationships of chemical structures, while complementing 2-D similarity analysis approaches, PubChem3D represents a new resource for scientists to exploit when exploring the biological annotations in PubChem. C1 [Bolton, Evan E.; Chen, Jie; Kim, Sunghwan; Han, Lianyi; He, Siqian; Shi, Wenyao; Simonyan, Vahan; Sun, Yan; Thiessen, Paul A.; Wang, Jiyao; Yu, Bo; Zhang, Jian; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Bolton, EE (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Dept Hlth & Human Serv, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov RI Kim, Sunghwan/A-6738-2008 OI Kim, Sunghwan/0000-0001-9828-2074 FU National Library of Medicine, National Institutes of Health, U. S. Department of Health and Human Services FX This research was supported (in part) by the Intramural Research Program of the National Library of Medicine, National Institutes of Health, U. S. Department of Health and Human Services. This effort utilized the high-performance computational capabilities of the Helix Systems at the National Institutes of Health, Bethesda, MD (http://helix.nih.gov). NR 47 TC 43 Z9 43 U1 2 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD SEP 20 PY 2011 VL 3 AR 32 DI 10.1186/1758-2946-3-32 PG 15 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA 891QR UT WOS:000300232200001 PM 21933373 ER PT J AU Ravichandran, V Major, EO Ibe, C Monaco, MC Girisetty, MKH Hewlett, IK AF Ravichandran, Veerasamy Major, Eugen O. Ibe, Carol Monaco, Maria Chiara Girisetty, Mohan Kumar Haleyur Hewlett, Indira K. TI Susceptibility of human primary neuronal cells to Xenotropic Murine Leukemia Virus-related (XMRV) virus infection SO VIROLOGY JOURNAL LA English DT Article DE XMRV infection; Primary neuronal cells; Non-neuronal cells; Nuclear factors ID JC VIRUS; PROGENITOR CELLS; BONE-MARROW; PATHWAY AB Background: Xenotropic Murine Leukemia Virus-related (XMRV) virus is a recently identified mouse gammaretrovirus that has the ability to infect certain human cells. In this study, we investigated the susceptibility of primary neuronal cell types to infection with XMRV. Findings: We observed that the human primary progenitors, progenitor-derived neurons, and progenitor-derived astrocytes supported XMRV multiplication. Interestingly, both progenitors and progenitor-derived neurons were more susceptible compared with progenitor-derived astrocytes. In addition, XMRV-infected Jurkat cells were able to transmit infection to neuronal cells. Conclusions: These data suggest that neuronal cells are susceptible for XMRV infection. C1 [Ravichandran, Veerasamy; Girisetty, Mohan Kumar Haleyur; Hewlett, Indira K.] US FDA, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Major, Eugen O.; Ibe, Carol; Monaco, Maria Chiara] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Hewlett, IK (reprint author), US FDA, Mol Virol Lab, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM indira.hewlett@fda.hhs.gov RI Haleyur Giri Setty, Mohan Kumar/F-5841-2014 OI Haleyur Giri Setty, Mohan Kumar/0000-0001-6423-1420 NR 9 TC 8 Z9 9 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD SEP 20 PY 2011 VL 8 AR 443 DI 10.1186/1743-422X-8-443 PG 4 WC Virology SC Virology GA 832XG UT WOS:000295843300003 PM 21933387 ER PT J AU You, W Almeida, FA Zoellner, JM Hill, JL Pinard, CA Allen, KC Glasgow, RE Linnan, LA Estabrooks, PA AF You, Wen Almeida, Fabio A. Zoellner, Jamie M. Hill, Jennie L. Pinard, Courtney A. Allen, Kacie C. Glasgow, Russell E. Linnan, Laura A. Estabrooks, Paul A. TI Who participates in internet-based worksite weight loss programs? SO BMC PUBLIC HEALTH LA English DT Article ID HEALTH-PROMOTION; INTERVENTIONS; BEHAVIOR; IMPACT; REACH; OVERWEIGHT; ENROLLMENT; LITERACY; OUTCOMES; TRIAL AB Background: The reach and representativeness are seldom examined in worksite weight loss studies. This paper describes and illustrates a method for directly assessing the reach and representativeness of a internet-based worksite weight loss program. Methods: A brief health survey (BHS) was administered, between January 2008 and November 2009, to employees at 19 worksites in Southwest Virginia. The BHS included demographic, behavioral, and health questions. All employees were blinded to the existence of a future weight loss program until the completion of the BHS. Results: The BHS has a participation rate of 66 percent and the subsequent weight loss program has a participation rate of 30 percent. Employees from higher income households, with higher education levels and health literacy proficiency were significantly more likely to participate in the program (p's < .01). Conclusions: Worksite weight loss programs should include targeted marketing strategies to engage employees with lower income, education, and health literacy. C1 [You, Wen] Virginia Polytech Inst & State Univ, Dept Agr & Appl Econ, Blacksburg, VA 24061 USA. [Almeida, Fabio A.; Zoellner, Jamie M.; Hill, Jennie L.; Allen, Kacie C.; Estabrooks, Paul A.] Virginia Polytech Inst & State Univ, Dept Human Nutr Foods & Exercise, Blacksburg, VA 24061 USA. [Pinard, Courtney A.] Gretchen Swanson Ctr Human Nutr, Omaha, NE USA. [Glasgow, Russell E.] NCI, Disseminat & Implementat Sci Div Canc Control & P, Rockville, MD USA. [Linnan, Laura A.] Univ N Carolina, Dept Hlth Behav & Hlth Educ, Chapel Hill, NC USA. RP You, W (reprint author), Virginia Polytech Inst & State Univ, Dept Agr & Appl Econ, Blacksburg, VA 24061 USA. EM wenyou@vt.edu OI Almeida, Fabio/0000-0002-2404-0694 FU National Institute for Diabetes and Digestive and Kidney Diseases [5R01DK071664-04] FX We would like to thank all partners at each of the worksites that agreed to participate in the study. We would also like to acknowledge the work of Sarah Wall and Jennifer Parrish for coordinating and implementing the recruitment protocol necessary for this study. This study is supported by a grant from the National Institute for Diabetes and Digestive and Kidney Diseases: 5R01DK071664-04 (Estabrooks, PI). NR 27 TC 6 Z9 6 U1 3 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD SEP 20 PY 2011 VL 11 AR 709 DI 10.1186/1471-2458-11-709 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 832HA UT WOS:000295793400001 PM 21933429 ER PT J AU Buonaguro, L Wang, E Tornesello, ML Buonaguro, FM Marincola, FM AF Buonaguro, Luigi Wang, Ena Tornesello, Maria Lina Buonaguro, Franco M. Marincola, Francesco M. TI Systems biology applied to vaccine and immunotherapy development SO BMC SYSTEMS BIOLOGY LA English DT Review ID TOLL-LIKE RECEPTORS; T-CELL RESPONSES; VIRUS-LIKE PARTICLES; HUMAN-IMMUNODEFICIENCY-VIRUS; INNATE IMMUNE-RESPONSE; YELLOW-FEVER VACCINE; GENE-EXPRESSION PATTERNS; BACILLUS-CALMETTE-GUERIN; BLOOD MONONUCLEAR-CELLS; MONOPHOSPHORYL-LIPID-A AB Immunotherapies, including vaccines, represent a potent tool to prevent or contain disease with high morbidity or mortality such as infections and cancer. However, despite their widespread use, we still have a limited understanding of the mechanisms underlying the induction of protective immune responses. Immunity is made of a multifaceted set of integrated responses involving a dynamic interaction of thousands of molecules; among those is a growing appreciation for the role the innate immunity (i.e. pathogen recognition receptors - PRRs) plays in determining the nature and duration (immune memory) of adaptive T and B cell immunity. The complex network of interactions between immune manipulation of the host (immunotherapy) on one side and innate and adaptive responses on the other might be fully understood only employing the global level of investigation provided by systems biology. In this framework, the advancement of high-throughput technologies, together with the extensive identification of new genes, proteins and other biomolecules in the "omics" era, facilitate large-scale biological measurements. Moreover, recent development of new computational tools enables the comprehensive and quantitative analysis of the interactions between all of the components of immunity over time. Here, we review recent progress in using systems biology to study and evaluate immunotherapy and vaccine strategies for infectious and neoplastic diseases. Multi-parametric data provide novel and often unsuspected mechanistic insights while enabling the identification of common immune signatures relevant to human investigation such as the prediction of immune responsiveness that could lead to the improvement of the design of future immunotherapy trials. Thus, the paradigm switch from "empirical" to "knowledge-based" conduct of medicine and immunotherapy in particular, leading to patient-tailored treatment. C1 [Buonaguro, Luigi; Tornesello, Maria Lina; Buonaguro, Franco M.] Ist Nazl Tumori Fond Pascale, Dept Expt Oncol, I-80131 Naples, Italy. [Wang, Ena; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. RP Buonaguro, L (reprint author), Ist Nazl Tumori Fond Pascale, Dept Expt Oncol, Via Mariano Semmola 142, I-80131 Naples, Italy. EM lbuonaguro@tin.it RI Tornesello, Maria Lina/A-1564-2009; OI Tornesello, Maria Lina/0000-0002-3523-3264; Buonaguro, Luigi/0000-0002-6380-7114 NR 142 TC 18 Z9 18 U1 0 U2 11 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 SEP 20 PY 2011 VL 5 AR 146 DI 10.1186/1752-0509-5-146 PG 11 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 832JN UT WOS:000295801100001 PM 21933421 ER PT J AU Dayal, S Nedbal, J Hobson, P Cooper, AM Gould, HJ Gellert, M Felsenfeld, G Fear, DJ AF Dayal, Sandeep Nedbal, Jakub Hobson, Philip Cooper, Alison M. Gould, Hannah J. Gellert, Martin Felsenfeld, Gary Fear, David J. TI High Resolution Analysis of the Chromatin Landscape of the IgE Switch Region in Human B Cells SO PLOS ONE LA English DT Article ID CYTIDINE DEAMINASE AID; RNA-POLYMERASE-II; HEAVY-CHAIN GENES; HISTONE ACETYLATION; SOMATIC HYPERMUTATION; PLANT HOMEODOMAIN; GERMINAL CENTER; CROSS-TALK; RECOMBINATION; TRANSCRIPTION AB Antibodies are assembled by a highly orchestrated series of recombination events during B cell development. One of these events, class switch recombination, is required to produce the IgG, IgE and IgA antibody isotypes characteristic of a secondary immune response. The action of the enzyme activation induced cytidine deaminase is now known to be essential for the initiation of this recombination event. Previous studies have demonstrated that the immunoglobulin switch regions acquire distinct histone modifications prior to recombination. We now present a high resolution analysis of these histone modifications across the IgE switch region prior to the initiation of class switch recombination in primary human B cells and the human CL-01 B cell line. These data show that upon stimulation with IL-4 and an anti-CD40 antibody that mimics T cell help, the nucleosomes of the switch regions are highly modified on histone H3, accumulating acetylation marks and tri-methylation of lysine 4. Distinct peaks of modified histones are found across the switch region, most notably at the 5' splice donor site of the germline (I) exon, which also accumulates AID. These data suggest that acetylation and K4 tri-methylation of histone H3 may represent marks of recombinationally active chromatin and further implicates splicing in the regulation of AID action. C1 [Dayal, Sandeep; Gellert, Martin; Felsenfeld, Gary] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Nedbal, Jakub; Hobson, Philip; Cooper, Alison M.; Gould, Hannah J.; Fear, David J.] Kings Coll London, Div Asthma Allergy & Lung Biol, London WC2R 2LS, England. [Nedbal, Jakub; Hobson, Philip; Cooper, Alison M.; Gould, Hannah J.; Fear, David J.] Kings Coll London, MRC, London WC2R 2LS, England. [Nedbal, Jakub; Hobson, Philip; Cooper, Alison M.; Gould, Hannah J.; Fear, David J.] Kings Coll London, Asthma UK Ctr Allerg Mech Asthma, London WC2R 2LS, England. [Nedbal, Jakub; Hobson, Philip; Cooper, Alison M.; Gould, Hannah J.] Kings Coll London, Randall Div Cell & Mol Biophys, London WC2R 2LS, England. RP Dayal, S (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM garyf@intra.niddk.nih.gov; david.fear@kcl.ac.uk OI Cooper, Alison/0000-0002-0815-0084; Gould, Hannah/0000-0003-0411-688X FU Asthma U.K.; Biotechnology and Biological Sciences Research Council [BB/H019634/1]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA; UK Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre; King's College London; Research Councils U.K. FX D.F. is a Research Councils U.K. funded Fellow and has been further supported by Asthma U.K. funded core support for the MRC & Asthma U.K. Centre for Allergic Mechanisms of Asthma. This work has been supported by a Biotechnology and Biological Sciences Research Council grant BB/H019634/1, and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA. The authors further acknowledge financial support from the UK Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 5 Z9 5 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 20 PY 2011 VL 6 IS 9 AR e24571 DI 10.1371/journal.pone.0024571 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825GY UT WOS:000295260400007 PM 21949728 ER PT J AU Pan, CJ Chen, SY Jun, HS Lin, SR Mansfield, BC Chou, JY AF Pan, Chi-Jiunn Chen, Shih-Yin Jun, Hyun Sik Lin, Su Ru Mansfield, Brian C. Chou, Janice Y. TI SLC37A1 and SLC37A2 Are Phosphate-Linked, Glucose-6-Phosphate Antiporters SO PLOS ONE LA English DT Article ID DISEASE TYPE 1B; ESCHERICHIA-COLI; TRANSPORT-SYSTEMS; GENE; IB; DEFICIENT; RECONSTITUTION; SUPERFAMILY; THERAPY; MOUSE AB Blood glucose homeostasis between meals depends upon production of glucose within the endoplasmic reticulum (ER) of the liver and kidney by hydrolysis of glucose-6-phosphate (G6P) into glucose and phosphate (Pi). This reaction depends on coupling the G6P transporter (G6PT) with glucose-6-phosphatase-alpha (G6Pase-alpha). Only one G6PT, also known as SLC37A4, has been characterized, and it acts as a Pi-linked G6P antiporter. The other three SLC37 family members, predicted to be sugar-phosphate: Pi exchangers, have not been characterized functionally. Using reconstituted proteoliposomes, we examine the antiporter activity of the other SLC37 members along with their ability to couple with G6Pase-alpha. G6PT- and mock-proteoliposomes are used as positive and negative controls, respectively. We show that SLC37A1 and SLC37A2 are ER-associated, Pi-linked antiporters, that can transport G6P. Unlike G6PT, neither is sensitive to chlorogenic acid, a competitive inhibitor of physiological ER G6P transport, and neither couples to G6Pase-alpha. We conclude that three of the four SLC37 family members are functional sugar-phosphate antiporters. However, only G6PT/SLC37A4 matches the characteristics of the physiological ER G6P transporter, suggesting the other SLC37 proteins have roles independent of blood glucose homeostasis. C1 [Pan, Chi-Jiunn; Chen, Shih-Yin; Jun, Hyun Sik; Lin, Su Ru; Mansfield, Brian C.; Chou, Janice Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. RP Pan, CJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. EM chouja@mail.nih.gov RI Jun, Hyun Sik/C-6799-2013; OI Mansfield, Brian/0000-0002-8533-2789 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 17 Z9 21 U1 1 U2 13 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 SEP 20 PY 2011 VL 6 IS 9 AR e23157 DI 10.1371/journal.pone.0023157 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825GY UT WOS:000295260400001 PM 21949678 ER PT J AU Lauer, MS AF Lauer, Michael S. TI What Now With Screening Electrocardiography? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID SERVICES-TASK-FORCE; RANDOMIZED CONTROLLED-TRIAL; CORONARY-HEART-DISEASE; RECOMMENDATION STATEMENT; CANCER MORTALITY; HYPERTROPHY; PRESSURE; LUNG C1 NHLBI, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 18 TC 6 Z9 6 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 20 PY 2011 VL 155 IS 6 BP 395 EP 397 DI 10.7326/0003-4819-155-6-201109200-00011 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 822HA UT WOS:000295033400021 PM 21930859 ER PT J AU Yagi, H Tan, WF Dillenburg-Pilla, P Armando, S Amornphimoltham, P Simaan, M Weigert, R Molinolo, AA Bouvier, M Gutkind, JS AF Yagi, Hiroshi Tan, Wenfu Dillenburg-Pilla, Patricia Armando, Sylvain Amornphimoltham, Panomwat Simaan, May Weigert, Roberto Molinolo, Alfredo A. Bouvier, Michel Gutkind, J. Silvio TI A Synthetic Biology Approach Reveals a CXCR4-G(13)-RhoSignaling Axis Driving Transendothelial Migration of Metastatic Breast Cancer Cells SO SCIENCE SIGNALING LA English DT Article ID PROTEIN-COUPLED RECEPTORS; HETEROTRIMERIC G-PROTEINS; RHO-ASSOCIATED KINASE; TUMOR-CELLS; SIGNALING PATHWAYS; ALPHA-SUBUNIT; CXCR4; FAMILY; ANGIOGENESIS; ACTIVATION AB Tumor cells can co-opt the promigratory activity of chemokines and their cognate G protein-coupled receptors (GPCRs) to metastasize to regional lymph nodes or distant organs. Indeed, the migration toward SDF-1 (stromal cell-derived factor 1) of tumor cells bearing CXCR4 [chemokine (C-X-C motif) receptor 4] has been implicated in the lymphatic and organ-specific metastasis of various human malignancies. Here, we used chimeric G proteins and GPCRs activated solely by artificial ligands to selectively activate the signaling pathways downstream of specific G proteins and showed that CXCR4-mediated chemotaxis and transendothelial migration of metastatic basal-like breast cancer cells required activation of G alpha(13), a member of the G alpha(12/13) G protein family, and of the small guanosine triphosphatase Rho. Multiple complementary experimental strategies, including synthetic biology approaches, indicated that signaling-selective inhibition of the CXCR4-G alpha(13)-Rho axis prevents the metastatic spread of basal-like breast cancer cells. C1 [Amornphimoltham, Panomwat; Weigert, Roberto; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20852 USA. [Armando, Sylvain; Bouvier, Michel] Univ Montreal, Inst Res Immunol & Canc, Dept Biochem, Montreal, PQ H3C 3J7, Canada. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20852 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Bouvier, Michel/H-2758-2014 OI Bouvier, Michel/0000-0003-1128-0100 FU Gutkind labs; Bouvier lab; NIH, National Institute of Dental and Craniofacial Research; Intramural AIDS Targeted Antiviral Program; Canadian Institutes for Health Research [FRN-10501]; Research Chair in Cell Signalling and Molecular Pharmacology; Ministry of Research and Technology from France FX We thank all members of the Gutkind and Bouvier labs for encouragement and support. We thank B. Roth for providing the RASSL-Gi construct and B. Conklin for helpful advice. Funding: Supported by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research, and Intramural AIDS Targeted Antiviral Program. M.B. was supported by a grant from the Canadian Institutes for Health Research (FRN-10501) and the Research Chair in Cell Signalling and Molecular Pharmacology. S. A. was partially supported by a scholarship from the Ministry of Research and Technology from France. Author contributions: H.Y., W.T., P.D.-P., S.A., P.A., M.S., and A.A.M. performed the experiments; H.Y., W T., P.D.-P., S A., P.A., M.S., R.W., A.A.M., M.B., and J.S.G. analyzed the data; H.Y., W.T., R.W., M.B., and J.S.G. designed the experiments; and H.Y., R.W., A.A.M., M.B., and J.S.G. wrote the paper. Competing interests: M.B. and S.A. filed a patent application (USSN 11/816,517) for the BRET-based assay to monitor G protein activation. NR 66 TC 53 Z9 53 U1 0 U2 14 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 SEP 20 PY 2011 VL 4 IS 191 AR ra60 DI 10.1126/scisignal.2002221 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 822GO UT WOS:000295032200001 PM 21934106 ER PT J AU Amiri-Kordestani, L Jawed, I Wilkerson, J Stein, WD Bates, SE Swain, SM Fojo, AT AF Amiri-Kordestani, L. Jawed, I. Wilkerson, J. Stein, W. D. Bates, S. E. Swain, S. M. Fojo, A. T. TI Determining the rate of tumor growth and decay in patients with metastatic breast cancer as an early efficacy endpoint: A study assessing ixabepilone efficacy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Jerusalem, Israel. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Washington Hosp Ctr, Natl Surg Adjuvant Breast & Bowel Project, Washington Canc Inst, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 246 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600235 PM 27958168 ER PT J AU Ascierto, ML Kmieciak, M Idowu, MO Bedognetti, D De Maria, A Bear, HD Wang, E Marincola, F Manjili, M AF Ascierto, M. L. Kmieciak, M. Idowu, M. O. Bedognetti, D. De Maria, A. Bear, H. D. Wang, E. Marincola, F. Manjili, M. TI Immunologic markers associated with favorable prognosis in breast cancer patients: Role of innate immune system SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Richmond, VA USA. Univ Genoa, Genoa, Italy. Virginia Commonwealth Univ, Masey Canc Ctr, Richmond, VA USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RI de maria, andrea/F-7116-2016 OI de maria, andrea/0000-0001-5782-333X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 43 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600043 PM 27957969 ER PT J AU Banda, DR Mete, M Swain, SM AF Banda, D. R. Mete, M. Swain, S. M. TI A clinical trial with culturally appropriate video to increase paticipation of African Americans in cancer clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Washington Hosp Ctr, Washington, DC 20010 USA. MedStar Hlth Res Inst, Hyattsville, MD USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Washington Hosp Ctr, Washington Canc Inst, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 159 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600153 PM 27957972 ER PT J AU Erb, KM Julian, TB AF Erb, K. M. Julian, T. B. TI Patterns of reconstruction after unilateral and bilateral mastectomies. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 143 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600138 PM 27958005 ER PT J AU Julian, TB Anderson, SJ Mamounas, EP Krag, DN Weaver, D Ashikaga, T Harlow, SP Wolmark, N AF Julian, T. B. Anderson, S. J. Mamounas, E. P. Krag, D. N. Weaver, D. Ashikaga, T. Harlow, S. P. Wolmark, N. TI Effect of axillary dissection for occult detected sentinel nodes metastases on survival: NSABP B-32 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Allegheny Gen Hosp, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Natl Surg Adjuvant Breast & Bowel Project, Biostat Ctr, Pittsburgh, PA USA. Aultman Hlth Fdn, Natl Surg Adjuvant Breast & Bowel Project, Canton, OH USA. Univ Vermont, Natl Surg Adjuvant Breast & Bowel Project, Burlington, VT USA. Univ Vermont, Coll Med, Dept Pathol, Natl Surg Adjuvant Breast & Bowel Project, Burlington, VT 05405 USA. Univ Vermont, Coll Med, Dept Med Biostat, Burlington, VT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 80 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600078 PM 27958069 ER PT J AU Mamounas, EP Anderson, SJ Julian, TB Krag, DN Weaver, D Ashikaga, T Harlow, SP Wolmark, N AF Mamounas, E. P. Anderson, S. J. Julian, T. B. Krag, D. N. Weaver, D. Ashikaga, T. Harlow, S. P. Wolmark, N. TI Effect of serial sectioning and immunohistochemistry (IHC) on sentinel lymph nodes (SLNs) on the false-negative rate (FNR) of SLN biopsy (SLNB): Results from NSABP B-32 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Aultman Hlth Fdn, Natl Surg Adjuvant Breast & Bowel Project, Canton, OH USA. Univ Pittsburgh, Grad Sch Publ Hlth, Natl Surg Adjuvant Breast & Bowel Project, Biostat Ctr, Pittsburgh, PA USA. Allegheny Gen Hosp, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. Univ Vermont, Natl Surg Adjuvant Breast & Bowel Project, Burlington, VT USA. Univ Vermont, Coll Med, Dept Pathol, Natl Surg Adjuvant Breast & Bowel Project, Burlington, VT 05405 USA. Univ Vermont, Coll Med, Dept Med Biostat, Burlington, VT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 86 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600084 PM 27958077 ER PT J AU Rao, RD Siziopikou, KP Cobleigh, MA AF Rao, R. D. Siziopikou, K. P. Cobleigh, M. A. TI A phase II open-label trial to evaluate the efficacy and toxicity of erlotinib in women with metastatic, hormone receptor negative, and HER2-negative breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Rush Univ, Med Ctr, Chicago, IL 60612 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Rush Univ, Med Ctr, Natl Surg Adjuvant Breast & Bowel Project, Chicago, IL 60612 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 296 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600280 PM 27958041 ER PT J AU Sgroi, D Carney, E Richardson, E Steffel, L Binns, SN Finkelstein, DM Shepherd, LE Kesty, NC Schnabel, C Erlander, MG Ingle, JN Porter, P Paik, S Muss, HB Pritchard, KI Tu, D Goss, PE AF Sgroi, D. Carney, E. Richardson, E. Steffel, L. Binns, S. N. Finkelstein, D. M. Shepherd, L. E. Kesty, N. C. Schnabel, C. Erlander, M. G. Ingle, J. N. Porter, P. Paik, S. Muss, H. B. Pritchard, K. I. Tu, D. Goss, P. E. TI Prediction of late recurrences by breast cancer index in the NCIC CTG MA.17 cohort SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Queens Univ, NCIC Clin Trials Grp, Kingston, ON, Canada. BioTheranostics Inc, San Diego, CA USA. Mayo Clin, Rochester, MN USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ Toronto, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. NCIC Clin Trials Grp, Kingston, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 2 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600003 PM 27958176 ER PT J AU Bedognetti, D Balwit, JM Wang, E Disis, ML Britten, CM Delogu, LG Tomei, S Fox, BA Gajewski, TF Marincola, FM Butterfield, LH AF Bedognetti, Davide Balwit, James M. Wang, Ena Disis, Mary L. Britten, Cedrik M. Delogu, Lucia G. Tomei, Sara Fox, Bernard A. Gajewski, Thomas F. Marincola, Francesco M. Butterfield, Lisa H. TI SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document: Online resources and useful tools - a compass in the land of biomarker discovery SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID WORKSHOP AB Recent positive clinical results in cancer immunotherapy point to the potential of immune-based strategies to provide effective treatment of a variety of cancers. In some patients, the responses to cancer immunotherapy are durable, dramatically extending survival. Extensive research efforts are being made to identify and validate biomarkers that can help identify subsets of cancer patients that will benefit most from these novel immunotherapies. In addition to the clear advantage of such predictive biomarkers, immune biomarkers are playing an important role in the development, clinical evaluation and monitoring of cancer immunotherapies. This Cancer Immunotherapy Resource Document, prepared by the Society for Immunotherapy of Cancer (SITC, formerly the International Society for Biological Therapy of Cancer, iSBTc), provides key references and online resources relevant to the discovery, evaluation and clinical application of immune biomarkers. These key resources were identified by experts in the field who are actively pursuing research in biomarker identification and validation. This organized collection of the most useful references, online resources and tools serves as a compass to guide discovery of biomarkers essential to advancing novel cancer immunotherapies. C1 [Bedognetti, Davide; Balwit, James M.; Wang, Ena; Disis, Mary L.; Delogu, Lucia G.; Tomei, Sara; Fox, Bernard A.; Gajewski, Thomas F.; Marincola, Francesco M.; Butterfield, Lisa H.] Soc Immunotherapy Canc, Milwaukee, WI USA. [Bedognetti, Davide; Wang, Ena; Tomei, Sara; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Bedognetti, Davide; Wang, Ena; Tomei, Sara; Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Bedognetti, Davide] Univ Genoa, Dept Internal Med DiMI, Genoa, Italy. [Bedognetti, Davide] Natl Canc Res Inst Genoa, Dept Med Oncol, Genoa, Italy. [Disis, Mary L.] Univ Washington, Div Oncol, Tumor Vaccine Grp, Seattle, WA 98195 USA. [Britten, Cedrik M.] Johannes Gutenberg Univ Mainz, Dept Med, Univ Med Ctr, Mainz, Germany. [Britten, Cedrik M.] Ribological GmbH, Mainz, Germany. [Britten, Cedrik M.] Johannes Gutenberg Univ Mainz, Dept Internal Med, Univ Med Ctr, D-6500 Mainz, Germany. [Britten, Cedrik M.] BioNTech AG, Clin Dev, Mainz, Germany. [Delogu, Lucia G.] Univ Sassari, Dept Drug Sci, I-07100 Sassari, Italy. [Tomei, Sara] Univ Pisa, Dept Oncol, Div Surg Mol & Ultrastruct Pathol, Pisa, Italy. [Tomei, Sara] Pisa Univ Hosp, Pisa, Italy. [Fox, Bernard A.] Providence Portland Med Ctr, Robert W Franz Canc Ctr, Earle A Chiles Res Inst, Lab Mol & Tumor Immunol, Portland, OR USA. [Gajewski, Thomas F.] Univ Chicago, Dept Pathol, Hematol Oncol Sect, Chicago, IL 60637 USA. [Gajewski, Thomas F.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Butterfield, Lisa H.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Butterfield, Lisa H.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Butterfield, Lisa H.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA. RP Bedognetti, D (reprint author), Soc Immunotherapy Canc, Milwaukee, WI USA. EM Davide.Bedognetti@nih.gov RI Bedognetti, Davide/A-9090-2012; OI Bedognetti, Davide/0000-0002-5857-773X FU Conquer Cancer Foundation of the American Society of Clinical Oncology FX Davide Bedognetti is a participant in the NIH Graduate Partnership Program and a graduate student at University of Genoa. Davide Bedognetti's fellowship is supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology (2011 Young Investigator Award). NR 13 TC 18 Z9 19 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD SEP 19 PY 2011 VL 9 AR 155 DI 10.1186/1479-5876-9-155 PG 20 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 832RP UT WOS:000295824800001 PM 21929757 ER PT J AU McCarthy, JS Marjason, J Elliott, S Fahey, P Bang, G Malkin, E Tierney, E Aked-Hurditch, H Adda, C Cross, N Richards, JS Fowkes, FJI Boyle, MJ Long, C Druilhe, P Beeson, JG Anders, RF AF McCarthy, James S. Marjason, Joanne Elliott, Suzanne Fahey, Paul Bang, Gilles Malkin, Elissa Tierney, Eveline Aked-Hurditch, Hayley Adda, Christopher Cross, Nadia Richards, Jack S. Fowkes, Freya J. I. Boyle, Michelle J. Long, Carole Druilhe, Pierre Beeson, James G. Anders, Robin F. TI A Phase 1 Trial of MSP2-C1, a Blood-Stage Malaria Vaccine Containing 2 Isoforms of MSP2 Formulated with Montanide (R) ISA 720 SO PLOS ONE LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; MEROZOITE SURFACE PROTEIN-2; PAPUA-NEW-GUINEA; ANCHORED MEMBRANE-PROTEINS; IN-VITRO GROWTH; CLINICAL MALARIA; INHIBITORY ANTIBODIES; HUMORAL RESPONSE; ENDEMIC AREA; IMMUNOGENICITY AB Background: In a previous Phase 1/2b malaria vaccine trial testing the 3D7 isoform of the malaria vaccine candidate Merozoite surface protein 2 (MSP2), parasite densities in children were reduced by 62%. However, breakthrough parasitemias were disproportionately of the alternate dimorphic form of MSP2, the FC27 genotype. We therefore undertook a dose-escalating, double-blinded, placebo-controlled Phase 1 trial in healthy, malaria-naive adults of MSP2-C1, a vaccine containing recombinant forms of the two families of msp2 alleles, 3D7 and FC27 (EcMSP2-3D7 and EcMSP2-FC27), formulated in equal amounts with Montanide (R) ISA 720 as a water-in-oil emulsion. Methodology/Principal Findings: The trial was designed to include three dose cohorts (10, 40, and 80 mu g), each with twelve subjects receiving the vaccine and three control subjects receiving Montanide (R) ISA 720 adjuvant emulsion alone, in a schedule of three doses at 12-week intervals. Due to unexpected local reactogenicity and concern regarding vaccine stability, the trial was terminated after the second immunisation of the cohort receiving the 40 mu g dose; no subjects received the 80 mu g dose. Immunization induced significant IgG responses to both isoforms of MSP2 in the 10 mu g and 40 mu g dose cohorts, with antibody levels by ELISA higher in the 40 mu g cohort. Vaccine-induced antibodies recognised native protein by Western blots of parasite protein extracts and by immunofluorescence microscopy. Although the induced anti-MSP2 antibodies did not directly inhibit parasite growth in vitro, IgG from the majority of individuals tested caused significant antibody-dependent cellular inhibition (ADCI) of parasite growth. Conclusions/Significance: As the majority of subjects vaccinated with MSP2-C1 developed an antibody responses to both forms of MSP2, and that these antibodies mediated ADCI provide further support for MSP2 as a malaria vaccine candidate. However, in view of the reactogenicity of this formulation, further clinical development of MSP2-C1 will require formulation of MSP2 in an alternative adjuvant. C1 [McCarthy, James S.] Univ Queensland, Queensland Inst Med Res, Brisbane, Qld, Australia. [Marjason, Joanne; Elliott, Suzanne; Aked-Hurditch, Hayley] Q Pharm Pty Ltd, Brisbane, Qld, Australia. [Fahey, Paul; Malkin, Elissa; Tierney, Eveline] PATH Malaria Vaccine Initiat, Bethesda, MD USA. [Bang, Gilles; Druilhe, Pierre] Inst Pasteur, Paris, France. [Adda, Christopher; Anders, Robin F.] La Trobe Univ, Dept Biochem, Melbourne, Vic, Australia. [Cross, Nadia; Richards, Jack S.; Fowkes, Freya J. I.; Boyle, Michelle J.; Beeson, James G.] Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia. [Long, Carole] NIAID, NIH, Bethesda, MD 20892 USA. RP McCarthy, JS (reprint author), Univ Queensland, Queensland Inst Med Res, Brisbane, Qld, Australia. EM J.McCarthy@uq.edu.au OI Richards, Jack/0000-0001-5786-6989 FU PATH-MVI; NHMRC; Queensland Health Research Fellowship; Australian Research Council; National Institute of Allergy and Infectious Diseases, NIH FX The trial was funded by PATH-MVI. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JMC is supported by an NHMRC Practitioner Fellowship and a Queensland Health Research Fellowship. JGB was supported by a Career Development Award from the National Health and Medical Research Council, and a Future Fellowship from the Australian Research Council. Carole Long was supported in part by the intramural program of the National Institute of Allergy and Infectious Diseases, NIH. The GIA Reference Center at NIH is supported by the PATH-Malaria Vaccine Initiative. NR 64 TC 33 Z9 33 U1 0 U2 6 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 SEP 19 PY 2011 VL 6 IS 9 AR e24413 DI 10.1371/journal.pone.0024413 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825FZ UT WOS:000295257900013 PM 21949716 ER PT J AU Lee, S Chen, XY AF Lee, Seulki Chen, Xiaoyuan TI Selective Imaging of Mitochondrial Surfaces with Novel Fluorescent Probes SO CHEMBIOCHEM LA English DT Editorial Material DE bioconversions; fluorescent probes; high-throughput screening; mitochondria; organelles ID DYNAMICS C1 [Lee, Seulki; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural NIH HHS [Z99 EB999999, ZIA EB000073-02] NR 13 TC 6 Z9 6 U1 4 U2 21 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD SEP 19 PY 2011 VL 12 IS 14 BP 2120 EP 2121 DI 10.1002/cbic.201100365 PG 2 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 824UH UT WOS:000295227200002 PM 21793151 ER PT J AU Liu, LH Parent, CA AF Liu, Lunhua Parent, Carole A. TI TOR kinase complexes and cell migration SO JOURNAL OF CELL BIOLOGY LA English DT Review ID RICTOR-MTOR COMPLEX; MAMMALIAN TARGET; ACTIN CYTOSKELETON; TUBEROUS SCLEROSIS; GROWTH-FACTOR; SACCHAROMYCES-CEREVISIAE; DIRECTLY PHOSPHORYLATES; EUKARYOTIC CHEMOTAXIS; AKT PHOSPHORYLATION; MEDIATED ACTIVATION AB Cell migration is a fundamental process in a wide array of biological and pathological responses. It is regulated by complex signal transduction pathways in response to external cues that couple to growth factor and chemokine receptors. In recent years, the target of rapamycin (TOR) kinase, as part of either TOR complex 1 (TORC1) or TOR complex 2 (TORC2), has been shown to be an important signaling component linking external signals to the cytoskeletal machinery in a variety of cell types and organisms. Thus, these complexes have emerged as key regulators of cell migration and chemotaxis. C1 [Liu, Lunhua; Parent, Carole A.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Parent, CA (reprint author), NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM parentc@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 140 TC 44 Z9 48 U1 0 U2 10 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 SEP 19 PY 2011 VL 194 IS 6 BP 815 EP 824 DI 10.1083/jcb.201102090 PG 10 WC Cell Biology SC Cell Biology GA 822EK UT WOS:000295026500004 PM 21930774 ER PT J AU Kumar, A Kumar, V Alegria, AE Malhotra, SV AF Kumar, Ajay Kumar, Vineet Alegria, Antonio E. Malhotra, Sanjay V. TI N-Hydroxyethyl-4-aza-didehydropodophyllotoxin derivatives as potential antitumor agents SO EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE Azapodophyllotoxin; Antitumor; Anticancer ID DNA TOPOISOMERASE-II; PODOPHYLLOTOXIN DERIVATIVES; BIOLOGICAL EVALUATION; PHARMACOLOGICAL PROFILES; NATURAL-PRODUCTS; DRUG DISCOVERY; ANALOGS; ETOPOSIDE; DESIGN; (-)-PODOPHYLLOTOXIN AB Three different series of N-hydroxyethyl aza-podophyllotoxin derivatives containing (i) a five-membered methylenedioxy ring (7a-f), (ii) a five-membered ring with no heteroatom (8a-f) or (iii) a six membered ethylenedioxy ring (9a-f) as ring A were synthesized using a convenient one-pot multi-component reaction. Further variation on ring E was done by decorating it with methoxy and hydroxy groups at different positions. Calculation of log P values of these compounds indicates them to be better soluble than corresponding non-hydroxy derivatives. These novel aza-podophyllotoxin derivatives were screened for their cytostatic and cytotoxic activities on National Cancer Institute's 60 human tumor cell lines to study the structure activity relationship. The overall anticancer activity of these compounds was in the order of 8a-f > 9a-f > 7a-f. Furthermore, the compounds having 3'-methoxy and 3'.4'.5'-trimethoxy substitution at ring E were the most active within the series. The cytotoxicity of all the active compounds was low, while their antiproliferative (or cytostatic) activity was high, providing a wide therapeutic window for their potential application as anticancer drugs. (C) 2011 Elsevier B.V. All rights reserved. C1 [Kumar, Ajay; Alegria, Antonio E.] Univ Puerto Rico, Dept Chem, Humacao, PR 00791 USA. [Kumar, Vineet; Malhotra, Sanjay V.] NIH, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Alegria, AE (reprint author), Univ Puerto Rico, Dept Chem, Humacao, PR 00791 USA. EM antonio.alegria1@upr.edu; malhotrasa@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH [S06-GM008216, P20 RR-016470] FX The authors would like to thank the NCI Developmental Therapeutics Program for 60 cell line screen of compounds described in this paper funded by National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and Grants No. S06-GM008216 and P20 RR-016470 from NIH. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 33 TC 7 Z9 7 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0928-0987 J9 EUR J PHARM SCI JI Eur. J. Pharm. Sci. PD SEP 18 PY 2011 VL 44 IS 1-2 BP 21 EP 26 DI 10.1016/j.ejps.2011.04.013 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 823GB UT WOS:000295109400003 PM 21601635 ER PT J AU Little, RR Sacks, DB AF Little, Randie R. Sacks, David B. TI HbA(1c): what do the numbers really mean? SO LANCET LA English DT Letter C1 [Little, Randie R.] Univ Missouri Columbia, Sch Med, Dept Pathol & Anat Sci, Diabet Diagnost Lab M767, Columbia, MO 65212 USA. [Sacks, David B.] NIH, DLM, Bethesda, MD 20892 USA. RP Little, RR (reprint author), Univ Missouri Columbia, Sch Med, Dept Pathol & Anat Sci, Diabet Diagnost Lab M767, Columbia, MO 65212 USA. OI Little, Randie/0000-0001-6450-8012; Sacks, David/0000-0003-3100-0735 NR 4 TC 2 Z9 2 U1 0 U2 2 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 SEP 17 PY 2011 VL 378 IS 9796 BP 1068 EP 1069 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 829BE UT WOS:000295548900019 PM 21924987 ER PT J AU Ishaq, M Lin, BR Bosche, M Zheng, X Yang, J Huang, DW Lempicki, RA Natarajan, V AF Ishaq, Mohammad Lin, Bor-Ruei Bosche, Marjorie Zheng, Xin Yang, Jun Huang, Dawei Lempicki, Richard A. Natarajan, Ven TI LIM kinase 1-dependent cofilin 1 pathway and actin dynamics mediate nuclear retinoid receptor function in T lymphocytes SO BMC MOLECULAR BIOLOGY LA English DT Article ID POLYMERASE-I TRANSCRIPTION; CELL-ACTIVATION; PROTEIN-KINASE; BETA-ACTIN; HIV-1 NEF; RXR-ALPHA; MYOSIN-I; PHOSPHORYLATION; MITOSIS; ACID AB Background: It is known that retinoid receptor function is attenuated during T cell activation, a phenomenon that involves actin remodeling, suggesting that actin modification may play a role in such inhibition. Here we have investigated the role of actin dynamics and the effect of actin cytoskeleton modifying agents on retinoid receptor-mediated transactivation. Results: Agents that disturb the F-actin assembly or disassembly attenuated receptor-mediated transcription indicating that actin cytoskeletal homeostasis is important for retinoid receptor function. Overexpression or siRNA-induced knockdown of cofilin-1 (CFL1), a key regulator of F-actin assembly, induced the loss of receptor function. In addition, expression of either constitutively active or inactive/dominant-negative mutants of CFL1or CFL1 kinase LIMK1 induced loss of receptor function suggesting a critical role of the LIMK1-mediated CFL1 pathway in receptor-dependent transcription. Further evidence of the role of LMK1/CFL1-mediated actin dynamics, was provided by studying the effect of Nef, an actin modifying HIV-1 protein, on receptor function. Expression of Nef induced phosphorylation of CFL1 at serine 3 and LIMK1 at threonine 508, inhibited retinoid-receptor mediated reporter activity, and the expression of a number of genes that contain retinoid receptor binding sites in their promoters. The results suggest that the Nef-mediated inhibition of receptor function encompasses deregulation of actin filament dynamics by LIMK1 activation and phosphorylation of CFL1. Conclusion: We have identified a critical role of LIMK1-mediated CFL1 pathway and actin dynamics in modulating retinoid receptor mediated function and shown that LIMK1-mediated phosphocycling of CFL1 plays a crucial role in maintaining actin homeostasis and receptor activity. We suggest that T cell activation-induced repression of nuclear receptor-dependent transactivation is in part through the modification of actin dynamics. C1 [Ishaq, Mohammad; Lin, Bor-Ruei; Natarajan, Ven] NCI, Mol Cell Biol Lab, SAIC Frederick, Frederick, MD 21702 USA. [Bosche, Marjorie; Zheng, Xin; Yang, Jun; Huang, Dawei; Lempicki, Richard A.] NCI, Lab Immunopathogenesis & Bioinformat, SAIC Frederick, Frederick, MD 21702 USA. RP Ishaq, M (reprint author), NCI, Mol Cell Biol Lab, SAIC Frederick, Frederick, MD 21702 USA. EM mishaq@mail.nih.gov RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported by the National Institute of Allergy and Infectious Diseases. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Experiments and image analysis were performed in part through the Optical Microscopy and Analysis Laboratory of the Advanced Technology Program, SAIC-Frederick. NR 52 TC 8 Z9 8 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2199 J9 BMC MOL BIOL JI BMC Mol. Biol. PD SEP 16 PY 2011 VL 12 AR 41 DI 10.1186/1471-2199-12-41 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 832EB UT WOS:000295783600001 PM 21923909 ER PT J AU Barnitz, RA Chaigne-Delalande, B Bolton, DL Lenardo, MJ AF Barnitz, R. Anthony Chaigne-Delalande, Benjamin Bolton, Diane L. Lenardo, Michael J. TI Exposed Hydrophobic Residues in Human Immunodeficiency Virus Type 1 Vpr Helix-1 Are Important for Cell Cycle Arrest and Cell Death SO PLOS ONE LA English DT Article ID INDUCED G(2) ARREST; HIV-1 VPR; NUCLEAR-LOCALIZATION; VIRION INCORPORATION; PROTEIN VPR; T-CELLS; UBIQUITIN LIGASE; MUTATIONAL ANALYSIS; REGULATORY PROTEIN; ACCESSORY PROTEIN AB The human immunodeficiency virus type 1 (HIV-1) accessory protein viral protein R (Vpr) is a major determinant for virus-induced G2/M cell cycle arrest and cytopathicity. Vpr is thought to perform these functions through the interaction with partner proteins. The NMR structure of Vpr revealed solvent exposed hydrophobic amino acids along helices 1 and 3 of Vpr, which could be putative protein binding domains. We previously showed that the hydrophobic patch along helix-3 was important for G2/M blockade and cytopathicity. Mutations of the exposed hydrophobic residues along helix-1 were found to reduce Vpr-induced cell cycle arrest and cell death as well. The levels of toxicity during virion delivery of Vpr correlated with G2/M arrest. Thus, the exposed hydrophobic amino acids in the amino-terminal helix-1 are important for the cell cycle arrest and cytopathicity functions of Vpr. C1 [Barnitz, R. Anthony; Chaigne-Delalande, Benjamin; Bolton, Diane L.; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Barnitz, R. Anthony; Lenardo, Michael J.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. RP Barnitz, RA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM lenardo@nih.gov OI Barnitz, Tony/0000-0002-9634-4558; Tripp, Ralph/0000-0002-2924-9956 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 6 Z9 6 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 SEP 16 PY 2011 VL 6 IS 9 AR e24924 DI 10.1371/journal.pone.0024924 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 824BI UT WOS:000295173800049 PM 21949789 ER PT J AU Chelimo, K Embury, PB Sumba, PO Vulule, J Ofulla, AV Long, C Kazura, JW Moormann, AM AF Chelimo, Kiprotich Embury, Paula B. Sumba, Peter Odada Vulule, John Ofulla, Ayub V. Long, Carole Kazura, James W. Moormann, Ann M. TI Age-Related Differences in Naturally Acquired T Cell Memory to Plasmodium falciparum Merozoite Surface Protein 1 SO PLOS ONE LA English DT Article ID BLOOD LYMPHOCYTE SUBPOPULATIONS; IMMUNE-RESPONSES; MALARIA TRANSMISSION; DENDRITIC CELLS; B-CELLS; INFECTION; STAGE; PARASITE; CYTOKINE; ACTIVATION AB Naturally acquired immunity to Plasmodium falciparum malaria in malaria holoendemic areas is characterized by the gradual, age-related development of protection against high-density parasitemia and clinical malaria. Animal studies, and less commonly, observations of humans with malaria, suggest that T-cell responses are important in the development and maintenance of this immunity, which is mediated primarily by antibodies that slow repeated cycles of merozoites through erythrocytes. To advance our rather limited knowledge on human T-cell immunity to blood stage malaria infection, we evaluated CD4 and CD8 T-cell effector memory subset responses to the 42 kDa C-terminal fragment of Merozoite Surface Protein 1 (MSP1(42)), a malaria vaccine candidate, by 49 healthy 0.5 to >= 18 year old residents of a holoendemic area in western Kenya. The proportion of individuals with peripheral blood mononuclear cell MSP1(42) driven IFN-gamma ELISPOT responses increased from 20% (2/20) among 0.5-1 year old children to 90% (9/10) of adults >= 18 years (P = 0.01); parallel increases in the magnitude of IFN-gamma responses were observed across all age groups (0.5, 1, 2, 5 and >= 18 years, P = 0.001). Less than 1% of total CD4 and CD8 T-cells from both children and adults produced IFN-gamma in response to MSP1(42). However, adults had higher proportions of MSP142 driven IFN-gamma secreting CD4 and CD8 effector memory (CD45RA(-) CD62L(-)) T-cells than children (CD4: 50.9% vs. 28.8%, P = 0.036; CD8: 52.1% vs. 18.3%, respectively P = 0.009). In contrast, MSP1(42) driven IFN-gamma secreting naive-like, transitional (CD45RA(+) CD62L(+)) CD4 and CD8 cells were the predominant T-cell subset among children with significantly fewer of these cells in adults (CD4: 34.9% vs. 5.1%, P = 0.002; CD8: 47.0% vs. 20.5%, respectively, P = 0.030). These data support the concept that meaningful age-related differences exist in the quality of T-cell immunity to malaria antigens such as MSP1. C1 [Chelimo, Kiprotich; Sumba, Peter Odada; Vulule, John] Kenya Govt Med Res Ctr, Ctr Global Hlth Res, Kisumu, Kenya. [Embury, Paula B.; Kazura, James W.; Moormann, Ann M.] Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. [Long, Carole] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Chelimo, Kiprotich; Ofulla, Ayub V.] Maseno Univ, Maseno, Kenya. [Moormann, Ann M.] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA USA. [Moormann, Ann M.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. RP Chelimo, K (reprint author), Kenya Govt Med Res Ctr, Ctr Global Hlth Res, Kisumu, Kenya. EM ann.moormann@umassmed.edu FU National Institutes of Health (NIH), National Cancer Institute [5R01 CA134051]; NIH, National Institute of Allergy and Infectious Diseases (NIAID) [5R01 AI043906]; Fogarty International Center (FIC) [1D43 TW006576]; Division of Intramural Research, NIAID FX This research was supported by the National Institutes of Health (NIH), National Cancer Institute, 5R01 CA134051 (AMM); NIH, National Institute of Allergy and Infectious Diseases (NIAID), 5R01 AI043906 (JWK); Fogarty International Center (FIC) 1D43 TW006576 (KC, POS); and the intramural research program of the Division of Intramural Research, NIAID (CL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 19 Z9 19 U1 0 U2 0 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 SEP 16 PY 2011 VL 6 IS 9 AR e24852 DI 10.1371/journal.pone.0024852 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 824BI UT WOS:000295173800045 PM 21935482 ER PT J AU Texel, SJ Zhang, J Camandola, S Unger, EL Taub, DD Koehler, RC Harris, ZL Mattson, MP AF Texel, Sarah J. Zhang, Jian Camandola, Simonetta Unger, Erica L. Taub, Dennis D. Koehler, Raymond C. Harris, Z. Leah Mattson, Mark P. TI Ceruloplasmin Deficiency Reduces Levels of Iron and BDNF in the Cortex and Striatum of Young Mice and Increases Their Vulnerability to Stroke SO PLOS ONE LA English DT Article ID CEREBRAL-ARTERY OCCLUSION; INHERITED NEURODEGENERATIVE DISEASE; STABILIZING CALCIUM HOMEOSTASIS; NEUROTROPHIC FACTOR EXPRESSION; FIBROBLAST-GROWTH-FACTOR; LIPID-PEROXIDATION; FUNCTIONAL RECOVERY; DELAYED TOLERANCE; OXIDATIVE STRESS; ISCHEMIC-STROKE AB Ceruloplasmin (Cp) is an essential ferroxidase that plays important roles in cellular iron trafficking. Previous findings suggest that the proper regulation and subcellular localization of iron are very important in brain cell function and viability. Brain iron dyshomeostasis is observed during normal aging, as well as in several neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, coincident with areas more susceptible to insults. Because of their high metabolic demand and electrical excitability, neurons are particularly vulnerable to ischemic injury and death. We therefore set out to look for abnormalities in the brain of young adult mice that lack Cp. We found that iron levels in the striatum and cerebral cortex of these young animals are significantly lower than wild-type (WT) controls. Also mRNA levels of the neurotrophin brain derived neurotrophic factor (BDNF), known for its role in maintenance of cell viability, were decreased in these brain areas. Chelator-mediated depletion of iron in cultured neural cells resulted in reduced BDNF expression by a posttranscriptional mechanism, suggesting a causal link between low brain iron levels and reduced BDNF expression. When the mice were subjected to middle cerebral artery occlusion, a model of focal ischemic stroke, we found increased brain damage in Cp-deficient mice compared to WT controls. Our data indicate that lack of Cp increases neuronal susceptibility to ischemic injury by a mechanism that may involve reduced levels of iron and BDNF. C1 [Texel, Sarah J.; Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Texel, Sarah J.; Camandola, Simonetta; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Zhang, Jian; Koehler, Raymond C.] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Unger, Erica L.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Taub, Dennis D.] NIA, Labs Immunol, NIH, Baltimore, MD 21224 USA. [Harris, Z. Leah] Vanderbilt Univ, Dept Pediat, Nashville, TN USA. RP Texel, SJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institute on Aging; National Institutes of Health [NS038684, NS067525] FX This work was supported in part by the National Institute on Aging Intramural Research Program, and the National Institutes of Health grants NS038684 and NS067525 (R. C. K.) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 16 Z9 18 U1 0 U2 3 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 SEP 16 PY 2011 VL 6 IS 9 AR e25077 DI 10.1371/journal.pone.0025077 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 824BI UT WOS:000295173800063 PM 21949858 ER PT J AU Wildman, DE Uddin, M Romero, R Gonzalez, JM Than, NG Murphy, J Hou, ZC Fritz, J AF Wildman, Derek E. Uddin, Monica Romero, Roberto Gonzalez, Juan M. Than, Nandor Gabor Murphy, Jim Hou, Zhuo-Cheng Fritz, Jo TI Spontaneous Abortion and Preterm Labor and Delivery in Nonhuman Primates: Evidence from a Captive Colony of Chimpanzees (Pan troglodytes) SO PLOS ONE LA English DT Article ID BIRTH-WEIGHT; INFLAMMATORY RESPONSE; ANIMAL-MODELS; UNITED-STATES; PARTURITION; INFECTION; PREGNANCY; INFANTS; WOMEN; MECHANISMS AB Background: Preterm birth is a leading cause of perinatal mortality, yet the evolutionary history of this obstetrical syndrome is largely unknown in nonhuman primate species. Methodology/Principal Findings: We examined the length of gestation during pregnancies that occurred in a captive chimpanzee colony by inspecting veterinary and behavioral records spanning a total of thirty years. Upon examination of these records we were able to confidently estimate gestation length for 93 of the 97 (96%) pregnancies recorded at the colony. In total, 78 singleton gestations resulted in live birth, and from these pregnancies we estimated the mean gestation length of normal chimpanzee pregnancies to be 228 days, a finding consistent with other published reports. We also calculated that the range of gestation in normal chimpanzee pregnancies is approximately forty days. Of the remaining fifteen pregnancies, only one of the offspring survived, suggesting viability for chimpanzees requires a gestation of approximately 200 days. These fifteen pregnancies constitute spontaneous abortions and preterm deliveries, for which the upper gestational age limit was defined as 2 SD from the mean length of gestation (208 days). Conclusions/Significance: The present study documents that preterm birth occurred within our study population of captive chimpanzees. As in humans, pregnancy loss is not uncommon in chimpanzees, In addition, our findings indicate that both humans and chimpanzees show a similar range of normal variation in gestation length, suggesting this was the case at the time of their last common ancestor (LCA). Nevertheless, our data suggest that whereas chimpanzees' normal gestation length is similar to 20-30 days after reaching viability, humans' normal gestation length is approximately 50 days beyond the estimated date of viability without medical intervention. Future research using a comparative evolutionary framework should help to clarify the extent to which mechanisms at work in normal and preterm parturition are shared in these species. C1 [Wildman, Derek E.; Romero, Roberto; Hou, Zhuo-Cheng] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Wildman, Derek E.; Romero, Roberto; Gonzalez, Juan M.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Wildman, Derek E.; Romero, Roberto; Gonzalez, Juan M.; Than, Nandor Gabor; Hou, Zhuo-Cheng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. [Uddin, Monica] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Murphy, Jim; Fritz, Jo] Primate Fdn Arizona, Mesa, AZ USA. RP Wildman, DE (reprint author), Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. EM dwildman@wayne.edu; prbchiefstaff@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX This research was supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests NR 68 TC 2 Z9 3 U1 3 U2 19 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 SEP 16 PY 2011 VL 6 IS 9 AR e24509 DI 10.1371/journal.pone.0024509 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 824BI UT WOS:000295173800024 PM 21949724 ER PT J AU Miller, LH Su, XZ AF Miller, Louis H. Su, Xinzhuan TI Artemisinin: Discovery from the Chinese Herbal Garden SO CELL LA English DT Editorial Material ID PLASMODIUM-FALCIPARUM; QINGHAOSU; MALARIA; RESISTANCE; MEFLOQUINE; DRUG AB This year's Lasker DeBakey Clinical Research Award goes to Youyou Tu for the discovery of artemisinin and its use in the treatment of malaria-a medical advance that has saved millions of lives across the globe, especially in the developing world. C1 [Miller, Louis H.; Su, Xinzhuan] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Miller, LH (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM lmiller@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 FU Intramural NIH HHS [Z01 AI000241-27] NR 15 TC 112 Z9 124 U1 12 U2 72 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 16 PY 2011 VL 146 IS 6 BP 855 EP 858 DI 10.1016/j.cell.2011.08.024 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 825GB UT WOS:000295258100006 PM 21907397 ER PT J AU Storz, G Vogel, J Wassarman, KM AF Storz, Gisela Vogel, Joerg Wassarman, Karen M. TI Regulation by Small RNAs in Bacteria: Expanding Frontiers SO MOLECULAR CELL LA English DT Review ID STAPHYLOCOCCUS-AUREUS REVEALS; TARGET MESSENGER-RNAS; ESCHERICHIA-COLI; SOLUBLE-RNA; 6S RNA; ANTISENSE RNAS; GENE-EXPRESSION; TRANSLATIONAL INITIATION; LISTERIA-MONOCYTOGENES; CATABOLITE REPRESSION AB Research on the discovery and characterization of small, regulatory RNAs in bacteria has exploded in recent years. These sRNAs act by base pairing with target mRNAs with which they share limited or extended complementarity, or by modulating protein activity, in some cases by mimicking other nucleic acids. Mechanistic insights into how sRNAs bind mRNAs and proteins, how they compete with each other, and how they interface with ribonucleases are active areas of discovery. Current work also has begun to illuminate how sRNAs modulate expression of distinct regulons and key transcription factors, thus integrating sRNA activity into extensive regulatory networks. In addition, the application of RNA deep sequencing has led to reports of hundreds of additional sRNA candidates in a wide swath of bacterial species. Most importantly, recent studies have served to clarify the abundance of remaining questions about how, when, and why sRNA-mediated regulation is of such importance to bacterial lifestyles. C1 [Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. [Vogel, Joerg] Univ Wurzburg, Inst Mol Infect Biol, D-97080 Wurzburg, Germany. [Wassarman, Karen M.] Univ Wisconsin, Dept Bacteriol, Madison, WI 53706 USA. RP Storz, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, 18 Lib Dr, Bethesda, MD 20892 USA. EM storz@helix.nih.gov RI Vogel, Jorg/D-5574-2011; OI Vogel, Jorg/0000-0003-2220-1404; Storz, Gisela/0000-0001-6698-1241 FU Intramural NIH HHS [ZIA HD001608-19]; NIGMS NIH HHS [R01 GM067955-09, R01 GM067955, R13 GM096742, R13 GM096742-01] NR 111 TC 402 Z9 421 U1 9 U2 108 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 SEP 16 PY 2011 VL 43 IS 6 SI SI BP 880 EP 891 DI 10.1016/j.molcel.2011.08.022 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 825VI UT WOS:000295309800004 PM 21925377 ER PT J AU Yuan, TT Li, JJ Zhang, Y Wang, YP Streaker, E Dimitrov, DS Zhang, MY AF Yuan, Tingting Li, Jingjing Zhang, Yu Wang, Yanping Streaker, Emily Dimitrov, Dimiter S. Zhang, Mei-Yun TI Putative rhesus macaque germline predecessors of human broadly HIV-neutralizing antibodies: Differences from the human counterparts and implications for HIV-1 vaccine development SO VACCINE LA English DT Article DE HIV/AIDS; Vaccine; B-cell repertoire; Neutralizing antibodies; Somatic maturation; Rhesus macaque ID HUMAN MONOCLONAL-ANTIBODY; STRUCTURAL BASIS; ENVELOPE; RESPONSES; GP120; REPERTOIRE; MUCOSAL; BINDING; FAMILY AB Broadly neutralizing antibodies (bnAbs) are likely to be a key component of protective immunity conferred by an effective HIV-1 vaccine. We and others have reported that putative human germline predecessors of known human bnAbs lack measurable binding to HIV-1 envelope glycoproteins (Env), which could be a new challenge for eliciting human bnAbs. Rhesus macaques have been used as nonhuman primate models for testing vaccine candidates, but little is known about their germline Abs. Here we show the similarities and differences between putative rhesus macaque and human germline predecessors and possible intermediate antibodies of one of the best characterized bnAbs, b12. Similar to the human counterpart, a putative rhesus macaque b12 germline antibody lacks measurable binding to HIV-1 Envs, suggesting that initiation of somatic maturation of rhesus macaque germline b12 predecessor may also be a challenge. However, differences in sequence characteristics and binding properties between macaque and human b12 germline and intermediate antibodies suggest that the two germline predecessors may undergo different maturation pathways in rhesus macaques and in humans. These results indicate that immunogens that could initiate the immune responses and drive somatic mutations leading to elicitation of b12 or b12-like bnAbs in rhesus macaques and in humans are likely to be different. This has important implications for HIV-1 vaccine development. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Yuan, Tingting; Li, Jingjing; Zhang, Yu; Zhang, Mei-Yun] Univ Hong Kong, AIDS Inst, Dept Microbiol, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China. [Wang, Yanping; Streaker, Emily; Dimitrov, Dimiter S.; Zhang, Mei-Yun] NCI, Prot Interact Group, CCRNP, NIH, Frederick, MD 21702 USA. RP Zhang, MY (reprint author), Univ Hong Kong, AIDS Inst, Dept Microbiol, Li Ka Shing Fac Med, L5-45,Lab Block,21 Sassoon Rd, Pokfulam, Hong Kong, Peoples R China. EM zhangmy@hku.hk FU University of Hong Kong; General Research Fund (GRF) of Hong Kong; CCR, NCI, NIH; Bill and Melinda Gates Foundation FX We thank Jeffrey Lifson, Nancy Longo, Ruth Ruprecht, Peter Kwong, Tongqing Zhou, Xiaodong Xiao, Prabakaran Ponraj and Zhiwei Chen for helpful discussions, Jeffrey Lifson for providing rhesus macaque PBMCs, Gerald Quinnan and Dennis Burton for providing reagents. This work was supported by the Intramural Research Program of the University of Hong Kong, and by the General Research Fund (GRF) of Hong Kong to M-Y.Z., and by the Intramural Research Program of the CCR, NCI, NIH, and the Bill and Melinda Gates Foundation to D.S.D. NR 26 TC 9 Z9 9 U1 0 U2 4 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 SEP 16 PY 2011 VL 29 IS 40 BP 6903 EP 6910 DI 10.1016/j.vaccine.2011.07.046 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 825RT UT WOS:000295300500012 PM 21807049 ER PT J AU Olugbile, S Villard, V Bertholet, S Jafarshad, A Kulangara, C Roussilhon, C Frank, G Agak, GW Felger, I Nebie, I Konate, K Kajava, AV Schuck, P Druilhe, P Spertini, F Corradin, G AF Olugbile, Sope Villard, Viviane Bertholet, Sylvie Jafarshad, Ali Kulangara, Caroline Roussilhon, Christian Frank, Geraldine Agak, George W. Felger, Ingrid Nebie, Issa Konate, Karidia Kajava, Andrey V. Schuck, Peter Druilhe, Pierre Spertini, Francois Corradin, Giampietro TI Malaria vaccine candidate: Design of a multivalent subunit alpha-helical coiled coil poly-epitope SO VACCINE LA English DT Article DE Malaria; Vaccine; Long synthetic peptide; Antibodies ID HYBRID PEPTIDE VACCINES; PLASMODIUM-FALCIPARUM; IMMUNIZATION; PROTECTION; MONOCYTES AB A new strategy for the rapid identification of new malaria antigens based on protein structural motifs was previously described. We identified and evaluated the malaria vaccine potential of fragments of several malaria antigens containing alpha-helical coiled coil protein motifs. By taking advantage of the relatively short size of these structural fragments, we constructed different poly-epitopes in which 3 or 4 of these segments were joined together via a non-immunogenic linker. Only peptides that are targets of human antibodies with anti-parasite in vitro biological activities were incorporated. One of the constructs, P181, was well recognized by sera and peripheral blood mononuclear cells (PBMC) of adults living in malaria-endemic areas. Affinity purified antigen-specific human antibodies and sera from P181-immunized mice recognised native proteins on malaria-infected erythrocytes in both immunofluorescence and western blot assays. In addition, specific antibodies inhibited parasite development in an antibody dependent cellular inhibition (ADCI) assay. Naturally induced antigen-specific human antibodies were at high titers and associated with clinical protection from malaria in longitudinal follow-up studies in Senegal. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Villard, Viviane; Frank, Geraldine; Agak, George W.; Corradin, Giampietro] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Olugbile, Sope; Spertini, Francois] CHUV, Lausanne, Switzerland. [Bertholet, Sylvie] Infect Dis Res Inst, Seattle, WA 98104 USA. [Jafarshad, Ali; Roussilhon, Christian; Druilhe, Pierre] Inst Pasteur, Malaria Vaccine Dev Lab, Paris, France. [Kulangara, Caroline; Felger, Ingrid] Swiss Trop Inst, CH-4002 Basel, Switzerland. [Nebie, Issa] Ctr Natl Rech & Format Paludisme, Ouagadougou, Burkina Faso. [Konate, Karidia; Kajava, Andrey V.] Univ Montpellier, CNRS, CRBM, F-34059 Montpellier, France. [Schuck, Peter] NIBIB, Lab Cellular Imaging & Mol Biophys, NIH, Bethesda, MD USA. RP Corradin, G (reprint author), Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. EM Giampietro.Corradin@unil.ch RI Kajava, Andrey/E-1107-2014; OI Kajava, Andrey/0000-0002-2342-6886; Schuck, Peter/0000-0002-8859-6966 FU Swiss National Science Foundation [310000-112244]; Swiss Secretary for Education and Research [0536]; Commission of the European Communities [LSHP-CT-2003-503240]; NIBIB, NIH; Bill & Melinda Gates Foundation [42387] FX This work was supported by the Swiss National Science Foundation Grant No. 310000-112244 and by the grants of the Swiss Secretary for Education and Research (No. 0536) in the context of Commission of the European Communities, Sixth Framework Programme, contract LSHP-CT-2003-503240, "Mucosal Vaccines for Poverty-Related Diseases" (MUVAPRED) and the Intramural Research Program of the NIBIB, NIH. We would like to thank Drs S. Reed and T. Vedvick for providing advice and GLA-SE whose work was supported by a Grant No. 42387 from the Bill & Melinda Gates Foundation. NR 29 TC 12 Z9 13 U1 1 U2 4 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 SEP 16 PY 2011 VL 29 IS 40 BP 7090 EP 7099 DI 10.1016/j.vaccine.2011.06.122 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 825RT UT WOS:000295300500034 PM 21803099 ER PT J AU Fox, JT Lee, KY Myung, K AF Fox, Jennifer T. Lee, Kyoo-young Myung, Kyungjae TI Dynamic regulation of PCNA ubiquitylation/deubiquitylation SO FEBS LETTERS LA English DT Review DE Ubiquitylation; Deubiquitylation; PCNA; USP1; ELG1 ID CELL NUCLEAR ANTIGEN; DNA-POLYMERASE-ETA; GROSS CHROMOSOMAL REARRANGEMENTS; REPLICATION PROTEIN-A; UBIQUITIN-DEPENDENT DEGRADATION; POSTREPLICATION REPAIR PATHWAY; DAMAGE-INDUCED MUTAGENESIS; SACCHAROMYCES-CEREVISIAE; S-PHASE; GENOMIC INSTABILITY AB Proliferating Cell Nuclear Antigen (PCNA) ubiquitylation plays a crucial role in maintaining genomic stability during DNA replication. DNA damage stalling the DNA replication fork induces PCNA ubiquitylation that activates DNA damage bypass to prevent the collapse of DNA replication forks that could potentially produce double-strand breaks and chromosomal rearrangements. PCNA ubiquitylation dictates the mode of bypass depending on the level of ubiquitylation; monoubiquitylation and polyubiquitylation activate error-prone translesion synthesis and error-free template switching, respectively. Due to the error-prone nature of DNA damage bypass, PCNA ubiquitylation needs to be tightly regulated. Here, we review the molecular mechanisms to remove ubiquitin from PCNA including the emerging role of USP1 and ELG1 in this fascinating process. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Fox, Jennifer T.; Lee, Kyoo-young; Myung, Kyungjae] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Myung, K (reprint author), NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM kmyung@mail.nih.gov FU NHGRI, NIH FX We thank A. D'Andrea (Dana Faber Cancer Institute), J. McCulley (NHGRI, NIH) and R. Woodgate (NICHD, NIH) for helpful discussions and comments on the manuscript; K.M. especially thanks E. Cho. This research was supported by the intramural research program of the NHGRI, NIH to K.M. NR 81 TC 28 Z9 29 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD SEP 16 PY 2011 VL 585 IS 18 BP 2780 EP 2785 DI 10.1016/j.febslet.2011.05.053 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 824QJ UT WOS:000295216800003 PM 21640107 ER PT J AU Weil, CJ Compton, C AF Weil, Carol J. Compton, Carolyn TI Trade-Secret Model: Potential Pitfalls SO SCIENCE LA English DT Letter C1 [Weil, Carol J.; Compton, Carolyn] NCI, Off Biorepositories & Biospecimen Res, Ctr Strateg Sci Initiat, NIH, Bethesda, MD 20892 USA. RP Weil, CJ (reprint author), NCI, Off Biorepositories & Biospecimen Res, Ctr Strateg Sci Initiat, NIH, Bethesda, MD 20892 USA. EM carol.weil@nih.gov NR 9 TC 0 Z9 0 U1 0 U2 3 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 SEP 16 PY 2011 VL 333 IS 6049 BP 1574 EP 1575 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 820JE UT WOS:000294900900016 PM 21921176 ER PT J AU Wu, XL Zhou, TQ Zhu, J Zhang, BS Georgiev, I Wang, C Chen, XJ Longo, NS Louder, M McKee, K O'Dell, S Perfetto, S Schmidt, SD Shi, W Wu, L Yang, YP Yang, ZY Yang, ZJ Zhang, ZH Bonsignori, M Crump, JA Kapiga, SH Sam, NE Haynes, BF Simek, M Burton, DR Koff, WC Doria-Rose, NA Connors, M Mullikin, JC Nabel, GJ Roederer, M Shapiro, L Kwong, PD Mascola, JR AF Wu, Xueling Zhou, Tongqing Zhu, Jiang Zhang, Baoshan Georgiev, Ivelin Wang, Charlene Chen, Xuejun Longo, Nancy S. Louder, Mark McKee, Krisha O'Dell, Sijy Perfetto, Stephen Schmidt, Stephen D. Shi, Wei Wu, Lan Yang, Yongping Yang, Zhi-Yong Yang, Zhongjia Zhang, Zhenhai Bonsignori, Mattia Crump, John A. Kapiga, Saidi H. Sam, Noel E. Haynes, Barton F. Simek, Melissa Burton, Dennis R. Koff, Wayne C. Doria-Rose, Nicole A. Connors, Mark Mullikin, James C. Nabel, Gary J. Roederer, Mario Shapiro, Lawrence Kwong, Peter D. Mascola, John R. CA NISC Comparative Sequencing Progra TI Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing SO SCIENCE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; GP120; BROAD; INDIVIDUALS; SELECTION; BREADTH; EPITOPE; GLYCOPROTEIN; DIVERSITY AB Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development. C1 [Wu, Xueling; Zhou, Tongqing; Zhu, Jiang; Zhang, Baoshan; Georgiev, Ivelin; Wang, Charlene; Chen, Xuejun; Longo, Nancy S.; Louder, Mark; McKee, Krisha; O'Dell, Sijy; Perfetto, Stephen; Schmidt, Stephen D.; Shi, Wei; Wu, Lan; Yang, Yongping; Yang, Zhi-Yong; Yang, Zhongjia; Zhang, Zhenhai; Nabel, Gary J.; Roederer, Mario; Shapiro, Lawrence; Kwong, Peter D.; Mascola, John R.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Zhang, Zhenhai; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Bonsignori, Mattia; Haynes, Barton F.] Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Crump, John A.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Crump, John A.] Duke Univ, Med Ctr, Div Infect Dis & Int Hlth, Dept Med, Durham, NC 27710 USA. [Crump, John A.; Sam, Noel E.] Tumaini Univ, Kilimanjaro Christian Med Ctr, Moshi, Tanzania. [Crump, John A.; Sam, Noel E.] Tumaini Univ, Kilimanjaro Christian Med Coll, Moshi, Tanzania. [Kapiga, Saidi H.; Sam, Noel E.] Kilimanjaro Reprod Hlth Programme, Moshi, Tanzania. [Simek, Melissa; Koff, Wayne C.] Int AIDS Vaccine Initiat IAVI, New York, NY 10038 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbiol Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Burton, Dennis R.] Massachusetts Gen Hosp, Massachusetts Inst Technol & Harvard, Ragon Inst, Cambridge, MA 02129 USA. [Doria-Rose, Nicole A.; Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr NISC, NIH, Bethesda, MD 20892 USA. RP Kwong, PD (reprint author), NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. EM pdkwong@nih.gov; jmascola@nih.gov RI Schmidt, Stephen/B-5398-2012; Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Vaccine Research Center, National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute, NIH; International AIDS Vaccine Initiative's Neutralizing Antibody Consortium; NIH [AI 5U19 AI 067854-06]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX X.W., T.Z., J.Z., G.J.N., M. R., L. S., P. D. K., and J.R.M. designed research; B.Z., C. W., X. C., M. L., K. M., S.O.D., S. P., S. D. S., W. S., L. W., Y.Y., Z.Y.Y., Z.Y., NISC, and J.M. performed experiments; X. W. isolated and characterized VRC01-like antibodies by RSC3 probe, devised and prepared samples for 454 pyrosequencing, and assisted with functional characterization; T.Z. determined and analyzed structures of VRC-PG04 and VRC03 with gp120 and assisted with functional characterization; J.Z. devised and carried out computational bioinformatics on the antibodyome; M. B., J.A.C, S. H. K, N.E.S., and B. F. H. contributed donor 0219 materials; M. S., D. R. B., and W. C. K contributed Protocol G materials, including donor 74; N.D.R. and M. C. contributed donor 45 materials; X. W., T.Z., J.Z, I. G., N.S.L., Z.Z., L. S., P. D. K., and J. R. M. analyzed the data; and L. S., G.J.N., P. D. K., and J. R. M. wrote the paper, on which all authors commented. We thank J. Almeida and D. Douek for protocols of PBMC cDNA preparation and for helpful discussions; J. Stuckey for assistance with figures; T. Wrin for sequence information on the donor 74 virus; J. Binley, D. Montefiori, L. Morris, and G. Tomaras for donor 0219 serum characterization; and all of the IAVI Protocol G team members and the Protocol G clinical investigators, specifically, G. Miiro, A. Pozniak, D. McPhee, O. Manigart, E. Karita, A. Inwoley, W. Jaoko, J. DeHovitz, L.-G. Bekker, P. Pitisuttithum, R. Paris, J. Serwanga, and S. Allen. We also thank H. Sato, I. Wilson, and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions or comments on the manuscript. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and the National Human Genome Research Institute, NIH; by grants from the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium; and by the Center for HIV AIDS Vaccine Immunology grant AI 5U19 AI 067854-06 from NIH. Use of sector 22 (Southeast Region Collaborative Access Team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. Structure factors and coordinates for antibodies VRC03 and VRC-PG04 in complex with HIV-1 gp120 have been deposited with the Protein Data Bank under accession codes 3SE8 and 3SE9, respectively. We have also deposited deep sequencing data for donors 45 and 74 (Appendices 1 to 4) used in this study to National Center for Biotechnology Information Short Reads Archives (SRA) under accession no. SRP006992. Information deposited with GenBank includes the heavy-and light-chain variable region sequences of probe-identified antibodies VRC-PG04 and VRC-PG04b (accession nos. JN159464 to JN159467), VRC-CH30, VRC-CH31, and VRC-CH32 (JN159434 to JN159439), and VRC-CH33 and VRC-CH34 (JN159470 to 159473), as well as the sequences of genomically identified neutralizers: 24 heavy chains from donor 74, 2008 (JN159440 to JN159463), two heavy chains from donor 45, 2008 (JN159474 and JN159475), two light chains from donor 45, 2001 (JN159468 and JN159469), and 1561 unique sequences associated with neutralizing CDR H3 distributions with at least one low divergent member shown in Fig. 6B and fig. S16 (JN157873 to JN159433). NR 37 TC 431 Z9 436 U1 4 U2 79 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 SEP 16 PY 2011 VL 333 IS 6049 BP 1593 EP 1602 DI 10.1126/science.1207532 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 820JE UT WOS:000294900900034 PM 21835983 ER PT J AU Shi, WL Zhang, XL Jiang, X Yuan, HM Lee, JS Barry, CE Wang, HH Zhang, WH Zhang, Y AF Shi, Wanliang Zhang, Xuelian Jiang, Xin Yuan, Haiming Lee, Jong Seok Barry, Clifton E., III Wang, Honghai Zhang, Wenhong Zhang, Ying TI Pyrazinamide Inhibits Trans-Translation in Mycobacterium tuberculosis SO SCIENCE LA English DT Article ID RIBOSOMAL-PROTEIN S1; ESCHERICHIA-COLI; PYRAZINOIC ACID; PNCA MUTATIONS; MESSENGER-RNA; BINDING; RESISTANCE; TMRNA; SUSCEPTIBILITY; SYNTHASE AB Pyrazinamide (PZA) is a first-line tuberculosis drug that plays a unique role in shortening the duration of tuberculosis chemotherapy. PZA is hydrolyzed intracellularly to pyrazinoic acid (POA) by pyrazinamidase (PZase, encoded by pncA), an enzyme frequently lost in PZA-resistant strains, but the target of POA in Mycobacterium tuberculosis has remained elusive. Here, we identify a previously unknown target of POA as the ribosomal protein S1 (RpsA), a vital protein involved in protein translation and the ribosome-sparing process of trans-translation. Three PZA-resistant clinical isolates without pncA mutation harbored RpsA mutations. RpsA overexpression conferred increased PZA resistance, and we confirmed that POA bound to RpsA (but not a clinically identified DAla mutant) and subsequently inhibited trans-translation rather than canonical translation. Trans-translation is essential for freeing scarce ribosomes in nonreplicating organisms, and its inhibition may explain the ability of PZA to eradicate persisting organisms. C1 [Shi, Wanliang; Zhang, Ying] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Zhang, Xuelian; Yuan, Haiming; Wang, Honghai] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Jiang, Xin] Shanghai Univ Tradit Chinese Med, Dept Med Microbiol & Immunol, Shanghai 201203, Peoples R China. [Lee, Jong Seok] Int TB Res Ctr, Chang Won 4751, South Korea. [Barry, Clifton E., III] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. [Zhang, Wenhong; Zhang, Ying] Fudan Univ, Huashan Hosp, Dept Infect Dis, Shanghai 200040, Peoples R China. RP Zhang, Y (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. EM yzhang@jhsph.edu RI Barry, III, Clifton/H-3839-2012; 吴, 晶/D-3782-2013 FU NIH [AI44063]; NIAID, NIH; National Key Technologies Research and Development Program of China [2008ZX10003003] FX This work was supported in part by NIH grant AI44063, in part by the intramural research program of the NIAID, NIH, and by National Key Technologies Research and Development Program of China (2008ZX10003003). We thank D. E. Griffin and M. J. Klag for encouragement and support. Johns Hopkins University has filed a patent on detection of RpsA mutation as a marker for pyrazinamide resistance and use of trans-translation pathway as a target for development of new antibiotics against TB persister bacteria. NR 31 TC 187 Z9 199 U1 7 U2 78 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 SEP 16 PY 2011 VL 333 IS 6049 BP 1630 EP 1632 DI 10.1126/science.1208813 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 820JE UT WOS:000294900900043 PM 21835980 ER PT J AU Wake, H Lee, PR Fields, D AF Wake, Hiroaki Lee, Philip R. Fields, Douglas TI Control of Local Protein Synthesis and Initial Events in Myelination by Action Potentials SO SCIENCE LA English DT Article ID WHITE-MATTER; OLIGODENDROCYTE LINEAGE; FYN KINASE; CELLS; DIFFERENTIATION; COMMUNICATION; PROGRESSION; ACTIVATION; RELEASE; NEURONS AB Formation of myelin, the electrical insulation on axons produced by oligodendrocytes, is controlled by complex cell-cell signaling that regulates oligodendrocyte development and myelin formation on appropriate axons. If electrical activity could stimulate myelin induction, then neurodevelopment and the speed of information transmission through circuits could be modified by neural activity. We find that release of glutamate from synaptic vesicles along axons of mouse dorsal root ganglion neurons in culture promotes myelin induction by stimulating formation of cholesterol-rich signaling domains between oligodendrocytes and axons, and increasing local synthesis of the major protein in the myelin sheath, myelin basic protein, through Fyn kinase-dependent signaling. This axon-oligodendrocyte signaling would promote myelination of electrically active axons to regulate neural development and function according to environmental experience. C1 [Wake, Hiroaki; Lee, Philip R.; Fields, Douglas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Nervous Syst Dev & Plast Sect, Bethesda, MD 20892 USA. RP Fields, D (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Nervous Syst Dev & Plast Sect, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov FU National Institute of Child Health and Human Development; Japan Society for the Promotion of Science FX We thank M. D. Ehlers for the TfR construct; J. Lippincott-Schwartz for the photoactivatable GFP; E. A. Johnson for BnTX; D. Abebe for assistance with experimental animals; and J. Chan, R. Chittajallu, and J. Ou for critical comments on an earlier draft of this manuscript. This work was supported by the intramural research program at the National Institute of Child Health and Human Development and by a Japan Society for the Promotion of Science fellowship for H. Wake. NR 25 TC 202 Z9 207 U1 1 U2 23 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 SEP 16 PY 2011 VL 333 IS 6049 BP 1647 EP 1651 DI 10.1126/science.1206998 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 820JE UT WOS:000294900900048 PM 21817014 ER PT J AU Wang, SB Foster, DB Rucker, J O'Rourke, B Kass, DA Van Eyk, JE AF Wang, Sheng-Bing Foster, D. Brian Rucker, Jasma O'Rourke, Brian Kass, David A. Van Eyk, Jennifer E. TI Redox Regulation of Mitochondrial ATP Synthase Implications for Cardiac Resynchronization Therapy SO CIRCULATION RESEARCH LA English DT Article DE heart failure; mitochondria; Cys oxidative modification; oxidative phosphorylation ID MEMBRANE-PROTEIN COMPLEXES; OXIDATIVE STRESS; S-NITROSYLATION; NATIVE ELECTROPHORESIS; HEART-FAILURE; NITRIC-OXIDE; PHOSPHORYLATION; MODULATION; ACTIVATION; RESOLUTION AB Rationale: Cardiac resynchronization therapy (CRT) is an effective clinical treatment for heart failure patients with conduction delay, impaired contraction, and energetics. Our recent studies have revealed that mitochondrial posttranslational modifications (PTM) may contribute to its benefits, motivating the present study of the oxidative regulation of mitochondrial ATP synthase. Objectives: We tested whether CRT alteration of ATP synthase function is linked to cysteine (Cys) oxidative PTM (Ox-PTM) of specific ATP synthase subunits. Methods and Results: Canine left ventricular myocardium was collected under conditions to preserve Ox-PTM from control, dyssynchronous heart failure (DHF), or hearts that had undergone CRT. In-gel ATPase activity showed that CRT increased ATPase activity by approximate to 2-fold (P<0.05) over DHF, approaching control levels, and this effect was recapitulated with a reducing agent. ATP synthase function and 3 Ox-PTM: disulfide bond, S-glutathionylation and S-nitrosation were assessed. ATP synthase from DHF hearts contained 2 novel disulfide bonds, between ATP synthase alpha subunits themselves and between alpha and gamma subunits, both of which were decreased in CRT hearts (4.38 +/- 0.13-and 4.23 +/- 0.36-fold, respectively, P<0.01). S-glutathionylation of ATP synthase alpha. subunit occurred in DHF hearts and was decreased by CRT (1.56 +/- 0.16-fold, P<0.04). In contrast, S-nitrosation of ATP synthase alpha subunit in DHF hearts was lower than in CRT hearts (1.53 +/- 0.19-fold, P<0.05). All modifications occurred at ATP synthase alpha subunit Cys294 and Cys to Ser mutation indicated that this residue is critical for ATP synthase function. Conclusions: A selective Cys in ATP synthase alpha subunit is targeted by multiple Ox-PTM suggesting that this Cys residue may act as a redox sensor modulating ATP synthase function. (Circ Res. 2011; 109: 750-757.) C1 [Wang, Sheng-Bing; Foster, D. Brian; Rucker, Jasma; O'Rourke, Brian; Kass, David A.; Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Biol Chem, Baltimore, MD USA. RP Van Eyk, JE (reprint author), Hopkins NHLBI Prote Ctr Bayview, 5200 Eastern Ave,Mason F Lord Bldg,Ctr Tower,Room, Baltimore, MD 21224 USA. EM jvaneyk1@jhmi.edu RI Wang, Shengbing/B-2192-2012; Foster, D. Brian/C-6350-2009 OI Foster, D. Brian/0000-0002-9290-9590 FU National Heart, Lung, and Blood Institute (NHLBI) [P01HL77189-01, N01-HV28180]; Foundation Leducq; Peter Belfer Laboratory FX This work was supported by National Heart, Lung, and Blood Institute (NHLBI) grant P01HL77189-01 (to J.E.V.E., B.O'R., and D. A. K.), NHLBI Proteomics Contract N01-HV28180 (to J.E.V.E., B.O'R., and D.A.K.), Foundation Leducq (to D.A.K.), and the Peter Belfer Laboratory (to D.A.K.). NR 36 TC 71 Z9 72 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 16 PY 2011 VL 109 IS 7 BP 750 EP U117 DI 10.1161/CIRCRESAHA.111.246124 PG 36 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 821BO UT WOS:000294950000007 PM 21817160 ER PT J AU Xu, XQ Oliveira, F Chang, BW Collin, N Gomes, R Teixeira, C Reynoso, D Pham, VM Elnaiem, DE Kamhawi, S Ribeiro, JMC Valenzuela, JG Andersen, JF AF Xu, Xueqing Oliveira, Fabiano Chang, Bianca W. Collin, Nicolas Gomes, Regis Teixeira, Clarissa Reynoso, David Pham, Van My Elnaiem, Dia-Eldin Kamhawi, Shaden Ribeiro, Jose M. C. Valenzuela, Jesus G. Andersen, John F. TI Structure and Function of a "Yellow" Protein from Saliva of the Sand Fly Lutzomyia longipalpis That Confers Protective Immunity against Leishmania major Infection SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SOFT TICKS; IN-VITRO; BINDING; MODEL; EVOLUTION; VECTOR; MECHANISM; FAMILY; HYPERSENSITIVITY; IDENTIFICATION AB LJM11, an abundant salivary protein from the sand fly Lutzomyia longipalpis, belongs to the insect "yellow" family of proteins. In this study, we immunized mice with 17 plasmids encoding L. longiplapis salivary proteins and demonstrated that LJM11 confers protective immunity against Leishmania major infection. This protection correlates with a strong induction of a delayed type hypersensitivity (DTH) response following exposure to L. longipalpis saliva. Additionally, splenocytes of exposed mice produce IFN-gamma upon stimulation with LJM11, demonstrating the systemic induction of Th1 immunity by this protein. In contrast to LJM11, LJM111, another yellow protein from L. longipalpis saliva, does not produce a DTH response in these mice, suggesting that structural or functional features specific to LJM11 are important for the induction of a robust DTH response. To examine these features, we used calorimetric analysis to probe a possible ligand binding function for the salivary yellow proteins. LJM11, LJM111, and LJM17 all acted as high affinity binders of prohemostatic and proinflammatory biogenic amines, particularly serotonin, catecholamines, and histamine. We also determined the crystal structure of LJM11, revealing a six-bladed beta-propeller fold with a single ligand binding pocket located in the central part of the propeller structure on one face of the molecule. A hypothetical model of LJM11 suggests a positive electrostatic potential on the face containing entry to the ligand binding pocket, whereas LJM111 is negative to neutral over its entire surface. This may be the reason for differences in antigenicity between the two proteins. C1 [Xu, Xueqing; Oliveira, Fabiano; Chang, Bianca W.; Collin, Nicolas; Gomes, Regis; Teixeira, Clarissa; Reynoso, David; Pham, Van My; Elnaiem, Dia-Eldin; Kamhawi, Shaden; Ribeiro, Jose M. C.; Valenzuela, Jesus G.; Andersen, John F.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Collin, Nicolas] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Elnaiem, Dia-Eldin] Univ Maryland Eastern Shore, Dept Nat Sci, Princess Anne, MD 21853 USA. RP Andersen, JF (reprint author), 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM jandersen@niaid.nih.gov RI Oliveira, Fabiano/B-4251-2009; OI Oliveira, Fabiano/0000-0002-7924-8038; Ribeiro, Jose/0000-0002-9107-0818 FU National Institutes of Health, NIAID; United States Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This work was supported, in whole or in part, by the National Institutes of Health, NIAID, Intramural Research Program. Use of the Advanced Photon Source beamlines was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. NR 44 TC 38 Z9 39 U1 3 U2 12 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 SEP 16 PY 2011 VL 286 IS 37 BP 32383 EP 32393 DI 10.1074/jbc.M111.268904 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 818CK UT WOS:000294726800048 PM 21795673 ER PT J AU Fontaine, F Fuchs, RT Storz, G AF Fontaine, Fanette Fuchs, Ryan T. Storz, Gisela TI Membrane Localization of Small Proteins in Escherichia coli SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BACTERIAL CYTOPLASMIC MEMBRANE; SIGNAL RECOGNITION PARTICLE; F1F0 ATP SYNTHASE; SUBUNIT-C; TOPOLOGY PREDICTION; YIDC; INNER; INSERTION; TRANSLOCASE; PATHWAY AB Escherichia coli synthesize over 60 poorly understood small proteins of less than 50 amino acids. A striking feature of these proteins is that 65% contain a predicted alpha-helical transmembrane (TM) domain. This prompted us to examine the localization, topology, and membrane insertion of the small proteins. Biochemical fractionation showed that, consistent with the predicted TM helix, the small proteins generally are most abundant in the inner membrane fraction. Examples of both N-in-C-out and N-out-C-in orientations were found in assays of topology-reporter fusions to representative small TM proteins. Interestingly, however, three of nine tested proteins display dual topology. Positive residues close to the transmembrane domains are conserved, and mutational analysis of one small protein, YohP, showed that the positive inside rule applies for single transmembrane domain proteins as has been observed for larger proteins. Finally, fractionation analysis of small protein localization in strains depleted of the Sec or YidC membrane insertion pathways uncovered differential requirements. Some small proteins appear to be affected by both Sec and YidC depletion, others showed more dependence on one or the other insertion pathway, whereas one protein was not affected by depletion of either Sec or YidC. Thus, despite their diminutive size, small proteins display considerable diversity in topology, biochemical features, and insertion pathways. C1 [Fontaine, Fanette; Fuchs, Ryan T.; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Storz, G (reprint author), 18 Lib Dr, Bethesda, MD 20892 USA. EM storz@helix.nih.gov OI Storz, Gisela/0000-0001-6698-1241 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 38 TC 25 Z9 45 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 16 PY 2011 VL 286 IS 37 BP 32464 EP 32474 DI 10.1074/jbc.M111.245696 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 818CK UT WOS:000294726800056 PM 21778229 ER PT J AU Gentles, AJ Gallahan, D AF Gentles, Andrew J. Gallahan, Daniel TI Systems Biology: Confronting the Complexity of Cancer SO CANCER RESEARCH LA English DT Editorial Material ID REGULATORY NETWORKS; STATE; GENE; RECONSTRUCTION; CELLS AB The AACR-NCI Conference "Systems Biology: Confronting the Complexity of Cancer" took place from February 27 to March 2, 2011, in San Diego, CA. Several themes resonated during the meeting, notably (i) the need for better methods to distill insights from large-scale networks, (ii) the importance of integrating multiple data types in constructing more realistic models, (iii) challenges in translating insights about tumorigenic mechanisms into therapeutic interventions, and (iv) the role of the tumor microenvironment, at the physical, cellular, and molecular levels. The meeting highlighted concrete applications of systems biology to cancer, and the value of collaboration between interdisciplinary researchers in attacking formidable problems. Cancer Res; 71(18); 5961-4. (c) 2011 AACR. C1 [Gentles, Andrew J.] Stanford Univ, Sch Med, Ctr Canc Syst Biol, Stanford, CA 94305 USA. [Gentles, Andrew J.] Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA. [Gallahan, Daniel] Natl Canc Inst, Bethesda, MD USA. RP Gentles, AJ (reprint author), Stanford Univ, Sch Med, Ctr Canc Syst Biol, P060 Lucas Ctr, Stanford, CA 94305 USA. EM andrewg@stanford.edu; gallahad@mail.nih.gov FU NCI NIH HHS [U54 CA149145, U54 CA149145-01] NR 17 TC 11 Z9 11 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2011 VL 71 IS 18 BP 5961 EP 5964 DI 10.1158/0008-5472.CAN-11-1569 PG 4 WC Oncology SC Oncology GA 819QJ UT WOS:000294843600019 PM 21896642 ER PT J AU Taylor, RT Lubick, KJ Robertson, SJ Broughton, JP Bloom, ME Bresnahan, WA Best, SM AF Taylor, R. Travis Lubick, Kirk J. Robertson, Shelly J. Broughton, James P. Bloom, Marshall E. Bresnahan, Wade A. Best, Sonja M. TI TRIM79 alpha, an Interferon-Stimulated Gene Product, Restricts Tick-Borne Encephalitis Virus Replication by Degrading the Viral RNA Polymerase SO CELL HOST & MICROBE LA English DT Article ID TRIPARTITE MOTIF PROTEINS; TRIM FAMILY PROTEINS; RETROVIRAL RESTRICTION; JAPANESE ENCEPHALITIS; WEST-NILE; TRIM5-ALPHA RESTRICTION; IMMUNE-RESPONSES; RING DOMAIN; NS5; FLAVIVIRUS AB In response to virus infection, type I interferons (IFNs) induce several genes, most of whose functions are largely unknown. Here, we show that the tripartite motif (TRIM) protein, TRIM79 alpha, is an IFN-stimulated gene (ISG) product that specifically targets tick-borne encephalitis virus (TBEV), a Flavivirus that causes encephalitides in humans. TRIM79 alpha restricts TBEV replication by mediating lysosome-dependent degradation of the flavivirus NS5 protein, an RNA-dependent RNA polymerase essential for virus replication. NS5 degradation was specific to tick-borne flaviviruses, as TRIM79 alpha did not recognize NS5 from West Nile virus (WNV) or inhibit WNV replication. In the absence of TRIM79 alpha, IFN-beta was less effective in inhibiting tick-borne flavivirus infection of mouse macrophages, highlighting the importance of a single virus-specific ISG in establishing an antiviral state. The specificity of TRIM79 alpha for TBEV reveals a remarkable ability of the innate IFN response to discriminate between closely related flaviviruses. C1 [Taylor, R. Travis; Lubick, Kirk J.; Robertson, Shelly J.; Best, Sonja M.] NIAID, Rocky Mt Labs, Div Intramural Res, NIH,Innate Immun & Pathogenesis Unit,Lab Virol, Hamilton, MT 59840 USA. [Broughton, James P.; Bloom, Marshall E.] NIAID, Rocky Mt Labs, Div Intramural Res, NIH,Tick Borne Pathogenesis Unit,Lab Virol, Hamilton, MT 59840 USA. [Bresnahan, Wade A.] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. RP Best, SM (reprint author), NIAID, Rocky Mt Labs, Div Intramural Res, NIH,Innate Immun & Pathogenesis Unit,Lab Virol, Hamilton, MT 59840 USA. EM sbest@niaid.nih.gov RI Broughton, James/K-5251-2012 OI Broughton, James/0000-0001-5852-9546 FU National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID); NIH [AI059340] FX We thank members of the Laboratory of Virology for BSL-4 training, particularly Ricki Feldmann. We thank Anita Mora for graphical expertise and Drs. John Portis, Jean Celli, and Heinz Feldmann for critical reviews of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), and NIH AI059340 (W.A.B). NR 45 TC 36 Z9 38 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD SEP 15 PY 2011 VL 10 IS 3 BP 185 EP 196 DI 10.1016/j.chom.2011.08.004 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 831QL UT WOS:000295746100005 PM 21925107 ER PT J AU Berezhkovskii, AM Bezrukov, SM AF Berezhkovskii, Alexander M. Bezrukov, Sergey M. TI Effective drift and diffusion of a particle jumping between mobile and immobile states SO JOURNAL OF ELECTROANALYTICAL CHEMISTRY LA English DT Article DE Stochastic transport; Effective propagator ID INTEGRIN-CYTOSKELETAL INTERACTIONS; MIGRATING FIBROBLASTS; CHROMATOGRAPHY; MODEL AB We study propagation of a particle that jumps between two states, in which it moves with different velocities and diffusion coefficients. To simplify analysis, in the main part of the paper we derive formulas assuming that in one of the states the particle is immobile. A generalization to the case when the particle is mobile in both states is given at the end of the paper. The formulas show how the effective drift velocity and effective diffusion coefficient depend on jump rates between the two states as well as on the particle velocities and diffusion coefficients in these states. Specifically, we find that the effective diffusion coefficient can exhibit a non-monotonic behavior as a function of the ratio of the jump rates. Published by Elsevier B.V. C1 [Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Phys & Struct Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Bezrukov, SM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Phys & Struct Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM bezrukos@mail.nih.gov FU NIH, Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This study was supported by the Intramural Research Program of the NIH, Center for Information Technology and Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 18 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1572-6657 J9 J ELECTROANAL CHEM JI J. Electroanal. Chem. PD SEP 15 PY 2011 VL 660 IS 2 SI SI BP 352 EP 355 DI 10.1016/j.jelechem.2010.08.017 PG 4 WC Chemistry, Analytical; Electrochemistry SC Chemistry; Electrochemistry GA 837BG UT WOS:000296165500021 PM 21966285 ER PT J AU Harrison, DM Newsome, SD Skolasky, RL McArthur, JC Nath, A AF Harrison, Daniel M. Newsome, Scott D. Skolasky, Richard L. McArthur, Justin C. Nath, Avindra TI Immune reconstitution is not a prognostic factor in progressive multifocal leukoencephalopathy SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Leukoencephalopathy; Progressive multifocal; Immune reconstitution inflammatory syndrome; Immunosuppression; HIV ID ACTIVE ANTIRETROVIRAL THERAPY; HIV-INFECTED PATIENTS; INFLAMMATORY SYNDROME; CLINICAL-MANIFESTATIONS; NEGATIVE PATIENTS; UNITED-STATES; RISK-FACTORS; AIDS; HAART; EPIDEMIOLOGY AB Progressive multifocal leukoencephalopathy (PML) is typically associated with minimal inflammation; however, patients may develop an inflammatory response due to immune reconstitution (IRIS). The authors aimed to determine if characteristics and outcomes of PML are altered in those with IRIS. A retrospective records review was performed on 87 patients diagnosed with PML at Johns Hopkins, 27 of which had a syndrome consistent with IRIS. Gadolinium enhancement on MRI occurred in 44.4% of cases of PML-IRIS versus 5.1% in PML (p<0.05), and thus had low diagnostic sensitivity and specificity. In HIV+ cases, CD4 counts were lower in those who later developed IRIS (mean 34.8 vs. 71.7, p<0.05) and was predictive of the development of IRIS (p<0.05). Improved prognosis was seen with higher cerebrospinal fluid (CSF) white blood cell counts and protein levels, but not for gadolinium enhancement and there were no differences in survival for PML versus PML-IRIS. (C) 2011 Elsevier B.V. All rights reserved. C1 [Harrison, Daniel M.; Newsome, Scott D.; McArthur, Justin C.; Nath, Avindra] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Skolasky, Richard L.] Johns Hopkins Univ, Sch Med, Dept Orthopaed Surg, Baltimore, MD USA. [McArthur, Justin C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Med, Baltimore, MD USA. [McArthur, Justin C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Pathol, Baltimore, MD USA. [McArthur, Justin C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. RP Harrison, DM (reprint author), 600 N Wolfe St,Pathol 627, Baltimore, MD 21287 USA. EM dharri90@jhmi.edu OI Skolasky, Richard/0000-0002-2598-4427 FU NIH [R01NS056884, 1P30MH075673, NS44807] FX Supported in part by grant R01NS056884 from the NIH to AN and grants 1P30MH075673 and NS44807 from the NIH to JCM. NR 30 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD SEP 15 PY 2011 VL 238 IS 1-2 BP 81 EP 86 DI 10.1016/j.jneuroim.2011.07.003 PG 6 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 831CK UT WOS:000295706100010 PM 21840066 ER PT J AU Le Menach, A Tatem, AJ Cohen, JM Hay, SI Randell, H Patil, AP Smith, DL AF Le Menach, Arnaud Tatem, Andrew J. Cohen, Justin M. Hay, Simon I. Randell, Heather Patil, Anand P. Smith, David L. TI Travel risk, malaria importation and malaria transmission in Zanzibar SO SCIENTIFIC REPORTS LA English DT Article ID HUMAN MOVEMENT; ELIMINATION; INFECTION; FEASIBILITY; PATTERNS; NETS AB The prevalence of Plasmodium falciparum malaria in Zanzibar has reached historic lows. Improving control requires quantifying malaria importation rates, identifying high-risk travelers, and assessing onwards transmission. Estimates of Zanzibar's importation rate were calculated through two independent methodologies. First, mobile phone usage data and ferry traffic between Zanzibar and mainland Tanzania were re-analyzed using a model of heterogeneous travel risk. Second, a dynamic mathematical model of importation and transmission rates was used. Zanzibar residents traveling to malaria endemic regions were estimated to contribute 1-15 times more imported cases than infected visitors. The malaria importation rate was estimated to be 1.6 incoming infections per 1,000 inhabitants per year. Local transmission was estimated too low to sustain transmission in most places. Malaria infections in Zanzibar largely result from imported malaria and subsequent transmission. Plasmodium falciparum malaria elimination appears feasible by implementing control measures based on detecting imported malaria cases and controlling onward transmission. C1 [Le Menach, Arnaud; Randell, Heather; Smith, David L.] Ctr Dis Dynam Econ & Policy, Washington, DC USA. [Tatem, Andrew J.; Smith, David L.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Tatem, Andrew J.; Hay, Simon I.; Smith, David L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Cohen, Justin M.] Clinton Hlth Access Initiat, Boston, MA USA. [Hay, Simon I.; Patil, Anand P.] Univ Oxford, Dept Zool, Oxford OX1 2JD, England. [Randell, Heather] Brown Univ, Dept Sociol, Providence, RI 02912 USA. [Smith, David L.] Univ Florida, Dept Biol, Gainesville, FL USA. RP Le Menach, A (reprint author), Ctr Dis Dynam Econ & Policy, Washington, DC USA. EM arnaudlemenach@gmail.com RI Smith, David/L-8850-2013; Hay, Simon/F-8967-2015; OI Smith, David/0000-0003-4367-3849; Hay, Simon/0000-0002-0611-7272; Cohen, Justin/0000-0003-4481-6784 FU Bill and Melinda Gates Foundation [49446]; Wellcome Trust [079091, 091835]; Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX The author would like to thank members of the Zanzibar Malaria Control Programme. ALM, HR, DLS, AJT are supported by a grant from the Bill and Melinda Gates Foundation (#49446)(http://www.gatesfoundation.org). SIH is funded by a Senior Research Fellowship from the Wellcome Trust (#079091). DLS, AJT and SIH also acknowledge funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (http://www.fic.nih.gov). APP is paid by a Biomedical Resources Grant from the Wellcome Trust (#091835). This work forms part of the output of the Malaria Atlas Project (MAP, http://www.map.ox.ac.uk), principally funded by the Wellcome Trust, U.K (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 37 Z9 37 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD SEP 15 PY 2011 VL 1 AR 93 DI 10.1038/srep00093 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 835RT UT WOS:000296054200001 PM 22355611 ER PT J AU Roberts, WC AF Roberts, William Clifford TI Natural History, Clinical Consequences, and Morphologic Features of Coronary Arterial Aneurysms in Adults SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article AB Clinical and morphologic features are described in 20 adults (15 men) aged 17 to 85 years (mean 56) who at necropsy were found to have >= 1 aneurysm in >= 1 of their 3 major (right, left anterior descending, and left circumflex) epicardial coronary arteries. Of the 34 coronary aneurysms in the 20 patients (single in 10 patients, >= 2 in 10 patients), 27 (79%) contained intra-aneurysmal thrombi, and in each, the thrombus severely narrowed the lumen. Additionally, atherosclerotic plaque was present in the aneurysmal wall in all 27 aneurysms containing thrombi and also in the major coronary arteries uninvolved by aneurysm. The causes of the aneurysms in the 16 patients with intra-aneurysmal thrombi were therefore considered atherosclerotic. In the other 4 patients, with 7 aneurysms, none contained intra-aneurysmal thrombus or atherosclerotic plaque, and the aneurysms were considered congenital. Clinical diagnosis of coronary aneurysm was not made in any of the 20 patients, but none had proper imaging studies during life. Despite the coronary aneurysms and the associated luminal narrowing, only 8 patients (40%) had left ventricular wall scarring or necrosis or clinical evidence of myocardial ischemia. Proper therapy remains ill defined. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:814-821) C1 [Roberts, William Clifford] Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Dallas, TX USA. [Roberts, William Clifford] NHLBI, Pathol Branch, NIH, Bethesda, MD 20892 USA. RP Roberts, WC (reprint author), Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Dallas, TX USA. EM wc.roberts@baylorhealth.edu NR 15 TC 4 Z9 6 U1 0 U2 3 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 SEP 15 PY 2011 VL 108 IS 6 BP 814 EP 821 DI 10.1016/j.amjcard.2011.05.009 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 826KJ UT WOS:000295352700011 PM 21791334 ER PT J AU Deziel, NC Viet, SM Rogers, JW Camann, DE Marker, DA Heikkinen, MSA Yau, AY Stout, DM Dellarco, M AF Deziel, Nicole C. Viet, Susan M. Rogers, John W. Camann, David E. Marker, David A. Heikkinen, Maire S. A. Yau, Alice Y. Stout, Daniel M., II Dellarco, Michael TI Comparison of wipe materials and wetting agents for pesticide residue collection from hard surfaces SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Collection efficiency; Precision; Pesticide; Wipe; National Children's Study ID EXPOSURE ASSESSMENT; RESIDENTIAL SURFACES; POTENTIAL EXPOSURE; DERMAL TRANSFER; CHILDREN; DUST; HOMES; CHLORPYRIFOS; CYFLUTHRIN; COMMUNITY AB Different wipe materials and wetting agents have been used to collect pesticide residues from surfaces, but little is known about their comparability. To inform the selection of a wipe for the National Children's Study, the analytical feasibility, collection efficiency, and precision of Twillwipes wetted with isopropanol (TI), Ghost Wipes (GW), and Twillwipes wetted with water (TW), were evaluated. Wipe samples were collected from stainless steel surfaces spiked with high and low concentrations of 27 insecticides, including organochlorines, organophosphates, and pyrethroids. Samples were analyzed by GC/MS/SIM. No analytical interferences were observed for any of the wipes. The mean percent collection efficiencies across all pesticides for the TI. GW, and TW were 69.3%, 31.1%, and 10.3% at the high concentration, respectively, and 55.6%, 22.5%, and 6.9% at the low concentration, respectively. The collection efficiencies of the TI were significantly greater than that of GW or TW (p<0.0001). Collection efficiency also differed significantly by pesticide (p<0.0001) and spike concentration (p<0.0001). The pooled coefficients of variation (CVs) of the collection efficiencies for the TI. GW, and TW at high concentration were 0.08, 0.17, and 0.24, respectively. The pooled CV of the collection efficiencies for the TI, GW, and TW at low concentration were 0.15, 0.19, and 0.36, respectively. The TI had significantly lower CVs than either of the other two wipes (p=0.0008). Though the TI was superior in terms of both accuracy and precision, it requires multiple preparation steps, which could lead to operational challenges in a large-scale study. (C) 2011 Elsevier B.V. All rights reserved. C1 [Deziel, Nicole C.; Viet, Susan M.; Rogers, John W.; Marker, David A.; Heikkinen, Maire S. A.] WESTAT Corp, Rockville, MD 20850 USA. [Camann, David E.; Yau, Alice Y.] SW Res Inst, San Antonio, TX 78228 USA. [Stout, Daniel M., II] US EPA, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA. [Dellarco, Michael] Natl Childrens Study, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Viet, SM (reprint author), WESTAT Corp, 1600 Res Blvd, Rockville, MD 20850 USA. EM susanviet@westat.com FU NICHD NIH HHS [N01HD53395] NR 26 TC 8 Z9 8 U1 2 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD SEP 15 PY 2011 VL 409 IS 20 BP 4442 EP 4448 DI 10.1016/j.scitotenv.2011.07.002 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA 825UB UT WOS:000295306500032 PM 21816452 ER PT J AU Wagner, W McCroskery, S Hammer, JA AF Wagner, Wolfgang McCroskery, Seumas Hammer, John A., III TI An efficient method for the long-term and specific expression of exogenous cDNAs in cultured Purkinje neurons SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Cerebellar culture; Purkinje cells; Dendritic spines; L7 (Pcp2); Amaxa nucleofection; Transfection; Live cell microscopy ID METABOTROPIC GLUTAMATE RECEPTORS; CELLS IN-VITRO; DISSOCIATED CEREBELLAR CULTURES; GREEN FLUORESCENT PROTEIN; PARALLEL FIBER SYNAPSES; HOMER FAMILY PROTEINS; SCA1 TRANSGENIC MICE; AMPA-RECEPTOR; SYNAPTIC DEPRESSION; INTERACTING PROTEIN AB We present a simple and efficient method for expressing cDNAs in Purkinje neurons (PNs) present in heterogeneous mouse cerebellar cultures. The method combines the transfection of freshly dissociated cerebellar cells via nucleofection with the use of novel expression plasmids containing a fragment of the L7 (Pcp2) gene that, within the cerebellum, drives PN-specific expression. The efficiency of PN transfection (determined 13 days post nucleofection) is approximately 70%. Double and triple transfections are routinely achieved at slightly lower efficiencies. Expression in PNs is obvious after one week in culture and still strong after three weeks, by which time these neurons are well-developed. Moreover, high-level expression is restricted almost exclusively to the PNs present in these mixed cultures, which greatly facilitates the characterization of PN-specific functions. As proof of principle, we used this method to visualize (1) the morphology of living PNs expressing mGFP, (2) the localization and dynamics of the dendritic spine proteins PSD-93 and Homer-3a tagged with mGFP and (3) the interaction of live PNs expressing mGFP with other cerebellar neurons expressing mCherry from a beta-Actin promoter plasmid. Finally, we created a series of L7-plasmids containing different fluorescent protein cDNAs that are suited for the expression of cDNAs of interest as N- and C-terminally tagged fluorescent fusion proteins. In summary, this procedure allows for the highly efficient, long-term, and specific expression of multiple cDNAs in differentiated PNs, and provides a favorable alternative to two procedures (viral transduction, ballistic gene delivery) used previously to express genes in cultured PNs. Published by Elsevier B.V. C1 [Wagner, Wolfgang; McCroskery, Seumas; Hammer, John A., III] NHLBI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. RP Hammer, JA (reprint author), NHLBI, NIH, Cell Biol Lab, Bldg 50,Room 2306,MSC 8017,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov FU Intramural NIH HHS [Z01 HL000514-25] NR 90 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD SEP 15 PY 2011 VL 200 IS 2 BP 95 EP 105 DI 10.1016/j.jneumeth.2011.06.006 PG 11 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 825AC UT WOS:000295242300001 PM 21708190 ER PT J AU Hong, S Optican, LM FitzGibbon, EJ Zee, DS Shaikh, AG AF Hong, Simon Optican, Lance M. FitzGibbon, Edmond J. Zee, David S. Shaikh, Aasef G. TI OrbitView: Eye movement visualization software SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Data visualization; Emulation of eye movements; Clinical tool; Research tool; Teaching tool ID SACCADIC OSCILLATIONS; TREMOR AB Measurement of eye movements often helps to diagnose ocular motor disorders in the clinic, and is also used as a research tool in ocular motor, vision and vestibular research. Eye movements, however, are usually recorded without simultaneous video recordings, making offline interpretation difficult. We developed a tool that converts the measured eye movement data into a three-dimensional (3D) movie of eye movements. Having useful functions such as slow-play, pause and exaggeration of the movements, this new software provides a research and teaching tool to aid interpretation of the recorded eye movements. Published by Elsevier B.V. C1 [Hong, Simon] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Zee, David S.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Shaikh, Aasef G.] Case Western Reserve Univ, Dept Neurol, Cleveland, OH 44106 USA. RP Hong, S (reprint author), NEI, Sensorimotor Res Lab, NIH, 49 Convent Dr,Room 2A50, Bethesda, MD 20892 USA. EM hongy@nei.nih.gov FU National Eye Institute; NIH; DHHS FX We are grateful to Dr. B. M. Sheliga, for his help in collecting the eye movement data. This work was supported by the Intramural Research program of the National Eye Institute, NIH, and DHHS. NR 10 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD SEP 15 PY 2011 VL 200 IS 2 BP 181 EP 184 DI 10.1016/j.jneumeth.2011.06.002 PG 4 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 825AC UT WOS:000295242300010 PM 21689683 ER PT J AU Lada, AG Waisertreiger, ISR Grabow, CE Prakash, A Borgstahl, GEO Rogozin, IB Pavlov, YI AF Lada, Artem G. Waisertreiger, Irina S. -R. Grabow, Corinn E. Prakash, Aishwarya Borgstahl, Gloria E. O. Rogozin, Igor B. Pavlov, Youri I. TI Replication Protein A (RPA) Hampers the Processive Action of APOBEC3G Cytosine Deaminase on Single-Stranded DNA SO PLOS ONE LA English DT Article ID INDUCED CYTIDINE DEAMINASE; CLASS-SWITCH RECOMBINATION; SOMATIC HYPERMUTATION; ANTIBODY DIVERSIFICATION; ESCHERICHIA-COLI; MESSENGER-RNA; KINASE-A; IN-VIVO; AID; YEAST AB Background: Editing deaminases have a pivotal role in cellular physiology. A notable member of this superfamily, APOBEC3G (A3G), restricts retroviruses, and Activation Induced Deaminase (AID) generates antibody diversity by localized deamination of cytosines in DNA. Unconstrained deaminase activity can cause genome-wide mutagenesis and cancer. The mechanisms that protect the genomic DNA from the undesired action of deaminases are unknown. Using the in vitro deamination assays and expression of A3G in yeast, we show that replication protein A (RPA), the eukaryotic single-stranded DNA (ssDNA) binding protein, severely inhibits the deamination activity and processivity of A3G. Principal Findings/Methodology: We found that mutations induced by A3G in the yeast genomic reporter are changes of a single nucleotide. This is unexpected because of the known property of A3G to catalyze multiple deaminations upon one substrate encounter event in vitro. The addition of recombinant RPA to the oligonucleotide deamination assay severely inhibited A3G activity. Additionally, we reveal the inverse correlation between RPA concentration and the number of deaminations induced by A3G in vitro on long ssDNA regions. This resembles the "hit and run" single base substitution events observed in yeast. Significance: Our data suggest that RPA is a plausible antimutator factor limiting the activity and processivity of editing deaminases in the model yeast system. Because of the similar antagonism of yeast RPA and human RPA with A3G in vitro, we propose that RPA plays a role in the protection of the human genome cell from A3G and other deaminases when they are inadvertently diverged from their natural targets. We propose a model where RPA serves as one of the guardians of the genome that protects ssDNA from the destructive processive activity of deaminases by non-specific steric hindrance. C1 [Lada, Artem G.; Waisertreiger, Irina S. -R.; Grabow, Corinn E.; Prakash, Aishwarya; Borgstahl, Gloria E. O.; Pavlov, Youri I.] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE USA. [Rogozin, Igor B.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Rogozin, Igor B.] Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. RP Lada, AG (reprint author), Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE USA. EM ypavlov@unmc.edu FU NCI Eppley Cancer Center Support Grant [P30CA036727]; NCI [CA129925]; University of Nebraska Medical Center; Presidential graduate fellowship FX This work was supported by the NCI Eppley Cancer Center Support Grant [P30CA036727] and in part by NCI grant CA129925 to YIP. Aishwarya Prakash was supported by the University of Nebraska Medical Center graduate fellowship and the Presidential graduate fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 11 Z9 11 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 15 PY 2011 VL 6 IS 9 AR e24848 DI 10.1371/journal.pone.0024848 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822JR UT WOS:000295041700065 PM 21935481 ER PT J AU Naidu, MD Agarwal, R Pena, LA Cunha, L Mezei, M Shen, M Wilson, DM Liu, Y Sanchez, Z Chaudhary, P Wilson, SH Waring, MJ AF Naidu, Mamta D. Agarwal, Rakhi Pena, Louis A. Cunha, Luis Mezei, Mihaly Shen, Min Wilson, David M., III Liu, Yuan Sanchez, Zina Chaudhary, Pankaj Wilson, Samuel H. Waring, Michael J. TI Lucanthone and Its Derivative Hycanthone Inhibit Apurinic Endonuclease-1 (APE1) by Direct Protein Binding SO PLOS ONE LA English DT Article ID BASE EXCISION-REPAIR; DNA-POLYMERASE-BETA; RADIOTHERAPY IN-VITRO; MIRACIL-D; TOPOISOMERASE-II; CANCER CELLS; ABASIC ENDONUCLEASE; RADIATION-THERAPY; ALKYLATING-AGENTS; AUTOMATED DOCKING AB Lucanthone and hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas hycanthone was pulled out of Phase II trials. Their potential mechanism of action includes DNA intercalation, inhibition of nucleic acid biosyntheses, and inhibition of enzymes like topoisomerases and the dual function base excision repair enzyme apurinic endonuclease 1 (APE1). Lucanthone inhibits the endonuclease activity of APE1, without affecting its redox activity. Our goal was to decipher the precise mechanism of APE1 inhibition as a prerequisite towards development of improved therapeutics that can counteract higher APE1 activity often seen in tumors. The IC50 values for inhibition of APE1 incision of depurinated plasmid DNA by lucanthone and hycanthone were 5 mu M and 80 nM, respectively. The KD values (affinity constants) for APE1, as determined by BIACORE binding studies, were 89 nM for lucanthone/10 nM for hycanthone. APE1 structures reveal a hydrophobic pocket where hydrophobic small molecules like thioxanthenones can bind, and our modeling studies confirmed such docking. Circular dichroism spectra uncovered change in the helical structure of APE1 in the presence of lucanthone/hycanthone, and notably, this effect was decreased (Phe266Ala or Phe266Cys or Trp280Leu) or abolished (Phe266Ala/Trp280Ala) when hydrophobic site mutants were employed. Reduced inhibition by lucanthone of the diminished endonuclease activity of hydrophobic mutant proteins (as compared to wild type APE1) supports that binding of lucanthone to the hydrophobic pocket dictates APE1 inhibition. The DNA binding capacity of APE1 was marginally inhibited by lucanthone, and not at all by hycanthone, supporting our hypothesis that thioxanthenones inhibit APE1, predominantly, by direct interaction. Finally, lucanthone-induced degradation was drastically reduced in the presence of short and long lived free radical scavengers, e.g., TRIS and DMSO, suggesting that the mechanism of APE1 breakdown may involve free radical-induced peptide bond cleavage. C1 [Naidu, Mamta D.; Agarwal, Rakhi; Chaudhary, Pankaj] Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. [Pena, Louis A.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Cunha, Luis] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Mezei, Mihaly] Mt Sinai Sch Med, Dept Struct & Chem Biol, New York, NY USA. [Shen, Min] NIH, NIH Chem Genom Ctr, Rockville, MD USA. [Wilson, David M., III] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Liu, Yuan; Wilson, Samuel H.] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC USA. [Sanchez, Zina] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Waring, Michael J.] Univ Cambridge, Dept Pharmacol, Cambridge CB2 1QJ, England. RP Naidu, MD (reprint author), Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. EM mnaidu@bnl.gov OI Naidu, Mamta/0000-0002-2754-2470; Chaudhary, Pankaj/0000-0002-0381-3635 FU DOE [KP-1401020/MO-079]; NIH [R01-CA86897]; National Institute on Aging; NIH, National Institutes of Environmental Health Sciences [Z01ES050158, Z01-ES050159]; U.S. Department of Energy [DE-AC02-98CH10886] FX This work was supported by DOE grant KP-1401020/MO-079, NIH grant R01-CA86897, the Intramural Research Program of the National Institute on Aging and the Intramural Research Program of the NIH, National Institutes of Environmental Health Sciences (Z01ES050158 & Z01-ES050159). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; BNL is managed by Brookhaven Science Associates, L.L.C. for the U.S. Department of Energy under Contract DE-AC02-98CH10886. NR 63 TC 19 Z9 19 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 15 PY 2011 VL 6 IS 9 AR e23679 DI 10.1371/journal.pone.0023679 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822JR UT WOS:000295041700001 PM 21935361 ER PT J AU Ziats, MN Rennert, OM AF Ziats, Mark N. Rennert, Owen M. TI Expression Profiling of Autism Candidate Genes during Human Brain Development Implicates Central Immune Signaling Pathways SO PLOS ONE LA English DT Article ID SPECTRUM DISORDERS; NEURODEVELOPMENTAL DISORDERS; RETT-SYNDROME; GENETICS; ACTIVATION; DISEASE; TWIN; SCHIZOPHRENIA; ASSOCIATION; GLUTAMATE AB The Autism Spectrum Disorders (ASD) represent a clinically heterogeneous set of conditions with strong hereditary components. Despite substantial efforts to uncover the genetic basis of ASD, the genomic etiology appears complex and a clear understanding of the molecular mechanisms underlying Autism remains elusive. We hypothesized that focusing gene interaction networks on ASD-implicated genes that are highly expressed in the developing brain may reveal core mechanisms that are otherwise obscured by the genomic heterogeneity of the disorder. Here we report an in silico study of the gene expression profile from ASD-implicated genes in the unaffected developing human brain. By implementing a biologically relevant approach, we identified a subset of highly expressed ASD-candidate genes from which interactome networks were derived. Strikingly, immune signaling through NF kappa B, Tnf, and Jnk was central to ASD networks at multiple levels of our analysis, and cell-type specific expression suggested glia-in addition to neurons-deserve consideration. This work provides integrated genomic evidence that ASD-implicated genes may converge on central cytokine signaling pathways. C1 [Ziats, Mark N.; Rennert, Owen M.] NICHHD, Lab Clin & Dev Genom, NIH, Bethesda, MD 20892 USA. [Ziats, Mark N.] Baylor Coll Med, Med Scientist Training Program, Houston, TX 77030 USA. [Ziats, Mark N.] Univ Cambridge, Dept Physiol Dev & Neurosci, Natl Inst Hlth, Biomed Scholars Program, Cambridge, England. RP Ziats, MN (reprint author), NICHHD, Lab Clin & Dev Genom, NIH, Bethesda, MD 20892 USA. EM ziatsm@mail.nih.gov FU National Institute of Child Health and Human Development; National Institutes of Health (NIH); NIH-University of Cambridge; Baylor College of Medicine MSTP FX This work was supported by the Intramural Research Program at National Institute of Child Health and Human Development, National Institutes of Health (NIH). MNZ was also supported by the NIH-University of Cambridge Biomedical Scholars Program and Baylor College of Medicine MSTP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 29 Z9 29 U1 1 U2 10 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 SEP 15 PY 2011 VL 6 IS 9 AR e24691 DI 10.1371/journal.pone.0024691 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822JR UT WOS:000295041700050 PM 21935439 ER PT J AU Maravillas-Montero, JL Gillespie, PG Patino-Lopez, G Shaw, S Santos-Argumedo, L AF Maravillas-Montero, Jose L. Gillespie, Peter G. Patino-Lopez, Genaro Shaw, Stephen Santos-Argumedo, Leopoldo TI Myosin 1c Participates in B Cell Cytoskeleton Rearrangements, Is Recruited to the Immunologic Synapse, and Contributes to Antigen Presentation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LYMPHOCYTE SURFACE MACROMOLECULES; 2 DISTINCT MECHANISMS; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; BRUSH-BORDER; LIPID RAFTS; MEMBRANE; LOCALIZATION; MICROVILLI; PROTEINS; MOTOR AB Myosin 1c (Myo1c) is a member of the unconventional class I myosins of vertebrates, which directly link the plasma membrane with the microfilament cortical web. Although this molecular motor has been implicated in cell functions such as cytoskeleton organization, cell motility, nuclear transcription, and endocytosis, its role in hematopoietic cells is largely unknown. In this study, we show that Myo1c is abundantly expressed in murine B lymphocytes and is preferentially located at the plasma membrane, especially in peripheral processes such as microvilli. We observed that this motor concentrates at the growing membrane protrusions generated during B cell spreading and that it is actively recruited to the immune synapse. Interestingly, Myo1c was detected in lipid rafts of B cells and showed strong colocalization with MHC-II, particularly after cross-linking of these molecules. By transfection of a dominant negative form of Myo1c or specific siRNA, we also detected alterations in the spreading and Ag-presenting ability of these cells. The data suggest that Myo1c is involved in the cytoskeleton dynamics and membrane protein anchoring or sorting in B lymphocytes. The Journal of Immunology, 2011, 187: 3053-3063. C1 [Maravillas-Montero, Jose L.; Santos-Argumedo, Leopoldo] Inst Politecn Nacl, Dept Biomed Mol, Ctr Invest & Estudios Avanzados, Mexico City 07360, DF, Mexico. [Gillespie, Peter G.] Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97239 USA. [Gillespie, Peter G.] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. [Patino-Lopez, Genaro; Shaw, Stephen] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Santos-Argumedo, L (reprint author), Inst Politecn Nacl, Dept Biomed Mol, Ctr Invest & Estudios Avanzados, Apartado Postal 14-740, Mexico City 07360, DF, Mexico. EM lesantos@cinvestav.mx OI Santos-Argumedo, Leopoldo/0000-0002-4772-0713; Patino-Lopez, Genaro/0000-0002-8716-722X; Barr-Gillespie, Peter/0000-0002-9787-5860 FU Consejo Nacional de Ciencia y Tecnologia [56836] FX This work was supported by Consejo Nacional de Ciencia y Tecnologia (Grant 56836). J.L.M.-M. is Fellow 203768 at Consejo Nacional de Ciencia y Tecnologia. NR 47 TC 16 Z9 17 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2011 VL 187 IS 6 BP 3053 EP 3063 DI 10.4049/jimmunol.1004018 PG 11 WC Immunology SC Immunology GA 822HI UT WOS:000295034200024 PM 21841128 ER PT J AU Upadhyaya, B Yin, YZ Hill, BJ Douek, DC Prussin, C AF Upadhyaya, Bhaskar Yin, Yuzhi Hill, Brenna J. Douek, Daniel C. Prussin, Calman TI Hierarchical IL-5 Expression Defines a Subpopulation of Highly Differentiated Human Th2 Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; PROBABILISTIC REGULATION; CYTOKINE PRODUCTION; RESPONSES; IMMUNITY; GATA-3; HETEROGENEITY; MECHANISMS; PLASTICITY; TOLERANCE AB Each of the three Th2 cytokine genes, IL-4, IL-5, and IL-13, has different functions. We hypothesized that Th2 heterogeneity could yield Th2 subpopulations with different cytokine expression and effector functions. Using multiple approaches, we demonstrate that human Th2 cells are composed of two major subpopulations: a minority IL-5(+) (IL-5(+), IL-4(+), IL-13(+)) and majority IL-5(-) Th2 (IL-5(-), IL-4(+), IL-13(+)) population. IL-5(+) Th2 cells comprised only 20% of all Th2 cells. Serial rounds of in vitro differentiation initially yielded IL-5(-) Th2, but required multiple rounds of differentiation to generate IL-5(+) Th2 cells. IL-5(+) Th2 cells expressed less CD27 and greater programmed cell death-1 than IL-5(-) Th2 cells, consistent with their being more highly differentiated, Ag-exposed memory cells. IL-5(+) Th2 cells expressed greater IL-4, IL-13, and GATA-3 relative to IL-5(-) Th2 cells. GATA-3 and H3K4me(3) binding to the IL5 promoter (IL5p) was greater in IL-5(+) relative to IL-5(-) Th2 cells, whereas there was no difference in their binding to the IL4p and IL13p. Conversely, H3K27me(3) binding to the IL5p was greater in IL-5(-) Th2 cells. These findings demonstrate Th2 lineage heterogeneity, in which the IL5 gene is regulated in a hierarchical manner relative to other Th2 genes. IL-5(+) Th2 cells are phenotypically distinct and have epigenetic changes consistent with greater IL5p accessibility. Recurrent antigenic exposure preferentially drives the differentiation of IL-5(+) Th2 cells. These results demonstrate that IL-5(+) and IL-5(-) Th2 cells, respectively, represent more and less highly differentiated Th2 cell subpopulations. Such Th2 subpopulations may differentially contribute to Th2-driven pathology. The Journal of Immunology, 2011, 187: 3111-3120. C1 [Upadhyaya, Bhaskar; Yin, Yuzhi; Prussin, Calman] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Hill, Brenna J.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Prussin, C (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C207, Bethesda, MD 20892 USA. EM cprussin@niaid.nih.gov OI Prussin, Calman/0000-0002-3917-3326 FU National Institute of Allergy and Infectious Diseases, Division of Intramural Research [AI001128-01 LAD] FX This work was supported by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research, project number AI001128-01 LAD. NR 51 TC 30 Z9 31 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2011 VL 187 IS 6 BP 3111 EP 3120 DI 10.4049/jimmunol.1101283 PG 10 WC Immunology SC Immunology GA 822HI UT WOS:000295034200030 PM 21849680 ER PT J AU Kastenmuller, W Gasteiger, G Subramanian, N Sparwasser, T Busch, DH Belkaid, Y Drexler, I Germain, RN AF Kastenmuller, Wolfgang Gasteiger, Georg Subramanian, Naeha Sparwasser, Tim Busch, Dirk H. Belkaid, Yasmine Drexler, Ingo Germain, Ronald N. TI Regulatory T Cells Selectively Control CD8(+) T Cell Effector Pool Size via IL-2 Restriction SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MODIFIED VACCINIA VIRUS; DENDRITIC CELLS; IN-VIVO; IMMUNE REGULATION; MEMORY; TOLERANCE; RESPONSES; INTERLEUKIN-2; INFECTION; CTLA-4 AB Regulatory T cells (Treg) are key players in maintaining immune homeostasis but have also been shown to regulate immune responses against infectious pathogens. Therefore, Treg are a promising target for modulating immune responses to vaccines to improve their efficacy. Using a viral vector system, we found that Treg act on the developing immune response early postinfection by reducing the extent of dendritic cell costimulatory molecule expression. Due to this change and the lower IL-2 production that results, a substantial fraction of CD8(+) effector T cells lose CD25 expression several days after activation. Surprisingly, such Treg-dependent limitations in IL-2 signaling by Ag-activated CD8(+) T cells prevent effector differentiation without interfering with memory cell formation. In this way, Treg fine-tune the numbers of effector T cells generated while preserving the capacity for a rapid recall response upon pathogen re-exposure. This selective effect of Treg on a subpopulation of CD8(+) T cells indicates that although manipulation of the Treg compartment might not be optimal for prophylactic vaccinations, it can be potentially exploited to optimize vaccine efficacy for therapeutic interventions. The Journal of Immunology, 2011, 187: 3186-3197. C1 [Kastenmuller, Wolfgang; Subramanian, Naeha; Germain, Ronald N.] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Gasteiger, Georg; Drexler, Ingo] Tech Univ Munich, Inst Virol, D-81675 Munich, Germany. [Gasteiger, Georg; Busch, Dirk H.; Drexler, Ingo] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Clin Cooperat Grp, D-85764 Neuherberg, Germany. [Gasteiger, Georg; Busch, Dirk H.; Drexler, Ingo] Tech Univ Munich, Clin Cooperat Grp, D-81675 Munich, Germany. [Sparwasser, Tim] Ctr Expt & Clin Infect Res Hannover, TWINCORE, Inst Infect Immunol, D-30625 Hannover, Germany. [Busch, Dirk H.] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-81675 Munich, Germany. [Belkaid, Yasmine] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Drexler, Ingo] Helmholtz Ctr Munich, Inst Virol, D-85764 Munich, Germany. [Drexler, Ingo] Univ Dusseldorf, Inst Virol, D-40225 Dusseldorf, Germany. RP Germain, RN (reprint author), NIAID, Lab Syst Biol, NIH, Bldg 10,Room 11N-311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM kastenmullerw@mail.nih.gov; rgermain@nih.gov OI Gasteiger, Georg/0000-0001-6986-127X FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; Deutsche Forschungsgemeinschaft [KA 3091/1-1, SFB 576 TPA8, SFB 900] FX This work was supported by the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Deutsche Forschungsgemeinschaft (Grants KA 3091/1-1 to W.K., SFB 576 TPA8 to D.H.B., and SFB 900 to T.S.). NR 58 TC 41 Z9 43 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 SEP 15 PY 2011 VL 187 IS 6 BP 3186 EP 3197 DI 10.4049/jimmunol.1101649 PG 12 WC Immunology SC Immunology GA 822HI UT WOS:000295034200037 PM 21849683 ER PT J AU Kothapalli, NR Collura, KM Norton, DD Fugmann, SD AF Kothapalli, Naga Rama Collura, Kaitlin M. Norton, Darrell D. Fugmann, Sebastian D. TI Separation of Mutational and Transcriptional Enhancers in Ig Genes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INDUCED CYTIDINE DEAMINASE; CLASS SWITCH RECOMBINATION; LIGHT-CHAIN GENE; SOMATIC HYPERMUTATION; B-CELLS; AID; DNA; DIVERSIFICATION; TARGETS; GENOME AB Secondary Ig gene diversification relies on activation-induced cytidine deaminase (AID) to create U:G mismatches that are subsequently fixed by mutagenic repair pathways. AID activity is focused to Ig loci by cis-regulatory DNA sequences named targeting elements. In this study, we show that in contrast to prevailing thought in the field, the targeting elements in the chicken IGL locus are distinct from classical transcriptional enhancers. These mutational enhancer elements (MEEs) are required over and above transcription to recruit AID-mediated mutagenesis to Ig loci. We identified a small 222-bp fragment in the chicken IGL locus that enhances mutagenesis without boosting transcription, and this sequence represents a key component of an MEE. Lastly, MEEs are evolutionarily conserved among birds, both in sequence and function, and contain several highly conserved sequence modules that are likely involved in recruiting trans-acting targeting factors. We propose that MEEs represent a novel class of cis-regulatory elements for which the function is to control genomic integrity. The Journal of Immunology, 2011, 187: 3247-3255. C1 [Kothapalli, Naga Rama; Collura, Kaitlin M.; Norton, Darrell D.; Fugmann, Sebastian D.] NIA, Mol Immunol Unit, Lab Mol Biol & Immunol, NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Fugmann, SD (reprint author), NIA, Mol Immunol Unit, Lab Mol Biol & Immunol, NIH,Biomed Res Ctr, 251 Bayview Blvd,Suite 100,Room 06C218, Baltimore, MD 21224 USA. EM fugmanns@mail.nih.gov OI Kothapalli, Naga Rama/0000-0001-7993-8525 FU National Institutes of Health, National Institute on Aging FX This work was entirely supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 30 TC 11 Z9 11 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 SEP 15 PY 2011 VL 187 IS 6 BP 3247 EP 3255 DI 10.4049/jimmunol.1101568 PG 9 WC Immunology SC Immunology GA 822HI UT WOS:000295034200043 PM 21844395 ER PT J AU Ishihara, S Schwartz, RH AF Ishihara, Satoru Schwartz, Ronald H. TI Two-Step Binding of Transcription Factors Causes Sequential Chromatin Structural Changes at the Activated IL-2 Promoter SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; INTERLEUKIN-2 GENE; NUCLEAR FACTOR; IL2 GENE; IN-VIVO; C-FOS; EXPRESSION; JUN; PROTEIN; REGION AB Most gene promoters have multiple binding sequences for many transcription factors, but the contribution of each of these factors to chromatin remodeling is still unclear. Although we previously found a dynamic change in the arrangement of nucleosome arrays at the Il2 promoter during T cell activation, its timing preceded that of a decrease in nucleosome occupancy at the promoter. In this article, we show that the initial nucleosome rearrangement was temporally correlated with the binding of NFAT1 and AP-1 (Fos/Jun), whereas the second step occurred in parallel with the recruitment of other transcription factors and RNA polymerase II. Pharmacologic inhibitors for activation of NFAT1 or induction of Fos blocked the initial phase in the sequential changes. This step was not affected, however, by inhibition of c-Jun phosphorylation, which instead blocked the binding of the late transcription factors, the recruitment of CREB-binding protein, and the acetylation of histone H3 at lysine 27. Thus, the sequential recruitment of transcription factors appears to facilitate two separate steps in chromatin remodeling at the Il2 locus. The Journal of Immunology, 2011, 187: 3292-3299. C1 [Ishihara, Satoru] Fujita Hlth Univ, Sch Med, Dept Biochem, Aichi 4701192, Japan. [Ishihara, Satoru; Schwartz, Ronald H.] NIAID, Lab Cellular & Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Ishihara, S (reprint author), Fujita Hlth Univ, Sch Med, Dept Biochem, 1-98 Kutsukake Cho, Aichi 4701192, Japan. EM satorui@fujita-hu.ac.jp FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 52 TC 8 Z9 8 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 SEP 15 PY 2011 VL 187 IS 6 BP 3292 EP 3299 DI 10.4049/jimmunol.1003173 PG 8 WC Immunology SC Immunology GA 822HI UT WOS:000295034200048 PM 21832163 ER PT J AU Lu, MF Munford, RS AF Lu, Mingfang Munford, Robert S. TI The Transport and Inactivation Kinetics of Bacterial Lipopolysaccharide Influence Its Immunological Potency In Vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SUBCAPSULAR SINUS MACROPHAGES; DENDRITIC CELLS; ACYLOXYACYL HYDROLASE; LYMPH-NODES; B-CELLS; ENDOTOXIN; DEACYLATION; LPS; ACTIVATION; TOLERANCE AB The extraordinary potency and pathological relevance of Gram-negative bacterial LPSs have made them very popular experimental agonists, yet little is known about what happens to these stimulatory molecules within animal tissues. We tracked fluorescent and radiolabeled LPS from a s.c. inoculation site to its draining lymph nodes (DLN), blood, and liver. Although we found FITC-labeled LPS in DLN within minutes of injection, drainage of radiolabeled LPS continued for >6 wk. Within the DLN, most of the LPS was found in the subcapsular sinus or medulla, near or within lymphatic endothelial cells and CD169(+) macrophages. Whereas most of the LPS seemed to pass through the DLN without entering B cell follicles, by 24 h after injection a small amount of LPS was found in the paracortex. In wild-type mice, >= 70% of the injected radiolabeled LPS underwent inactivation by deacylation before it left the footpad; in animals that lacked acyloxyacyl hydrolase, the LPS-deacylating enzyme, prolonged drainage of fully acylated (active) LPS boosted polyclonal IgM and IgG3 Ab titers. LPS egress from a s.c. injection site thus occurred during many weeks and was mainly via lymphatic channels. Its immunological potency, as measured by its ability to stimulate polyclonal Ab production, was greatly influenced by the kinetics of both lymphatic drainage and enzymatic inactivation. The Journal of Immunology, 2011, 187: 3314-3320. C1 [Lu, Mingfang; Munford, Robert S.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Lu, MF (reprint author), NIAID, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lum3@niaid.nih.gov FU National Institutes of Health [AI18188]; Jan and Henri Bromberg Chair in Internal Medicine, University of Texas Southwestern Medical School (Dallas, TX); Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by extramural National Institutes of Health Grant AI18188 to the University of Texas Southwestern Medical School (Dallas, TX), the Jan and Henri Bromberg Chair in Internal Medicine, University of Texas Southwestern Medical School (Dallas, TX), and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 32 TC 11 Z9 11 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 SEP 15 PY 2011 VL 187 IS 6 BP 3314 EP 3320 DI 10.4049/jimmunol.1004087 PG 7 WC Immunology SC Immunology GA 822HI UT WOS:000295034200050 PM 21849675 ER PT J AU Oh, HM Yu, CR Lee, Y Chan, CC Maminishkis, A Egwuagu, CE AF Oh, Hyun-Mee Yu, Cheng-Rong Lee, YongJun Chan, Chi-Chao Maminishkis, Arvydas Egwuagu, Charles E. TI Autoreactive Memory CD4(+) T Lymphocytes That Mediate Chronic Uveitis Reside in the Bone Marrow through STAT3-Dependent Mechanisms SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE UVEITIS; CD154 EXPRESSION; CELL MEMORY; HOMEOSTATIC PROLIFERATION; IMMUNOLOGICAL MEMORY; MULTIPLE-SCLEROSIS; DISEASE; ORGANIZATION; OSTEOPONTIN; SUPPRESSORS AB Organ-specific autoimmune diseases are usually characterized by repeated cycles of remission and recurrent inflammation. However, where the autoreactive memory T cells reside in between episodes of recurrent inflammation is largely unknown. In this study, we have established a mouse model of chronic uveitis characterized by progressive photoreceptor cell loss, retinal degeneration, focal retinitis, retinal vasculitis, multifocal choroiditis, and choroidal neovascularization, providing for the first time to our knowledge a useful model for studying long-term pathological consequences of chronic inflammation of the neuroretina. We show that several months after inception of acute uveitis, autoreactive memory T cells specific to retinal autoantigen, interphotoreceptor retinoid-binding protein (IRBP), relocated to bone marrow (BM). The IRBP-specific memory T cells (IL-7R alpha(High)Ly6C(High)CD4(+)) resided in BM in resting state but upon restimulation converted to IL-17/IFN-gamma-expressing effectors (IL-7R alpha(Low)Ly6C(Low)CD4(+)) that mediated uveitis. We further show that T cells from STAT3-deficient (CD4-STAT3KO) mice are defective in alpha 4 beta 1 and osteopontin expression, defects that correlated with inability of IRBP-specific memory CD4-STAT3KO T cells to traffic into BM. We adoptively transferred uveitis to naive mice using BM cells from wild-type mice with chronic uveitis but not BM cells from CD4-STAT3KO, providing direct evidence that memory T cells that mediate uveitis reside in BM and that STAT3-dependent mechanism may be required for migration into and retention of memory T cells in BM. Identifying BM as a survival niche for T cells that cause uveitis suggests that BM stromal cells that provide survival signals to autoreactive memory T cells and STAT3-dependent mechanisms that mediate their relocation into BM are attractive therapeutic targets that can be exploited to selectively deplete memory T cells that drive chronic inflammation. The Journal of Immunology, 2011, 187: 3338-3346. C1 [Oh, Hyun-Mee; Yu, Cheng-Rong; Lee, YongJun; Egwuagu, Charles E.] NEI, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. [Chan, Chi-Chao] NEI, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. [Maminishkis, Arvydas] NEI, Sect Epithelial & Retinal Physiol, NIH, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, NIH, Bldg 10,Room 10N116,10 Ctr Dr,MSC 1857, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov FU National Eye Institute; National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Eye Institute and the National Institutes of Health. NR 36 TC 22 Z9 22 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2011 VL 187 IS 6 BP 3338 EP 3346 DI 10.4049/jimmunol.1004019 PG 9 WC Immunology SC Immunology GA 822HI UT WOS:000295034200053 PM 21832158 ER PT J AU De Rosa, SC Thomas, EP Bui, J Huang, YD Decamp, A Morgan, C Kalams, SA Tomaras, GD Akondy, R Ahmed, R Lau, CY Graham, BS Nabel, GJ McElrath, MJ AF De Rosa, Stephen C. Thomas, Evan P. Bui, John Huang, Yunda deCamp, Allan Morgan, Cecilia Kalams, Spyros A. Tomaras, Georgia D. Akondy, Rama Ahmed, Rafi Lau, Chuen-Yen Graham, Barney S. Nabel, Gary J. McElrath, M. Juliana CA Natl Inst Allergy Infect Dis HIV TI HIV-DNA Priming Alters T Cell Responses to HIV-Adenovirus Vaccine Even When Responses to DNA Are Undetectable SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CANDIDATE VACCINE; IMMUNOGENICITY EVALUATION; PHASE-1 SAFETY; REPLICATION; IMMUNITY; TRIALS; EXPRESSION; ANTIBODIES; EFFECTOR; SUBSETS AB Many candidate HIV vaccines are designed to primarily elicit T cell responses. Although repeated immunization with the same vaccine boosts Ab responses, the benefit for T cell responses is ill defined. We compared two immunization regimens that include the same recombinant adenoviral serotype 5 (rAd5) boost. Repeated homologous rAd5 immunization fails to increase T cell responses, but increases gp140 Ab responses 10-fold. DNA prime, as compared with rAd5 prime, directs long-term memory CD8(+) T cells toward a terminally differentiated effector memory phenotype with cytotoxic potential. Based on the kinetics of activated cells measured directly ex vivo, the DNA vaccination primes for both CD4(+) and CD8(+) T cells, despite the lack of detection of the latter until after the boost. These results suggest that heterologous prime-boost combinations have distinct immunological advantages over homologous prime-boosts and suggest that the effect of DNA on subsequent boosting may not be easily detectable directly after the DNA vaccination. The Journal of Immunology, 2011, 187: 3391-3401. C1 [De Rosa, Stephen C.; Thomas, Evan P.; Bui, John; Huang, Yunda; deCamp, Allan; Morgan, Cecilia; McElrath, M. Juliana] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. [De Rosa, Stephen C.; McElrath, M. Juliana] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [De Rosa, Stephen C.; Thomas, Evan P.; Huang, Yunda; Morgan, Cecilia; McElrath, M. Juliana] HIV Vaccine Trials Network, Seattle, WA 98109 USA. [Kalams, Spyros A.] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA. [Tomaras, Georgia D.] Duke Univ, Human Vaccine Inst, Durham, NC 27710 USA. [Akondy, Rama; Ahmed, Rafi] Emory Univ, Emory Vaccine Inst, Atlanta, GA 30329 USA. [Lau, Chuen-Yen] NIH, Div Aids, Bethesda, MD 20892 USA. [Graham, Barney S.; Nabel, Gary J.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [McElrath, M. Juliana] Univ Washington, Dept Med, Seattle, WA 98195 USA. RP De Rosa, SC (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1100 Fairview Ave N,LE-200, Seattle, WA 98109 USA. EM sderosa@fhcrc.org RI Tomaras, Georgia/J-5041-2016; OI Akondy, Rama/0000-0003-4737-5240 FU HIV Vaccine Trials Network and Statistical Center for HIV/AIDS Research Prevention; National Institutes of Health Division of AIDS (National Institute of Allergy and Infectious Diseases) [U01 AI068614, U01 AI068618, U01 AI068635]; University of Washington Center for AIDS Research; National Institutes of Health [P30 AI027757] FX This work was supported by the HIV Vaccine Trials Network and Statistical Center for HIV/AIDS Research & Prevention, a cooperative agreement with the National Institutes of Health Division of AIDS (National Institute of Allergy and Infectious Diseases) (U01 AI068614, U01 AI068618, and U01 AI068635). This work is also supported through the University of Washington Center for AIDS Research, a National Institutes of Health-funded program (P30 AI027757). NR 37 TC 36 Z9 36 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 SEP 15 PY 2011 VL 187 IS 6 BP 3391 EP 3401 DI 10.4049/jimmunol.1101421 PG 11 WC Immunology SC Immunology GA 822HI UT WOS:000295034200059 PM 21844392 ER PT J AU Sun, Y Kojima, C Chignell, C Mason, R Waalkes, MP AF Sun, Yang Kojima, Chikara Chignell, Colin Mason, Ronald Waalkes, Michael P. TI Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Ultraviolet; Arsenic; Skin cancer; Apoptosis; Oxidative DNA damage; Keratinocytes ID INDUCED MALIGNANT-TRANSFORMATION; HUMAN HACAT KERATINOCYTES; OXIDATIVE STRESS; GENE-EXPRESSION; ANIMAL-MODEL; MOUSE SKIN; ULTRAVIOLET-RADIATION; CHRONIC STIMULATION; MAMMALIAN-CELLS; GROWTH-FACTORS AB Inorganic arsenic and UV, both human skin carcinogens, may act together as skin co-carcinogens. We find human skin keratinocytes (HaCaT cells) are malignantly transformed by low-level arsenite (100 nM, 30 weeks; termed As-TM cells) and with transformation concurrently undergo full adaptation to arsenic toxicity involving reduced apoptosis and oxidative stress response to high arsenite concentrations. Oxidative DNA damage (ODD) is a possible mechanism in arsenic carcinogenesis and a hallmark of UV-induced skin cancer. In the current work, inorganic arsenite exposure (100 nM) did not induce ODD during the 30 weeks required for malignant transformation. Although acute UV-treatment (UVA, 25 J/cm(2)) increased ODD in passage-matched control cells, once transformed by arsenic to As-TM cells, acute UV actually further increased ODD (>50%). Despite enhanced ODD. As-TM cells were resistant to UV-induced apoptosis. The response of apoptotic factors and oxidative stress genes was strongly mitigated in As-TM cells after UV exposure including increased Bcl2/Bax ratio and reduced Caspase-3, Nrf2, and Keap1 expression. Several Nrf2-related genes (HO-1, Gas, SOD) showed diminished responses in As-TM cells after UV exposure consistent with reduced oxidant stress response. UV-exposed As-TM cells showed increased expression of cyclin D1 (proliferation gene) and decreased p16 (tumor suppressor). UV exposure enhanced the malignant phenotype of As-TM cells. Thus, the co-carcinogenicity between UV and arsenic in skin cancer might involve adaptation to chronic arsenic exposure generally mitigating the oxidative stress response, allowing apoptotic by-pass after UV and enhanced cell survival even in the face of increased UV-induced oxidative stress and increased ODD. Published by Elsevier Inc. C1 [Waalkes, Michael P.] NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI,NTP Labs, Res Triangle Pk, NC 27709 USA. [Sun, Yang; Kojima, Chikara; Waalkes, Michael P.] NIH, Natl Toxicol Labs, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Chignell, Colin; Mason, Ronald] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI,NTP Labs, POB 12233,Mail Drop F0-09,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS); NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS) and by the Intramural Research program of the NIH, National Cancer Institute, Center for Cancer Research. This article may be the work product of an employee or group of employees of the NIEHS, National Institutes of Health (NIH), however, the statements contained herein do not necessarily represent the statements, opinions or conclusions of the NIEHS, NIH of the United States Government. The content of this publication does not necessarily reflect the views or the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 50 TC 12 Z9 12 U1 0 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 15 PY 2011 VL 255 IS 3 BP 242 EP 250 DI 10.1016/j.taap.2011.07.006 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 822CK UT WOS:000295021100002 PM 21820459 ER PT J AU Jegalian, AG Eberle, FC Pack, SD Mirvis, M Raffeld, M Pittaluga, S Jaffe, ES AF Jegalian, Armin G. Eberle, Franziska C. Pack, Svetlana D. Mirvis, Mariya Raffeld, Mark Pittaluga, Stefania Jaffe, Elaine S. TI Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; LASER-CAPTURE-MICRODISSECTION; COMPOSITE MANTLE CELL; B-CELLS; BCL-2/IGH REARRANGEMENT; T(14/18) TRANSLOCATION; HEALTHY-INDIVIDUALS; PERIPHERAL-BLOOD; GERMINAL-CENTERS; FREQUENCY AB Follicular lymphoma in situ (FLIS) was first described nearly a decade ago, but its clinical significance remains uncertain. We reevaluated our original series and more recently diagnosed cases to develop criteria for the distinction of FLIS from partial involvement by follicular lymphoma (PFL). A total of 34 cases of FLIS were identified, most often as an incidental finding in a reactive lymph node. Six of 34 patients had prior or concurrent FL, and 5 of 34 had FLIS composite with another lymphoma. Of patients with negative staging at diagnosis and available follow-up (21 patients), only one (5%) developed FL (follow-up: median, 41 months; range, 10-118 months). Follow-up was not available in 2 cases. Fluorescence in situ hybridization for BCL2 gene rearrangement was positive in all 17 cases tested. PFL patients were more likely to develop FL, diagnosed in 9 of 17 (53%) who were untreated. Six patients with PFL were treated with local radiation therapy (4) or rituximab (2) and remained with no evidence of disease. FLIS can be reliably distinguished from PFL and has a very low rate of progression to clinically significant FL. FLIS may represent the tissue counterpart of circulating t(14;18)positive B cells. (Blood. 2011;118(11): 2976-2984) C1 [Jegalian, Armin G.; Eberle, Franziska C.; Pack, Svetlana D.; Mirvis, Mariya; Raffeld, Mark; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Pathol Lab, 10 Ctr Dr,MSC-1500,Bldg 10,Room 2B42, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov RI Pack, Svetlana/C-2020-2014; OI Jaffe, Elaine/0000-0003-4632-0301 FU Center for Cancer Research, National Cancer Institute FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute. NR 49 TC 52 Z9 56 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2011 VL 118 IS 11 BP 2976 EP 2984 DI 10.1182/blood-2011-05-355255 PG 9 WC Hematology SC Hematology GA 821DU UT WOS:000294955900013 PM 21768298 ER PT J AU Park, YP Choi, SC Kiesler, P Gil-Krzewska, A Borrego, F Weck, J Krzewski, K Coligan, JE AF Park, Yuk Pheel Choi, Seung-Chul Kiesler, Patricia Gil-Krzewska, Aleksandra Borrego, Francisco Weck, Jennifer Krzewski, Konrad Coligan, John E. TI Complex regulation of human NKG2D-DAP10 cell surface expression: opposing roles of the gamma(c) cytokines and TGF-beta 1 SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; CD8(+) T-CELLS; NK CELLS; IN-VIVO; CYTOMEGALOVIRUS-INFECTION; NKG2D RECEPTOR; CUTTING EDGE; TGF-BETA; INTERLEUKIN-2; CANCER AB Natural killer (NK) cells help protect the host against viral infections and tumors. NKG2D is a vital activating receptor, also expressed on subsets of T cells, whose ligands are up-regulated by cells in stress. Ligation of NKG2D leads to phosphorylation of the associated DAP10 adaptor protein, thereby activating immune cells. Understanding how the expression of NKG2D-DAP10 is regulated has implications for immunotherapy. We show that IL-2 and TGF-beta 1 oppositely regulate NKG2D-DAP10 expression by NK cells. IL-2 stimulation increases NKG2D surface expression despite a decrease in NKG2D mRNA levels. Stimulation with IL-2 results in a small increase of DAP10 mRNA and a large up-regulation of DAP10 protein synthesis, indicating that IL-2-mediated effects are mostly posttranscriptional. Newly synthesized DAP10 undergoes glycosylation that is required for DAP10 association with NKG2D and stabilization of NKG2D expression. TGF-beta 1 has an opposite and dominant effect to IL-2. TGF-beta 1 treatment decreases DAP10, as its presence inhibits the association of RNA polymerase II with the DAP10 promoter, but not NKG2D mRNA levels. This leads to the down-regulation of DAP10 expression and, as a consequence, NKG2D protein as well. Finally, we show that other gamma(c) cytokines act similarly to IL-2 in up-regulating DAP10 expression and NKG2D-DAP10 surface expression. (Blood. 2011; 118(11):3019-3027) C1 [Park, Yuk Pheel; Choi, Seung-Chul; Kiesler, Patricia; Gil-Krzewska, Aleksandra; Weck, Jennifer; Krzewski, Konrad; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD USA. [Borrego, Francisco] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, CDER, Silver Spring, MD USA. RP Coligan, JE (reprint author), 12441 Parklawn Dr,Twinbrook II,Rm 205, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov NR 50 TC 34 Z9 35 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2011 VL 118 IS 11 BP 3019 EP 3027 DI 10.1182/blood-2011-04-346825 PG 9 WC Hematology SC Hematology GA 821DU UT WOS:000294955900019 PM 21816829 ER PT J AU Zhang, JH Mullighan, CG Harvey, RC Wu, G Chen, X Edmonson, M Buetow, KH Carroll, WL Chen, IM Devidas, M Gerhard, DS Loh, ML Reaman, GH Relling, MV Camitta, BM Bowman, WP Smith, MA Willman, CL Downing, JR Hunger, SP AF Zhang, Jinghui Mullighan, Charles G. Harvey, Richard C. Wu, Gang Chen, Xiang Edmonson, Michael Buetow, Kenneth H. Carroll, William L. Chen, I-Ming Devidas, Meenakshi Gerhard, Daniela S. Loh, Mignon L. Reaman, Gregory H. Relling, Mary V. Camitta, Bruce M. Bowman, W. Paul Smith, Malcolm A. Willman, Cheryl L. Downing, James R. Hunger, Stephen P. TI Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group SO BLOOD LA English DT Article ID FLT3 MUTATIONS; GENETIC ALTERATIONS; B-PROGENITOR; RAS; THERAPY; RELAPSE; IKZF1; CRLF2; MLL; REARRANGEMENTS AB We sequenced 120 candidate genes in 187 high-risk childhood B-precursor acute lymphoblastic leukemias, the largest pediatric cancer genome sequencing effort reported to date. Integrated analysis of 179 validated somatic sequence mutations with genome-wide copy number alterations and gene expression profiles revealed a high frequency of recurrent somatic alterations in key signaling pathways, including B-cell development/differentiation (68% of cases), the TP53/RB tumor suppressor pathway (54%), Ras signaling (50%), and Janus kinases (11%). Recurrent mutations were also found in ETV6 (6 cases), TBL1XR1 (3), CREBBP (3), MUC4 (2), ASMTL (2), and ADARB2 (2). The frequency of mutations within the 4 major pathways varied markedly across genetic subtypes. Among 23 leukemias expressing a BCR-ABL1-like gene expression profile, 96% had somatic alterations in B-cell development/differentiation, 57% in JAK, and 52% in both pathways, whereas only 9% had Ras pathway mutations. In contrast, 21 cases defined by a distinct gene expression profile coupled with focal ERG deletion rarely had B-cell development/differentiation or JAK kinase alterations but had a high frequency (62%) of Ras signaling pathway mutations. These data extend the range of genes that are recurrently mutated in high-risk childhood B-precursor acute lymphoblastic leukemia and highlight important new therapeutic targets for selected patient subsets. (Blood. 2011; 118(11):3080-3087) C1 [Zhang, Jinghui; Mullighan, Charles G.; Wu, Gang; Chen, Xiang; Relling, Mary V.; Downing, James R.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Harvey, Richard C.; Chen, I-Ming; Willman, Cheryl L.] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. [Harvey, Richard C.; Chen, I-Ming; Willman, Cheryl L.] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Edmonson, Michael; Buetow, Kenneth H.] NCI, Ctr Biomed Informat & Informat Technol, NIH, Rockville, MD USA. [Carroll, William L.] NYU, Inst Canc, New York, NY USA. [Devidas, Meenakshi] Univ Florida, Coll Med, Dept Biostat, Gainesville, FL USA. [Gerhard, Daniela S.] NCI, Off Canc Genom, NIH, Bethesda, MD 20892 USA. [Loh, Mignon L.] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA. [Reaman, Gregory H.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Camitta, Bruce M.] Med Coll Wisconsin, Dept Pediat, Midwest Childrens Canc Ctr, Milwaukee, WI 53226 USA. [Camitta, Bruce M.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Bowman, W. Paul] Cook Childrens Hosp, Ft Worth, TX USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Hunger, Stephen P.] Univ Colorado, Sch Med, Aurora, CO USA. [Hunger, Stephen P.] Childrens Hosp Colorado, Ctr Canc & Blood Disorders, Aurora, CO 80045 USA. RP Downing, JR (reprint author), St Jude Childrens Hosp, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM cwillman@salud.unm.edu; james.downing@stjude.org; stephen.hunger.@childrenscolorado.org OI Harvey, Richard/0000-0002-4904-9767; Mullighan, Charles/0000-0002-1871-1850 FU Children's Oncology Group [CA098543]; National Cancer Institute [CA114762, U10 CA98413, U24 CA114766]; National Institutes of Health Cancer Center [CA21765, CA118100]; St Jude Children's Research Hospital; University of New Mexico Cancer Center; Leukemia & Lymphoma Society Specialized Center of Research [7388-06]; CureSearch; St Baldrick's Foundation; National Health and Medical Research Council (Australia); American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital; National Cancer Institute, National Institutes of Health [N01-C0-12400] FX This work was supported by the Children's Oncology Group (Chair's Award CA098543, G.H.R.; and a supplement to that grant to support the TARGET initiative); National Cancer Institute Strategic Partnering to Evaluate Cancer Signatures (Program Award CA114762, W.L.C., I.-M.C., R.C.H., and C.L.W.); National Institutes of Health Cancer Center (Support Grant CA21765, J.R.D. and C.G.M.; and Support Grant CA118100, R.C.H., I.-M.C., and C.L.W.), which also provided support for critical Shared Resources at St Jude Children's Research Hospital and University of New Mexico Cancer Center; National Cancer Institute (grant U10 CA98413, supporting the Statistical Center, G.H.R.; grant U24 CA114766, Human Specimen Banking in CNI Supported Cancer Trials); Leukemia & Lymphoma Society Specialized Center of Research (grant 7388-06, C.L.W.); CureSearch; St Baldrick's Foundation (M.L.L.); National Health and Medical Research Council (Australia; C.J. Martin Traveling Fellowship, C.G.M.); and the American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital. C.G.M. is a Pew Scholar in the Biomedical Sciences. S. P. H. is the Ergen Family Chair in Pediatric Cancer. The sequencing was funded with federal funds from the National Cancer Institute, National Institutes of Health (contract N01-C0-12400). NR 49 TC 119 Z9 123 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2011 VL 118 IS 11 BP 3080 EP 3087 DI 10.1182/blood-2011-03-341412 PG 8 WC Hematology SC Hematology GA 821DU UT WOS:000294955900025 PM 21680795 ER PT J AU Luchenko, VL Salcido, CD Zhang, YW Agama, K Komlodi-Pasztor, E Murphy, RF Giaccone, G Pommier, Y Bates, SE Varticovski, L AF Luchenko, Victoria L. Salcido, Crystal D. Zhang, Yongwei Agama, Keli Komlodi-Pasztor, Edina Murphy, Robert F. Giaccone, Giuseppe Pommier, Yves Bates, Susan E. Varticovski, Lyuba TI Schedule-dependent synergy of histone deacetylase inhibitors with DNA damaging agents in small cell lung cancer SO CELL CYCLE LA English DT Article DE combination index; drug interaction; gamma H2AX phosphorylation; dsDNA break; synergy; PARP degradation ID INDUCED APOPTOSIS; CARCINOMA-CELLS; TOPOISOMERASE-II; SODIUM-BUTYRATE; TARGETING DNA; CYCLE ARREST; LINES; RADIATION; CYTOTOXICITY; GAMMA-H2AX AB Small cell lung cancer (SCLC) is an aggressive lung cancer subtype in need of better therapies. Histone deacetylase inhibitors (HDIs) promote increased lysine acetylation in nucleosomal histones, and are thought to relax chromatin, thereby allowing increased access of transcription factors and DNA damaging agents alike to DNA. We studied whether two HDIs, belinostat and romidepsin, can be effectively combined with cisplatin or etoposide (VP-16) for SCLC cells. Analysis of cell survival and synergy was performed using CalcuSyn mathematical modeling to calculate a combination index. Immunostaining of gamma H2AX was performed to evaluate persistence of DNA damage following simultaneous or sequential exposure. Based on CalcuSyn modeling, HDIs synergized with DNA damaging agents only when added simultaneously. An additive-to-antagonistic effect was seen with HDI pretreatment for 24 h or with addition after cisplatin or etoposide. Furthermore, pretreatment with HDIs resulted in normalization of cell cycle and reduced PARP degradation as compared with simultaneous treatment. The increase in gamma H2AX phosphorylation confirmed that simultaneous, but not sequential treatment enhanced double-stranded DNA breaks. These results suggest that DNA relaxation is not required for synergy of HDIs with DNA damaging agents and that scheduling of drug administration will be critical for rational development of clinical protocols. C1 [Salcido, Crystal D.; Varticovski, Lyuba] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Luchenko, Victoria L.; Komlodi-Pasztor, Edina; Giaccone, Giuseppe; Bates, Susan E.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Zhang, Yongwei; Agama, Keli; Pommier, Yves] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Murphy, Robert F.] NCI, Pediat Branch, NIH, Bethesda, MD 20892 USA. RP Varticovski, L (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM varticol@mail.nih.gov RI ZHANG, YONGWEI/E-6252-2012 FU National Cancer Institute, NIH FX The authors wish to thank William Telford and Robert Robey for assistance with FACS analysis, Lois Bangiolo for assistance with immunoblot analysis, and Mollie Wright for advice on drug interaction studies. This work was supported by the Intramural Research Program at the National Cancer Institute, NIH. NR 48 TC 3 Z9 3 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 15 PY 2011 VL 10 IS 18 PG 10 WC Cell Biology SC Cell Biology GA 821DG UT WOS:000294954400025 PM 21900747 ER PT J AU Blake-Haskins, JA Lechleider, RJ Kreitman, RJ AF Blake-Haskins, John A. Lechleider, Robert J. Kreitman, Robert J. TI Thrombotic Microangiopathy with Targeted Cancer Agents SO CLINICAL CANCER RESEARCH LA English DT Review ID HEMOLYTIC-UREMIC SYNDROME; VON-WILLEBRAND-FACTOR; RENAL-CELL CARCINOMA; PHASE-I TRIAL; IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; ANTI-VEGF THERAPY; THROMBOCYTOPENIC PURPURA; MALIGNANCIES; SUNITINIB; LEUKEMIA AB Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are clinically similar disorders characterized by microvascular thrombosis, hemolysis, thrombocytopenia, and end-organ damage. Although they may present with overlapping symptoms, multiple etiologies have been proposed for these thrombotic microangiopathies (TMA). Chemotherapy-induced TMA, which has been described with the use of mitomycin, gemcitabine, and other drugs, has a poor prognosis. Recently, reports of TMA associated with targeted cancer agents have surfaced in the literature. We discuss the clinical presentation, outcome, and etiology of TMA reported with the use of immunotoxins, monoclonal antibodies, and tyrosine kinase inhibitors. A search of PubMed and meeting abstracts was conducted for cases of TMA with the use of targeted cancer agents. The defining symptoms, laboratory values, time to onset, and patient outcomes were compiled. Consistent definitions of TMA and grading of severity in these cases are lacking. However, presentation of TMA in these cases revealed the importance of monitoring for renal toxicity, hemolysis, and thrombocytopenia. Patient outcomes seem to differ from those seen in cases of chemotherapy-induced TMA and may reflect a different underlying etiology. Little is known about the pathogenesis of TMA with targeted cancer agents. In contrast to chemotherapy-induced TMA, partial to full reversibility may be a common outcome. However, further research is warranted into optimal management of patients diagnosed with TMA following treatment with targeted agents. Clin Cancer Res; 17(18); 5858-66. (C) 2011 AACR. C1 [Kreitman, Robert J.] NCI, Clin Immunotherapy Sect, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Blake-Haskins, John A.; Lechleider, Robert J.] MedImmune LLC, Gaithersburg, MD USA. [Blake-Haskins, John A.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. RP Kreitman, RJ (reprint author), NCI, Clin Immunotherapy Sect, Mol Biol Lab, NIH, Bldg 37,Room 5124B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU MedImmune, LLC. FX J.A. Blake-Haskins: postdoctoral fellow sponsored by MedImmune, LLC. R. Lechleider: employee, MedImmune, LLC. However, the majority of the agents reviewed have no relation to MedImmune. R.J. Kreitman is a coinventor on the government-owned patent for anti-CD22 recombinant immunotoxins, although these agents constitute a minority of those reviewed. NR 51 TC 28 Z9 30 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2011 VL 17 IS 18 BP 5858 EP 5866 DI 10.1158/1078-0432.CCR-11-0804 PG 9 WC Oncology SC Oncology GA 821CM UT WOS:000294952400004 PM 21813634 ER PT J AU Du, X Xiang, LM Mackall, C Pastan, I AF Du, Xing Xiang, Laiman Mackall, Crystal Pastan, Ira TI Killing of Resistant Cancer Cells with Low Bak by a Combination of an Antimesothelin Immunotoxin and a TRAIL Receptor 2 Agonist Antibody SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-NECROSIS-FACTOR; PHASE-I TRIAL; MEDIATED APOPTOSIS; MESOTHELIN IMMUNOTOXIN; RFB4(DSFV)-PE38 BL22; MONOCLONAL-ANTIBODY; PANCREATIC CANCERS; DOWN-REGULATION; LIGAND TRAIL; SOLID TUMORS AB Purpose: Many solid tumors express cell surface mesothelin making them attractive targets for antibody-based therapies of cancer. SS1P [antimesothelin(Fv)PE38] is a recombinant immunotoxin (RIT) that has potent cytotoxic activity on several cancer cell lines and clinical activity in mesothelioma patients. Pancreatic cancers express mesothelin and are known to be resistant to most chemotherapeutic agents. The goal of this study is to treat pancreatic cancer with RIT by targeting mesothelin. Experimental Design: We measured the cytotoxic activity of an antimesothelin immunotoxin on pancreatic cancer cells. We also measured the levels of several pro-and antiapoptotic proteins, as well as the ability of TNF-related apoptosis-inducing ligand (TRAIL) or the anti-TRAIL receptor 2 agonist antibody (HGS-ETR2) to kill pancreatic cells, and the cytotoxic activity of the two agents together in cell culture and against tumors in mice. Results: In two pancreatic cancer cell lines, immunotoxin treatment inhibited protein synthesis but did not produce significant cell death. The resistant lines had low levels of the proapoptotic protein Bak. Increasing Bak expression enhanced the sensitivity to immunotoxins, whereas Bak knockdown diminished it. We also found that combining immunotoxin with TRAIL or HGS-ETR2 caused synergistic cell death, and together triggered caspase-8 recruitment and activation, Bid cleavage and Bax activation. Combining SS1P with HGS-ETR2 also acted synergistically to decrease tumor burden in a mouse model. Conclusion: Our data show that low Bak can cause cancer cells to be resistant to immunotoxin treatment and that combining immunotoxin with TRAIL or a TRAIL agonist antibody can overcome resistance. Clin Cancer Res; 17(18); 5926-34. (C) 2011 AACR. C1 [Du, Xing; Xiang, Laiman; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Mackall, Crystal] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU NIH, National Cancer Institute; Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, and Center for Cancer Research. NR 40 TC 20 Z9 21 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2011 VL 17 IS 18 BP 5926 EP 5934 DI 10.1158/1078-0432.CCR-11-1235 PG 9 WC Oncology SC Oncology GA 821CM UT WOS:000294952400010 PM 21813632 ER PT J AU Kim, A Dombi, E Solomon, J Fox, E Balis, FM Widemann, BC AF Kim, AeRang Dombi, Eva Solomon, Jeffrey Fox, Elizabeth Balis, Frank M. Widemann, Brigitte C. TI Automated Volumetric Growth Plate Measurement Using Magnetic Resonance Imaging for Monitoring Skeletal Toxicity in Children Treated on Investigational Drug Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID TYROSINE KINASE INHIBITOR; REFRACTORY SOLID TUMORS; PHASE-I; PLEXIFORM NEUROFIBROMAS; PEDIATRIC-PATIENTS; BONE; BEVACIZUMAB; ANGIOGENESIS; VIVO AB Purpose: Targeted anticancer agents have been reported to have side effects on the skeletal system such as thickening of the epiphyseal growth plate in preclinical models of juvenile, but not mature, animals. Careful evaluation of skeletal toxicity in the clinical development of targeted therapies for children is required. We validated a novel method to measure the growth plate volume using MRI. Experimental Design: A semiautomated method of volumetric growth plate measurement was developed on the basis of the differences of pixel intensity of the growth plate from surrounding bone on T(1) sagittal MRI. Two observers measured the femoral growth plate volume and thickness on three different days using 20 pediatric knee MRIs obtained at the NIH. Five subjects had two knee MRIs obtained on the same day to evaluate intrasubject reproducibility. Results: Volumetric analysis showed low intraobserver variability, with the coefficient of variation for the two observers ranging from 0.2% to 6.1%. Interobserver correlation was 0.99, and good concordance was shown with a mean volume difference of -1.8mm 3. One-dimensional measurements had poorer intra and interobserver consistency. No statistically significant differences in volumetric measurements were observed between the two scans done on the same day in five subjects (P = 0.5). Conclusions: MRI volumetric growth plate measurement is a reproducible and sensitive method to evaluate meaningful growth plate volume changes over time. This tool, along with close monitoring of height and laboratory evaluations for bone metabolism, may be used to evaluate potential bone and growth toxicities of children enrolled in trials of investigational drugs. Clin Cancer Res; 17(18); 5982-90. (C) 2011 AACR. C1 [Kim, AeRang] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Solomon, Jeffrey] Med Numer Inc, Germantown, MD USA. [Kim, AeRang; Dombi, Eva; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Fox, Elizabeth; Balis, Frank M.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Kim, A (reprint author), Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, 111 Michigan Ave NW, Washington, DC 20010 USA. EM aekim@cnmc.org FU NIH, National Cancer Institute, Center for Cancer Research FX This study was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 22 TC 6 Z9 6 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 SEP 15 PY 2011 VL 17 IS 18 BP 5982 EP 5990 DI 10.1158/1078-0432.CCR-10-2259 PG 9 WC Oncology SC Oncology GA 821CM UT WOS:000294952400016 PM 21807634 ER PT J AU Naing, A Kurzrock, R Burger, A Gupta, S Lei, XD Busaidy, N Hong, D Chen, HX Doyle, LA Heilbrun, LK Rohren, E Ng, C Chandhasin, C LoRusso, P AF Naing, Aung Kurzrock, Razelle Burger, Angelika Gupta, Sachin Lei, Xiudong Busaidy, Naifa Hong, David Chen, Helen X. Doyle, Lawrence A. Heilbrun, Lance K. Rohren, Eric Ng, Chaan Chandhasin, Chandtip LoRusso, Patricia TI Phase I Trial of Cixutumumab Combined with Temsirolimus in Patients with Advanced Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID MAMMALIAN TARGET; MTOR INHIBITION; SOLID TUMORS; AKT; RAPAMYCIN; KINASE; PATHWAY AB Purpose: Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor (IGF-1R)-dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully human immunoglobulin G1 monoclonal antibody directed against IGF-1R, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. The objectives of this phase I study were to evaluate the tolerability and activity of temsirolimus and cixutumumab. Experimental Design: Patients in sequential cohorts ("3 + 3" design) received escalating doses of temsirolimus with cixutumumab weekly for 28 days. At the maximum tolerated dose (MTD), 21 patients were randomized into three separate drug sequence treatment groups for serial blood draws and 2[18F]fluoro-2-deoxy-D-glucose positron emission tomography combined with X-ray computed tomography (FDG-PET/CT) scans for pharmacodynamic analyses (PD). Results: Forty-two patients with advanced cancer (19 male/23 female, median age 53, median number of prior therapies 4) were enrolled. MTD was reached at cixutumumab, 6 mg/kg IV and temsirolimus, 25 mg IV. Dose-limiting toxicities included grade 3 mucositis, febrile neutropenia, and grade 4 thrombocytopenia. The most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, thrombocytopenia, and mucositis. Tumor reduction was observed in 2 of 3 patients with Ewing's sarcoma and in 4 of 10 patients with adrenocortical carcinoma. PD data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGF binding protein 3. FDG-PET/CT showed the odds of achieving stable disease decreased by 58% (P = 0.1213) with a one-unit increase in absolute change of standard uptake value from baseline to day 3. Conclusions: Temsirolimus combined with cixutumumab was well tolerated. We are currently enrolling expansion cohorts at the MTD for Ewing's sarcoma and adrenocortical carcinoma. Clin Cancer Res; 17(18); 6052-60. (C) 2011 AACR. C1 [Naing, Aung; Kurzrock, Razelle; Hong, David; Chandhasin, Chandtip] Univ Texas MD Anderson Canc Ctr, Phase Clin Trials Program 1, Dept Invest Canc Therapeut, Houston, TX 77030 USA. [Lei, Xiudong] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Busaidy, Naifa] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormone Disorders, Houston, TX 77030 USA. [Rohren, Eric] Univ Texas MD Anderson Canc Ctr, Dept Nucl Med, Houston, TX 77030 USA. [Ng, Chaan] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX 77030 USA. [Chen, Helen X.; Doyle, Lawrence A.] NCI, Canc Therapy Evaluat Program, NIH, Rockville, MD USA. [Burger, Angelika; Gupta, Sachin; Heilbrun, Lance K.; LoRusso, Patricia] Wayne State Univ, Barbara Ann Karmanos Canc Inst, Detroit, MI USA. RP Naing, A (reprint author), Univ Texas MD Anderson Canc Ctr, Phase Clin Trials Program 1, Dept Invest Canc Therapeut, 1515 Holcombe Blvd,Box 455, Houston, TX 77030 USA. EM anaing@mdanderson.org FU [R21CA13763301A1]; [U01CA62461]; [U01CA62487] FX This study was supported by R21CA13763301A1 (A. Naing), U01CA62461 (R. Kurzrock), and U01CA62487 (P. LoRusso). NR 15 TC 58 Z9 62 U1 0 U2 14 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 SEP 15 PY 2011 VL 17 IS 18 BP 6052 EP 6060 DI 10.1158/1078-0432.CCR-10-2979 PG 9 WC Oncology SC Oncology GA 821CM UT WOS:000294952400023 PM 21750201 ER PT J AU Howard, G McClure, LA Moy, CS Safford, MM Cushman, M Judd, SE Kissela, BM Kleindorfer, DO Howard, VJ Rhodes, DJ Muntner, P Tiwari, HK AF Howard, George McClure, Leslie A. Moy, Claudia S. Safford, Monika M. Cushman, Mary Judd, Suzanne E. Kissela, Brett M. Kleindorfer, Dawn O. Howard, Virginia J. Rhodes, David J. Muntner, Paul Tiwari, Hemant K. TI Imputation of Incident Events in Longitudinal Cohort Studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; imputation; longitudinal studies; missing data ID BLOOD-PRESSURE; STROKE INCIDENCE; RISK PROFILE; FRAMINGHAM; COMMUNITIES AB Longitudinal cohort studies normally identify and adjudicate incident events detected during follow-up by retrieving medical records. There are several reasons why the adjudication process may not be successfully completed for a suspected event including the inability to retrieve medical records from hospitals and an insufficient time between the suspected event and data analysis. These "incomplete adjudications" are normally assumed not to be events, an approach which may be associated with loss of precision and introduction of bias. In this article, the authors evaluate the use of multiple imputation methods designed to include incomplete adjudications in analysis. Using data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, 2008-2009, they demonstrate that this approach may increase precision and reduce bias in estimates of the relations between risk factors and incident events. C1 [Howard, George; McClure, Leslie A.; Judd, Suzanne E.; Rhodes, David J.; Tiwari, Hemant K.] Univ Alabama, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Moy, Claudia S.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Safford, Monika M.] Univ Alabama, Sch Med, Dept Med, Birmingham, AL 35294 USA. [Cushman, Mary] Univ Vermont, Sch Med, Dept Med, Burlington, VT 05405 USA. [Kissela, Brett M.; Kleindorfer, Dawn O.] Univ Cincinnati, Sch Med, Dept Neurol, Cincinnati, OH USA. [Howard, Virginia J.; Muntner, Paul] Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. RP Howard, G (reprint author), Univ Alabama, Sch Publ Hlth, Dept Biostat, Ryals Bldg,Room 327D,1665 Univ Blvd, Birmingham, AL 35294 USA. EM ghoward@uab.edu RI McClure, Leslie/P-2929-2015; OI Kissela, Brett/0000-0002-9773-4013 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health, US Department of Health and Human Services [U01 NS041588] FX This work was supported by cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, US Department of Health and Human Services. NR 14 TC 16 Z9 16 U1 0 U2 3 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 SEP 15 PY 2011 VL 174 IS 6 BP 718 EP 726 DI 10.1093/aje/kwr155 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 818ER UT WOS:000294734600010 PM 21804050 ER PT J AU Abraham, AG Lau, B Deeks, S Moore, RD Zhang, JB Eron, J Harrigan, R Gill, MJ Kitahata, M Klein, M Napravnik, S Rachlis, A Rodriguez, B Rourke, S Benson, C Bosch, R Collier, A Gebo, K Goedert, J Hogg, R Horberg, M Jacobson, L Justice, A Kirk, G Martin, J McKaig, R Silverberg, M Sterling, T Thorne, J Willig, J Gange, SJ AF Abraham, Alison G. Lau, Bryan Deeks, Steven Moore, Richard D. Zhang, Jinbing Eron, Joseph Harrigan, Richard Gill, M. John Kitahata, Mari Klein, Marina Napravnik, Sonia Rachlis, Anita Rodriguez, Benigno Rourke, Sean Benson, Constance Bosch, Ron Collier, Ann Gebo, Kelly Goedert, James Hogg, Robert Horberg, Michael Jacobson, Lisa Justice, Amy Kirk, Greg Martin, Jeff McKaig, Rosemary Silverberg, Michael Sterling, Timothy Thorne, Jennifer Willig, James Gange, Stephen J. CA N Amer AIDS Cohort Collaboration TI Missing Data on the Estimation of the Prevalence of Accumulated Human Immunodeficiency Virus Drug Resistance in Patients Treated With Antiretroviral Drugs in North America SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE antiretroviral therapy; highly active; drug resistance; genotype; HIV ID DISEASE PROGRESSION; VIROLOGICAL FAILURE; REVERSE-TRANSCRIPTASE; HIV-1 INFECTION; THERAPY; RISK; PROTEASE; COHORT; TIME; PREDICTORS AB Determination of the prevalence of accumulated antiretroviral drug resistance among persons infected with human immunodeficiency virus (HIV) is complicated by the lack of routine measurement in clinical care. By using data from 8 clinic-based cohorts from the North American AIDS Cohort Collaboration on Research and Design, drug-resistance mutations from those with genotype tests were determined and scored using the Genotypic Resistance Interpretation Algorithm developed at Stanford University. For each year from 2000 through 2005, the prevalence was calculated using data from the tested subset, assumptions that incorporated clinical knowledge, and multiple imputation methods to yield a complete data set. A total of 9,289 patients contributed data to the analysis; 3,959 had at least 1 viral load above 1,000 copies/mL, of whom 2,962 (75%) had undergone at least 1 genotype test. Using these methods, the authors estimated that the prevalence of accumulated resistance to 2 or more antiretroviral drug classes had increased from 14% in 2000 to 17% in 2005 (P < 0.001). In contrast, the prevalence of resistance in the tested subset declined from 57% to 36% for 2 or more classes. The authors' use of clinical knowledge and multiple imputation methods revealed trends in HIV drug resistance among patients in care that were markedly different from those observed using only data from patients who had undergone genotype tests. C1 [Abraham, Alison G.; Lau, Bryan; Moore, Richard D.; Zhang, Jinbing; Gebo, Kelly; Jacobson, Lisa; Kirk, Greg; Thorne, Jennifer; Gange, Stephen J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Lau, Bryan] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Moore, Richard D.; Gebo, Kelly] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. [Thorne, Jennifer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Div Ocular Immunol, Baltimore, MD 21205 USA. [Deeks, Steven; Martin, Jeff] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Deeks, Steven; Martin, Jeff] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Eron, Joseph] Univ N Carolina, Div Infect Dis, Chapel Hill, NC USA. [Napravnik, Sonia] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Harrigan, Richard] BC Ctr Excellence HIV AIDS, Drug Treatment Program, Lab Program, Vancouver, BC, Canada. [Hogg, Robert] BC Ctr Excellence HIV AIDS, Epidemiol & Populat Hlth Program, Vancouver, BC, Canada. [Gill, M. John] Univ Calgary, Dept Med, Calgary, AB, Canada. [Gill, M. John] Univ Calgary, Dept Microbiol, Calgary, AB, Canada. [Gill, M. John] Univ Calgary, Dept Immunol & Infect Dis, Calgary, AB, Canada. [Gill, M. John] Univ Calgary, Dept Pathol, Calgary, AB, Canada. [Gill, M. John] Univ Calgary, Dept Lab Med, Calgary, AB, Canada. [Kitahata, Mari; Collier, Ann] Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA USA. [Klein, Marina] McGill Univ, Dept Med, Div Infect Dis, Montreal, PQ, Canada. [Klein, Marina] McGill Univ, Immunodeficiency Serv, Montreal, PQ, Canada. [Rachlis, Anita] Univ Toronto, Dept Med, Div Infect Dis, Toronto, ON, Canada. [Rourke, Sean] Univ Toronto, Dept Psychiat, Ontario HIV Treatment Network, Toronto, ON, Canada. [Rodriguez, Benigno] Case Western Reserve Univ, Div Infect Dis, Cleveland, OH 44106 USA. [Benson, Constance] Univ Calif San Diego, Sch Med, Div Infect Dis, San Diego, CA 92103 USA. [Bosch, Ron] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Goedert, James] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, NIH, Bethesda, MD 20892 USA. [McKaig, Rosemary] NIAID, Epidemiol Branch, Off Clin Res Operat, NIH, Bethesda, MD 20892 USA. [Horberg, Michael; Silverberg, Michael] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Justice, Amy] VA Connecticut Healthcare Syst, Dept Internal Med, New Haven, CT USA. [Justice, Amy] Yale Univ, Sch Med, New Haven, CT USA. [Sterling, Timothy] Vanderbilt Univ, Med Ctr, Dept Med, Div Infect Dis, Nashville, TN USA. [Willig, James] Univ Alabama Birmingham, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. RP Abraham, AG (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,Suite E7640, Baltimore, MD 21205 USA. EM aabraham@jhsph.edu RI Hogg, Robert/B-2783-2012; Rodriguez, Benigno/C-3365-2009; Gill, John/G-7083-2016; OI Rodriguez, Benigno/0000-0001-9736-7957; Gill, John/0000-0002-8546-8790; Gange, Stephen/0000-0001-7842-512X; Hogg, Robert/0000-0003-3463-5488 FU National Institutes of Health; Centers for Disease Control and Prevention [CDC200-2006-18797]; Canadian Institutes for Health Research [TGF-96118, HCP-97105, CBR-86906, CBR-94036, KRS-86251, 169621]; Canadian Trials Network [242] FX This work was supported by the National Institutes of Health (grants U01-AI069918, U01-AA013566, U01-AI31834, U01-AI34989, U01-AI34993, U01-AI34994, U01-AI35004, U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, U01-AI35043, U01-AI37613, U01-AI37984, U01-AI38855, U01-AI38858, U01-AI42590, U01-AI68634, U01-AI68636, U01-HD32632, U10-EY08057, U10-EY08052, U10- EY08067, UL1-RR024131, MO1-RR-00052, M01-RR00071, M01-RR00079, M01-RR00083, M01-RR00722, MM01- RR025747, P30-AI27757, P30-AI27767, P30-AI50410, P30-AI54999, R01-DA04334, R01-DA12568, R01-MH54907, R24-AI067039, Z01-CP010176, AHQ290-01-0012, N02-CP55504, R01-DA11602, AI-69432, AI-69434, K01-AI071725, K01-AI071754, R01-AA16893, K24-00432, K23-AI-61-0320, and K23 EY013707); the Centers for Disease Control and Prevention (grant CDC200-2006-18797); the Canadian Institutes for Health Research (grants TGF-96118, HCP-97105, CBR-86906, CBR-94036, KRS-86251, and 169621); and the Canadian Trials Network (project number 242). NR 36 TC 5 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2011 VL 174 IS 6 BP 727 EP 735 DI 10.1093/aje/kwr141 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 818ER UT WOS:000294734600011 PM 21813792 ER PT J AU Schempf, AH Kaufman, JS Messer, LC Mendola, P AF Schempf, Ashley H. Kaufman, Jay S. Messer, Lynne C. Mendola, Pauline TI The Neighborhood Contribution to Black-White Perinatal Disparities: An Example From Two North Carolina Counties, 1999-2001 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE health status disparities; infant; low birth weight; infant; small for gestational age; minority health; multilevel analysis; premature birth; residence characteristics ID LOW-BIRTH-WEIGHT; FOR-GESTATIONAL-AGE; RACIAL RESIDENTIAL SEGREGATION; PRETERM BIRTH; UNITED-STATES; HEALTH DISPARITIES; SOCIOECONOMIC MEASURES; CHICAGO NEIGHBORHOODS; MULTILEVEL ANALYSIS; ETHNIC-DIFFERENCES AB Previous studies of black-white disparities in perinatal outcomes have generally not controlled for both observed and unobserved neighborhood inequalities with models that compare only black and white women living in the same neighborhoods. Using 1999-2001 birth certificate data from 2 counties in North Carolina, the authors employed a hybrid fixed-effects approach to assess the total contribution of neighborhood factors to both absolute and relative racial disparities in low birth weight, preterm birth (PTB), and smallness for gestational age at term. Neighborhood factors made a notable contribution to racial disparities for PTB only, accounting for an additional 15% reduction in crude disparities beyond individual sociodemographic characteristics, which accounted for approximately 40% of racial disparities. The neighborhood contribution was greater for moderate PTB (32-36 weeks' gestation) than for very PTB (< 32 weeks' gestation). A neighborhood deprivation index accounted for a smaller percentage of PTB disparities than the hybrid fixed-effects estimates, which suggests that measured socioeconomic deprivation does not account for all health-relevant neighborhood inequalities. Contemporaneous individual-level sociodemographic and neighborhood factors together explained one- to two-thirds of perinatal disparities. To fully explain racial disparities in perinatal outcomes, evaluation of other differential exposures (e.g., racism or wealth) and neighborhood factors across the life course may be necessary. C1 [Schempf, Ashley H.] Maternal & Child Hlth Bur, Off Epidemiol Policy & Evaluat, US Hlth Resources & Serv Adm, US Dept HHS, Rockville, MD 20857 USA. [Kaufman, Jay S.] McGill Univ, Fac Med, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Messer, Lynne C.] Duke Global Hlth Inst, Durham, NC USA. [Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Schempf, Ashley H.; Mendola, Pauline] Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Schempf, AH (reprint author), Maternal & Child Hlth Bur, Off Epidemiol Policy & Evaluat, US Hlth Resources & Serv Adm, US Dept HHS, 5600 Fishers Lane,Room 18-46, Rockville, MD 20857 USA. EM aschempf@hrsa.gov OI Hirai, Ashley/0000-0002-6980-1039; Kaufman, Jay/0000-0003-1606-401X; Mendola, Pauline/0000-0001-5330-2844 FU National Center for Health Statistics; Maternal and Child Health Bureau, Health Resources and Services Administration, US Department of Health and Human Services FX At the time this study was conducted, A. H. S. and P. M. were affiliated with the National Center for Health Statistics (Hyattsville, Maryland). A. H. S. was supported by an AcademyHealth Health Policy Fellowship from the National Center for Health Statistics.; Data acquisition was supported by a contract from the Maternal and Child Health Bureau, Health Resources and Services Administration, US Department of Health and Human Services. NR 65 TC 26 Z9 26 U1 3 U2 16 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 SEP 15 PY 2011 VL 174 IS 6 BP 744 EP 752 DI 10.1093/aje/kwr128 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 818ER UT WOS:000294734600013 PM 21771918 ER PT J AU Chen, L Chan, TH Choyke, PL Hillman, EMC Chi, CY Bhujwalla, ZM Wang, G Wang, SS Szabo, Z Wang, Y AF Chen, Li Chan, Tsung-Han Choyke, Peter L. Hillman, Elizabeth M. C. Chi, Chong-Yung Bhujwalla, Zaver M. Wang, Ge Wang, Sean S. Szabo, Zsolt Wang, Yue TI CAM-CM: a signal deconvolution tool for in vivo dynamic contrast-enhanced imaging of complex tissues SO BIOINFORMATICS LA English DT Article AB In vivo dynamic contrast-enhanced imaging tools provide non-invasive methods for analyzing various functional changes associated with disease initiation, progression and responses to therapy. The quantitative application of these tools has been hindered by its inability to accurately resolve and characterize targeted tissues due to spatially mixed tissue heterogeneity. Convex Analysis of Mixtures - Compartment Modeling (CAM-CM) signal deconvolution tool has been developed to automatically identify pure-volume pixels located at the corners of the clustered pixel time series scatter simplex and subsequently estimate tissue-specific pharmacokinetic parameters. CAM-CM can dissect complex tissues into regions with differential tracer kinetics at pixel-wise resolution and provide a systems biology tool for defining imaging signatures predictive of phenotypes. Availability: The MATLAB source code can be downloaded at the authors' website www.cbil.ece.vt.edu/software.htm Contact: yuewang@vt.edu Supplementary information: Supplementary data are available at Bioinformatics online. C1 [Chen, Li; Chan, Tsung-Han; Wang, Yue] Virginia Tech, Bradley Dept Elect & Comp Engn, Arlington, VA 22203 USA. [Chan, Tsung-Han; Chi, Chong-Yung] Natl Tsing Hua Univ, Dept Elect Engn, Hsinchu 30013, Taiwan. [Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Hillman, Elizabeth M. C.] Columbia Univ, Dept Biomed Engn & Radiol, New York, NY 10027 USA. [Bhujwalla, Zaver M.; Szabo, Zsolt] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. [Wang, Ge] Virginia Tech, Sch Biomed Engn & Sci, Blacksburg, VA 24061 USA. [Wang, Sean S.] Poolesville High Sch, Poolesville, MD 20837 USA. RP Wang, Y (reprint author), Virginia Tech, Bradley Dept Elect & Comp Engn, Arlington, VA 22203 USA. EM yuewang@vt.edu RI Chen, Li/H-4557-2013; OI Hillman, Elizabeth M. C./0000-0001-5511-1451 FU National Institutes of Health [EB000830, EB008627, HHSN261200800001E] FX National Institutes of Health, under Grants (EB000830, EB008627 and HHSN261200800001E) in part. NR 9 TC 12 Z9 12 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD SEP 15 PY 2011 VL 27 IS 18 BP 2607 EP 2609 DI 10.1093/bioinformatics/btr436 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 818MI UT WOS:000294755400020 PM 21785131 ER PT J AU Sack, U Walther, W Scudiero, D Selby, M Aumann, J Lemos, C Fichtner, I Schlag, PM Shoemaker, RH Stein, U AF Sack, Ulrike Walther, Wolfgang Scudiero, Dominic Selby, Mike Aumann, Jutta Lemos, Clara Fichtner, Iduna Schlag, Peter M. Shoemaker, Robert H. Stein, Ulrike TI S100A4-induced cell motility and metastasis is restricted by the Wnt/beta-catenin pathway inhibitor calcimycin in colon cancer cells SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID BINDING PROTEIN S100A4; BETA-CATENIN; CALCIUM-BINDING; TUMOR-CELLS; WNT PATHWAY; MYOSIN-IIA; TARGET; GENE; MTS1; EXPRESSION AB The calcium-binding protein S100A4 is a central mediator of metastasis formation in colon cancer. S100A4 is a target gene of the Wnt/beta-catenin pathway, which is constitutively active in the majority of colon cancers. In this study a high-throughput screen was performed to identify small-molecule compounds targeting the S100A4-promoter activity. In this screen calcimycin was identified as a transcriptional inhibitor of S100A4. In colon cancer cells calcimycin treatment reduced S100A4 mRNA and protein expression in a dose-and time-dependent manner. S100A4-induced cellular processes associated with metastasis formation, such as cell migration and invasion, were inhibited by calcimycin in an S100A4-specific manner. Calcimycin reduced beta-catenin mRNA and protein levels despite the expression of Delta 45-mutated beta-catenin. Consequently, calcimycin inhibited Wnt/beta-catenin pathway activity and the expression of prominent beta-catenin target genes such as S100A4, cyclin D1, c-myc, and dickkopf-1. Finally, calcimycin treatment of human colon cancer cells inhibited metastasis formation in xenografted immunodeficient mice. Our results demonstrate that targeting the expression of S100A4 with calcimycin provides a functional strategy to restrict cell motility in colon cancer cells. Therefore calcimycin may be useful for studying S100A4 biology, and these studies may serve as a lead for the development of treatments for colon cancer metastasis. C1 [Walther, Wolfgang; Schlag, Peter M.; Stein, Ulrike] Charite, Max Delbruck Ctr Mol Med, Expt & Clin Res Ctr, D-13125 Berlin, Germany. [Scudiero, Dominic; Selby, Mike] NCI, SAIC Frederick, Frederick, MD 21702 USA. [Schlag, Peter M.] Charite, Charite Comprehens Canc Ctr, D-10117 Berlin, Germany. [Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Stein, U (reprint author), Charite, Max Delbruck Ctr Mol Med, Expt & Clin Res Ctr, D-13125 Berlin, Germany. EM ustein@mdc-berlin.de FU German Research Association [STE 671/8-1]; Alexander von Humboldt Foundation; Max-Delbruck-Center for Molecular Medicine Helmholtz Association FX We are very grateful to Pia Hermann and Margit Lemm for technical assistance and to Franziska Siegel and Dennis Kobelt for methodological and scientific advice. This work was supported by the German Research Association (STE 671/8-1, to U.S. and P.M.S.), the Alexander von Humboldt Foundation (to U.S. and W.W.), and a Max-Delbruck-Center for Molecular Medicine Helmholtz Association Fellowship (to U.S.). NR 46 TC 44 Z9 50 U1 0 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP 15 PY 2011 VL 22 IS 18 BP 3344 EP 3354 DI 10.1091/mbc.E10-09-0739 PG 11 WC Cell Biology SC Cell Biology GA 819KG UT WOS:000294823200006 PM 21795396 ER PT J AU Golebiewska, U Kay, JG Masters, T Grinstein, S Im, W Pastor, RW Scarlata, S McLaughlin, S AF Golebiewska, Urszula Kay, Jason G. Masters, Thomas Grinstein, Sergio Im, Wonpil Pastor, Richard W. Scarlata, Suzanne McLaughlin, Stuart TI Evidence for a fence that impedes the diffusion of phosphatidylinositol 4,5-bisphosphate out of the forming phagosomes of macrophages SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; RECEPTOR-MEDIATED PHAGOCYTOSIS; SINGLE-MOLECULE TRACKING; PLASMA-MEMBRANE; CLEAVAGE FURROW; MAMMALIAN SEPTINS; PROTEINS; CYTOKINESIS; CELLS; ORGANIZATION AB To account for the many functions of phosphatidylinositol 4,5-bisphosphate (PIP2), several investigators have proposed that there are separate pools of PIP2 in the plasma membrane. Recent experiments show the surface concentration of PIP2 is indeed enhanced in regions where phagocytosis, exocytosis, and cell division occurs. Kinases that produce PIP2 are also concentrated in these regions. However, how is the PIP2 produced by these kinases prevented from diffusing rapidly away? First, proteins could act as "fences" around the perimeter of these regions. Second, some factor could markedly decrease the diffusion coefficient, D, of PIP2 within these regions. We used fluorescence correlation spectroscopy (FCS) and fluorescence recovery after photobleaching (FRAP) to investigate these two possibilities in the forming phagosomes of macrophages injected with fluorescent PIP2. FCS measurements show that PIP2 diffuses rapidly (D similar to 1 mu m(2)/s) in both the forming phagosomes and unengaged plasma membrane. FRAP measurements show that the fluorescence from PIP2 does not recover (> 100 s) after photobleaching the entire forming phagosome but recovers rapidly (similar to 10 s) in a comparable area of membrane outside the cup. These results (and similar data for a plasma membrane-anchored green fluorescent protein) support the hypothesis that a fence impedes the diffusion of PIP2 into and out of forming phagosomes. C1 [Golebiewska, Urszula; Scarlata, Suzanne; McLaughlin, Stuart] SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY 11794 USA. [Golebiewska, Urszula] CUNY Queensborough Community Coll, Dept Biol Sci & Geol, Bayside, NY 11364 USA. [Kay, Jason G.; Grinstein, Sergio] Hosp Sick Children, Cell Biol Program, Toronto, ON M5G 1X8, Canada. [Masters, Thomas; McLaughlin, Stuart] Natl Univ Singapore, Mechanobiol Inst, Singapore 117411, Singapore. [Im, Wonpil] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66047 USA. [Im, Wonpil] Univ Kansas, Ctr Bioinformat, Lawrence, KS 66047 USA. [Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP McLaughlin, S (reprint author), SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY 11794 USA. EM smclaughlin@notes.cc.sunysb.edu FU Mechanobiology Institute at the National University of Singapore; National Institutes of Health [GM053132] FX We thank William Trimble for extensive helpful discussions about septin filaments; Xianke Shi for calibration of the Confocor 3; the Mechanobiology Institute at the National University of Singapore for financial support (S. M. and T. M.); the National Institutes of Health for Grant GM053132 (S. S.); and the Intramural Research Program of the National Heart, Lung and Blood Institute, National Institutes of Health (R. W. P.). NR 60 TC 39 Z9 39 U1 2 U2 15 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP 15 PY 2011 VL 22 IS 18 BP 3498 EP 3507 DI 10.1091/mbc.E11-02-0114 PG 10 WC Cell Biology SC Cell Biology GA 819KG UT WOS:000294823200019 PM 21795401 ER PT J AU Chimowitz, MI Lynn, MJ Derdeyn, CP Turan, TN Fiorella, D Lane, BF Janis, LS Lutsep, HL Barnwell, SL Waters, MF Hoh, BL Hourihane, JM Levy, EI Alexandrov, AV Harrigan, MR Chiu, D Klucznik, RP Clark, JM McDougall, CG Johnson, MD Pride, GL Torbey, MT Zaidat, OO Rumboldt, Z Cloft, HJ AF Chimowitz, Marc I. Lynn, Michael J. Derdeyn, Colin P. Turan, Tanya N. Fiorella, David Lane, Bethany F. Janis, L. Scott Lutsep, Helmi L. Barnwell, Stanley L. Waters, Michael F. Hoh, Brian L. Hourihane, J. Maurice Levy, Elad I. Alexandrov, Andrei V. Harrigan, Mark R. Chiu, David Klucznik, Richard P. Clark, Joni M. McDougall, Cameron G. Johnson, Mark D. Pride, G. Lee, Jr. Torbey, Michel T. Zaidat, Osama O. Rumboldt, Zoran Cloft, Harry J. CA SAMMPRIS Trial Investigators TI Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ISCHEMIC-STROKE; ATHEROMATOUS DISEASE; INITIAL-EXPERIENCE; RECURRENT STROKE; WINGSPAN STENT; BLOOD-PRESSURE; ATHEROSCLEROSIS; RESTENOSIS; PATTERNS; RISK AB Background Atherosclerotic intracranial arterial stenosis is an important cause of stroke that is increasingly being treated with percutaneous transluminal angioplasty and stenting (PTAS) to prevent recurrent stroke. However, PTAS has not been compared with medical management in a randomized trial. Methods We randomly assigned patients who had a recent transient ischemic attack or stroke attributed to stenosis of 70 to 99% of the diameter of a major intracranial artery to aggressive medical management alone or aggressive medical management plus PTAS with the use of the Wingspan stent system. The primary end point was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. Results Enrollment was stopped after 451 patients underwent randomization, because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non-stroke-related death, 0.4%) (P=0.002). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Currently, the mean duration of follow-up, which is ongoing, is 11.9 months. The probability of the occurrence of a primary end-point event over time differed significantly between the two treatment groups (P=0.009), with 1-year rates of the primary end point of 20.0% in the PTAS group and 12.2% in the medical-management group. Conclusions In patients with intracranial arterial stenosis, aggressive medical management was superior to PTAS with the use of the Wingspan stent system, both because the risk of early stroke after PTAS was high and because the risk of stroke with aggressive medical therapy alone was lower than expected. (Funded by the National Institute of Neurological Disorders and Stroke and others; SAMMPRIS ClinicalTrials.gov number, NCT00576693.) C1 [Chimowitz, Marc I.] Med Univ S Carolina, Stroke Program, Dept Neurosci, Charleston, SC 29425 USA. [Rumboldt, Zoran] Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. [Lynn, Michael J.; Lane, Bethany F.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Dept Neurosurg, St Louis, MO USA. [Fiorella, David] SUNY Stony Brook, Dept Neurosurg, Stony Brook, NY 11794 USA. [Janis, L. Scott] NINDS, NIH, Bethesda, MD 20892 USA. [Lutsep, Helmi L.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Barnwell, Stanley L.] Oregon Hlth & Sci Univ, Dept Neurol Surg, Portland, OR 97201 USA. [Barnwell, Stanley L.] Oregon Hlth & Sci Univ, Dotter Intervent Inst, Portland, OR 97201 USA. [Waters, Michael F.] Univ Florida, Dept Neurol & Neurosci, Gainesville, FL USA. [Hoh, Brian L.] Univ Florida, Dept Neurosurg, Gainesville, FL USA. [Hourihane, J. Maurice] Dent Neurol Inst, Buffalo, NY USA. [Levy, Elad I.] SUNY Buffalo, Dept Neurosurg, Buffalo, NY 14260 USA. [Alexandrov, Andrei V.] Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA. [Harrigan, Mark R.] Univ Alabama, Dept Neurosurg, Birmingham, AL USA. [Chiu, David] Methodist Hosp, Dept Neurol, Houston, TX 77030 USA. [Klucznik, Richard P.] Methodist Hosp, Dept Radiol, Houston, TX 77030 USA. [Clark, Joni M.] Barrow Neurol Inst, Dept Neurol, Phoenix, AZ 85013 USA. [McDougall, Cameron G.] Barrow Neurol Inst, Dept Neurosurg, Phoenix, AZ 85013 USA. [Johnson, Mark D.] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Johnson, Mark D.] Univ Texas SW Med Ctr Dallas, Dept Neurotherapeut, Dallas, TX 75390 USA. [Pride, G. Lee, Jr.] Univ Texas SW Med Ctr Dallas, Dept Radiol, Dallas, TX 75390 USA. [Pride, G. Lee, Jr.] Univ Texas SW Med Ctr Dallas, Dept Neurosurg, Dallas, TX 75390 USA. [Torbey, Michel T.; Zaidat, Osama O.] Med Coll Wisconsin, Dept Neurol, Milwaukee, WI 53226 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Dept Radiol, Milwaukee, WI 53226 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Dept Neurosurg, Milwaukee, WI 53226 USA. [Cloft, Harry J.] Mayo Clin, Dept Radiol, Rochester, MN USA. RP Chimowitz, MI (reprint author), Med Univ S Carolina, Stroke Program, Dept Neurosci, 19 Hagood Ave,Harborview Off Tower,Suite 501, Charleston, SC 29425 USA. EM mchimow@musc.edu OI Alexandrov, Andrei V/0000-0001-8871-1023; Turan, Tanya/0000-0001-5399-8845; Derdeyn, Colin/0000-0002-5932-2683 FU National Institute of Neurological Disorders and Stroke (NINDS) [U01 NS058728]; National Institutes of Health; Medical University of South Carolina [UL1RR029882]; University of Florida [UL1RR029889]; University of Cincinnati [UL1RR029890]; University of California, San Francisco [UL1RR024131]; AstraZeneca; Stryker Neurovascular (formerly Boston Scientific Neurovascular); SAMMPRIS; National Institute of Neurological Disorders and Stroke [NCT00576693] FX Funded by the National Institute of Neurological Disorders and Stroke and others; SAMMPRIS ClinicalTrials.gov number, NCT00576693.; Supported by a research grant (U01 NS058728) from the National Institute of Neurological Disorders and Stroke (NINDS). In addition, the following institutions received Clinical and Translational Science Awards, funded by the National Institutes of Health, that provided local support for the evaluation of patients in the trial: Medical University of South Carolina (UL1RR029882), University of Florida (UL1RR029889), University of Cincinnati (UL1RR029890), and University of California, San Francisco (UL1RR024131). This research is also supported by the Investigator-Sponsored Study Program of AstraZeneca, which donates rosuvastatin (Crestor) to study patients. Stryker Neurovascular (formerly Boston Scientific Neurovascular) provided study devices and supplemental funding for third-party distribution of devices and continues to provide funding for site monitoring and study auditing, and Nationwide Better Health-INTERVENT provides the lifestyle modification program to the study at a discounted rate. The Regulatory and Clinical Research Institute (Minneapolis) provided assistance in designing the site monitoring processes and performs the site monitoring visits. The Cooperative Studies Program Clinical Research Pharmacy Coordinating Center of the Department of Veterans Affairs (Albuquerque, NM) handles the procurement, labeling, distribution, and inventory management of the study devices and rosuvastatin. Walgreens pharmacies provide study medications, except rosuvastatin, to patients at a discounted price (paid for by the study). The Physician-based Assessment and Counseling for Exercise (PACE) self-assessment forms for physical activity and smoking cessation were provided by the San Diego Center for Health Interventions.; We thank the patients for participating in this study; Drs. Oscar Benavente, Carole White, Robert Hart, Pablo Pergola, and Ana Roldan of the Secondary Prevention of Small Subcortical Strokes trial (SPS3, NCT00059306) for assisting with the development and implementation of the SAMMPRIS blood-pressure management protocol; Drs. George Howard and Thomas Brott for providing advice on study design and other issues on the basis of their experience with the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST, NCT00004732); and Rie Calcaterra for helping with the SAMMPRIS grant application and with launching the trial. NR 40 TC 529 Z9 576 U1 3 U2 43 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 SEP 15 PY 2011 VL 365 IS 11 BP 993 EP 1003 DI 10.1056/NEJMoa1105335 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 819UR UT WOS:000294857300007 PM 21899409 ER PT J AU Hudson, KL AF Hudson, Kathy L. TI GENOMIC MEDICINE Genomics, Health Care, and Society SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID GENETICS; CANCER; CETUXIMAB; PRIVACY; LEGAL; HYPERSENSITIVITY; CONFIDENTIALITY; ASSOCIATION; ATTITUDES; BIOBANKS C1 NIH, Off Director, Bethesda, MD 20892 USA. RP Hudson, KL (reprint author), NIH, Off Director, 9000 Rockville Pike,Bldg 1, Bethesda, MD 20892 USA. EM hudsonkl@od.nih.gov NR 52 TC 69 Z9 69 U1 2 U2 11 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 SEP 15 PY 2011 VL 365 IS 11 BP 1033 EP 1041 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 819UR UT WOS:000294857300011 PM 21916641 ER PT J AU Kwon, DY Motley, WW Fischbeck, KH Burnett, BG AF Kwon, Deborah Y. Motley, William W. Fischbeck, Kenneth H. Burnett, Barrington G. TI Increasing expression and decreasing degradation of SMN ameliorate the spinal muscular atrophy phenotype in mice SO HUMAN MOLECULAR GENETICS LA English DT Article ID PROTEASOME INHIBITOR BORTEZOMIB; DYSTROPHIN-ASSOCIATED PROTEINS; MOUSE MODEL; SKELETAL-MUSCLE; PEDIATRIC-PATIENTS; GENE ENCODES; PHASE-II; MDX MICE; UBIQUITIN; SURVIVAL AB Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by reduced levels of the survival motor neuron (SMN) protein. Here we show that the proteasome inhibitor, bortezomib, increases SMN in cultured cells and in peripheral tissues of SMA model mice. Bortezomib-treated animals had improved motor function, which was associated with reduced spinal cord and muscle pathology and improved neuromuscular junction size, but no change in survival. Combining bortezomib with the histone deacetylase inhibitor trichostatin A (TSA) resulted in a synergistic increase in SMN protein levels in mouse tissue and extended survival of SMA mice more than TSA alone. Our results demonstrate that a combined regimen of drugs that decrease SMN protein degradation and increase SMN gene transcription synergistically increases SMN levels and improves the lifespan of SMA model mice. Moreover, this study indicates that while increasing SMN levels in the central nervous system may help extend survival, peripheral tissues can also be targeted to improve the SMA disease phenotype. C1 [Kwon, Deborah Y.; Motley, William W.; Fischbeck, Kenneth H.; Burnett, Barrington G.] 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 National Institute of Neurological Disorders and Stroke (NINDS) at the NIH; NINDS FX This work was supported by intramural funds from the National Institute of Neurological Disorders and Stroke (NINDS) at the NIH and a NINDS Competitive Fellowship (to B.G.B.). NR 41 TC 26 Z9 26 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 15 PY 2011 VL 20 IS 18 BP 3667 EP 3677 DI 10.1093/hmg/ddr288 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 814IP UT WOS:000294442200012 PM 21693563 ER PT J AU Bazin, PL Ye, CY Bogovic, JA Shiee, N Reich, DS Prince, JL Pham, DL AF Bazin, Pierre-Louis Ye, Chuyang Bogovic, John A. Shiee, Navid Reich, Daniel S. Prince, Jerry L. Pham, Dzung L. TI Direct segmentation of the major white matter tracts in diffusion tensor images SO NEUROIMAGE LA English DT Article DE White matter tracts; DTI segmentation; Markov random field modeling ID FIBER TRACKING; MRI ANALYSIS; HUMAN BRAIN; TRACTOGRAPHY; ATLAS; FRAMEWORK; DTI; REPRODUCIBILITY; VARIABILITY; STRATEGIES AB Diffusion-weighted images of the human brain are acquired more and more routinely in clinical research settings, yet segmenting and labeling white matter tracts in these images is still challenging. We present in this paper a fully automated method to extract many anatomical tracts at once on diffusion tensor images, based on a Markov random field model and anatomical priors. The approach provides a direct voxel labeling, models explicitly fiber crossings and can handle white matter lesions. Experiments on simulations and repeatability studies show robustness to noise and reproducibility of the algorithm, which has been made publicly available. (C) 2011 Elsevier Inc. All rights reserved. C1 [Bazin, Pierre-Louis] Max Planck Inst Human Cognit & Brain Sci, Dept Neurophys, D-04103 Leipzig, Germany. [Bazin, Pierre-Louis; Shiee, Navid; Pham, Dzung L.] Johns Hopkins Univ, Dept Radiol & Radiol Sci, Neuroradiol Div, Lab Med Image Comp, Baltimore, MD 21287 USA. [Ye, Chuyang; Bogovic, John A.; Shiee, Navid; Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Image Anal & Comp Lab, Baltimore, MD 21218 USA. [Reich, Daniel S.] Natl Inst Neurol Disorders & Stroke, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Bazin, PL (reprint author), Max Planck Inst Human Cognit & Brain Sci, Dept Neurophys, D-04103 Leipzig, Germany. EM bazin@cbs.mpg.edu RI Prince, Jerry/A-3281-2010; Reich, Daniel/E-5701-2010 OI Bazin, Pierre-Louis/0000-0002-0141-5510; Prince, Jerry/0000-0002-6553-0876; Reich, Daniel/0000-0002-2628-4334 FU National Multiple Sclerosis Society [TR3760A3]; China Scholarship Council; NINDS; [NIH/NIDAK25DA025356]; [NIH/NINDSR01NS056307]; [R01NS070906]; [NIHK99NS064098]; [NIHP41RR015241] FX We thank Dr. Susumu Mori and Mr. Kegang Hua for providing us tensor images and tract delineations for their digital atlas used in preliminary versions of this work (Mori et al., 2005). and Dr. Peter Calabresi for providing the multiple sclerosis data used in the lesion experiments. This work was supported in part by the NIH/NIDAK25DA025356 grant, the NIH/NINDSR01NS056307 and R01NS070906 grants, the National Multiple Sclerosis Society-TR3760A3 grant, the NIHK99NS064098 grant, the NIHP41RR015241 grant, the China Scholarship Council and the Intramural Research Program of NINDS. NR 57 TC 25 Z9 25 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD SEP 15 PY 2011 VL 58 IS 2 BP 458 EP 468 DI 10.1016/j.neuroimage.2011.06.020 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 815KR UT WOS:000294525000017 PM 21718790 ER PT J AU Chu, C Mourao-Miranda, J Chiu, YC Kriegeskorte, N Tan, G Ashburner, J AF Chu, Carlton Mourao-Miranda, Janaina Chiu, Yu-Chin Kriegeskorte, Nikolaus Tan, Geoffrey Ashburner, John TI Utilizing temporal information in fMRI decoding: Classifier using kernel regression methods SO NEUROIMAGE LA English DT Article DE Kernel methods; Machine learning; Kernel ridge regression (KRR); fMRI prediction; Support vector machine (SVM); Relevance vector machines (RVM); Multi-class; Temporal compression; Temporal compacting ID SUPPORT VECTOR MACHINES; SPATIAL-PATTERNS; BRAIN ACTIVITY; PREDICTION; CORTEX; STATES; REPRESENTATIONS; SEGMENTATION; REGISTRATION; DEPRESSION AB This paper describes a general kernel regression approach to predict experimental conditions from activity patterns acquired with functional magnetic resonance image (fMRI). The standard approach is to use classifiers that predict conditions from activity patterns. Our approach involves training different regression machines for each experimental condition, so that a predicted temporal profile is computed for each condition. A decision function is then used to classify the responses from the testing volumes into the corresponding category, by comparing the predicted temporal profile elicited by each event, against a canonical hemodynamic response function. This approach utilizes the temporal information in the fMRI signal and maintains more training samples in order to improve the classification accuracy over an existing strategy. This paper also introduces efficient techniques of temporal compaction, which operate directly on kernel matrices for kernel classification algorithms such as the support vector machine (SVM). Temporal compacting can convert the kernel computed from each fMRI volume directly into the kernel computed from beta-maps, average of volumes or spatial-temporal kernel. The proposed method was applied to three different datasets. The first one is a block-design experiment with three conditions of image stimuli. The method outperformed the SVM classifiers of three different types of temporal compaction in single-subject leave-one-block-out cross-validation. Our method achieved 100% classification accuracy for six of the subjects and an average of 94% accuracy across all 16 subjects, exceeding the best SVM classification result, which was 83% accuracy (p = 0.008). The second dataset is also a block-design experiment with two conditions of visual attention (left or right). Our method yielded 96% accuracy and SVM yielded 92% (p = 0.005). The third dataset is from a fast event-related experiment with two categories of visual objects. Our method achieved 77% accuracy, compared with 72% using SVM (p = 0.0006). Published by Elsevier Inc. C1 [Chu, Carlton] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Chu, Carlton; Tan, Geoffrey; Ashburner, John] UCL, Wellcome Trust Ctr Neuroimaging, London WC1E 6BT, England. [Mourao-Miranda, Janaina] UCL, Dept Comp Sci, Ctr Computat Stat & Machine Learning, London, England. [Mourao-Miranda, Janaina] KCL, Inst Psychiat, Dept Neuroimaging, London, England. [Chiu, Yu-Chin] Univ Calif San Diego, Dept Psychol, San Diego, CA 92103 USA. [Kriegeskorte, Nikolaus] MRC, Cognit & Brain Sci Unit, Cambridge CB2 7EF, England. RP Chu, C (reprint author), NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Room 1D80,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM carltonchu1@gmail.com RI Ashburner, John/I-3757-2013; OI Ashburner, John/0000-0001-7605-2518; Kriegeskorte, Nikolaus/0000-0001-7433-9005 FU NIH, NIMH; Wellcome Trust; NIH [R01-DA013165] FX This research was supported in part by the Intramural Research Program of the NIH, NIMH. JMM was funded by a Wellcome Trust Career Development Fellowship. JA is funded by the Wellcome Trust. The authors thank Prof. Michael Brammer for providing the first dataset. The authors thank Prof. Steven Yantis for providing the second dataset, which was supported by NIH grant R01-DA013165. NR 50 TC 12 Z9 12 U1 2 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP 15 PY 2011 VL 58 IS 2 BP 560 EP 571 DI 10.1016/j.neuroimage.2011.06.053 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 815KR UT WOS:000294525000025 PM 21729756 ER PT J AU Karkera, J Steiner, H Li, WM Skradski, V Moser, PL Riethdorf, S Reddy, M Puchalski, T Safer, K Prabhakar, U Pantel, K Qi, M Culig, Z AF Karkera, Jayaprakash Steiner, Hannes Li, Weimin Skradski, Viktor Moser, Patrizia L. Riethdorf, Sabine Reddy, Manjula Puchalski, Thomas Safer, Karim Prabhakar, Uma Pantel, Klaus Qi, Ming Culig, Zoran TI The Anti-Interleukin-6 Antibody Siltuximab Down-Regulates Genes Implicated inTumorigenesis in Prostate Cancer Patients From a Phase I Study SO PROSTATE LA English DT Article DE prostate cancer; interleukin-6; siltuximab; STAT; MAPK; phase I study ID METASTATIC BREAST-CANCER; CIRCULATING TUMOR-CELLS; ANDROGEN RECEPTOR; MONOCLONAL-ANTIBODY; PROTEIN EXPRESSION; AUTOCRINE LOOP; INTERLEUKIN-6; GROWTH; ACTIVATION; LNCAP AB BACKGROUND. Interleukin-6 (IL-6) is associated with prostate cancer morbidity. In several experimental models, IL-6 has been reported to have anti-apoptotic and pro-angiogenic effects. Siltuximab (CNTO 328) is a monoclonal anti-IL-6 antibody which has been successfully applied in several models representing prostate cancer. This study was designed to assess preliminary safety of siltuximab in patients with early prostate cancer. PATIENTS AND METHODS. Twenty patients scheduled to undergo radical prostatectomy received either no drug or siltuximab (6 mg/kg, five patients per group with administration once, two times, and three times prior to surgery). Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Expression of elements of IL-6 signaling pathways was analyzed in tumor tissue by immunohistochemistry. Gene analysis in tumor specimens was performed with the DASL array. RESULTS. No adverse events related to siltuximab were observed. Patients treated with siltuximab presented with higher levels of proliferation and apoptosis markers. Following a single dose, serum concentrations of siltuximab declined in a biexponential manner. This study revealed a decrease in phosphorylation of Stat3 and p44/p42 mitogen-activated protein kinases. In addition, gene expression analyses indicate down-regulation of genes immediately downstream of the IL-6 signaling pathway and key enzymes of the androgen signaling pathway. CONCLUSIONS. Preliminary safety of siltuximab is favorable. Future studies in which siltuximab could be combined with androgen-deprivation therapy and experimental therapies in advanced prostate cancer are justified. Prostate 71: 1455-1465, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Steiner, Hannes; Skradski, Viktor; Culig, Zoran] Innsbruck Med Univ, Dept Urol, A-6020 Innsbruck, Austria. [Karkera, Jayaprakash; Li, Weimin; Reddy, Manjula; Puchalski, Thomas; Safer, Karim; Prabhakar, Uma; Qi, Ming] Centocor Res & Dev, Radnor, PA USA. [Moser, Patrizia L.; Culig, Zoran] Innsbruck Med Univ, Dept Pathol, A-6020 Innsbruck, Austria. [Riethdorf, Sabine; Pantel, Klaus] Univ Med Ctr, Inst Tumor Biol, Hamburg, Germany. [Prabhakar, Uma] NCI, Bethesda, MD 20892 USA. RP Culig, Z (reprint author), Innsbruck Med Univ, Dept Urol, Anichstr 35, A-6020 Innsbruck, Austria. EM zoran.culig@i-med.ac.at FU Centocor FX Grant sponsor: Centocor. NR 38 TC 41 Z9 42 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-4137 J9 PROSTATE JI Prostate PD SEP 15 PY 2011 VL 71 IS 13 BP 1455 EP 1465 DI 10.1002/pros.21362 PG 11 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 814JC UT WOS:000294443700010 PM 21321981 ER PT J AU Sekine, Y Suzuki, K Remaley, AT AF Sekine, Yoshitaka Suzuki, Kazuhiro Remaley, Alan T. TI HDL and Sphingosine-I-Phosphate Activate Stat3 in Prostate Cancer DU145 Cells Via ERK1/2 and SIP Receptors, and Promote Cell Migration and Invasion (vol 71, pg 690, 2011) SO PROSTATE LA English DT Correction C1 [Sekine, Yoshitaka; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Sekine, Yoshitaka; Suzuki, Kazuhiro] Gunma Univ, Grad Sch Med, Dept Urol, Gunma, Japan. RP Sekine, Y (reprint author), NHLBI, Lipoprot Metab Sect, Pulm & Vasc Med Branch, NIH, Bldg 10,Room 8N224,9000 Rockville Pike, Bethesda, MD 20892 USA. EM ysekine@showa.gunma-u.ac.jp NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-4137 J9 PROSTATE JI Prostate PD SEP 15 PY 2011 VL 71 IS 13 BP 1480 EP 1480 DI 10.1002/pros.21459 PG 1 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 814JC UT WOS:000294443700012 ER PT J AU Gao, ZG Verzijl, D Zweemer, A Ye, K Goblyos, A Ijzerman, AP Jacobson, KA AF Gao, Zhan-Guo Verzijl, Dennis Zweemer, Annelien Ye, Kai Goblyos, Aniko Ijzerman, Adriaan P. Jacobson, Kenneth A. TI Functionally biased modulation of A(3) adenosine receptor agonist efficacy and potency by imidazoquinolinamine allosteric enhancers SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE G protein-coupled receptors; Purines; Positive allosteric modulator; Second messenger; Nucleoside ID DERIVATIVES; ACTIVATION; LIGANDS; BINDING; SELECTIVITY; PATHWAYS; SERIES; CELLS; MODEL; RATS AB Allosteric modulators for the G(i)-coupled A(3) adenosine receptor (AR) are of considerable interest as therapeutic agents and as pharmacological tools to probe various signaling pathways. In this study, we initially characterized the effects of several imidazoquinolinamine allosteric modulators (LUF5999, LUF6000 and LUF6001) on the human A(3) AR stably expressed in CHO cells using a cyclic AMP functional assay. These modulators were found to affect efficacy and potency of the agonist CI-IB-MECA differently. LUF5999 (2-cyclobutyl derivative) enhanced efficacy but decreased potency. LUF6000 (2-cyclohexyl derivative) enhanced efficacy without affecting potency. LUF6001 (2-H derivative) decreased both efficacy and potency. We further compared the agonist enhancing effects of LUF6000 in several other A(3) AR-mediated events. It was shown that although LUF6000 behaved somewhat differently in various signaling pathways, it was more effective in enhancing the effects of low-efficacy than of high-efficacy agonists. In an assay of cyclic AMP accumulation, LUF6000 enhanced the efficacy of all agonists examined, but in the membrane hyperpolarization assay, it only enhanced the efficacy of partial agonists. In calcium mobilization, LUF6000 did not affect the efficacy of the full agonist NECA but was able to switch the nucleoside antagonist MRS542 into a partial agonist. In translocation of beta-arrestin2, the agonist-enhancing effect LUF6000 was not pronounced. In an assay of ERK1/2 phosphorylation LUF6000 did not show any effect on the efficacy of CI-IB-MECA. The differential effects of LUF6000 on the efficacy and potency of the agonist CI-IB-MECA in various signaling pathway were interpreted quantitatively using a mathematical model. Published by Elsevier Inc. C1 [Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Verzijl, Dennis; Zweemer, Annelien; Ye, Kai; Goblyos, Aniko; Ijzerman, Adriaan P.] Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Med Chem, NL-2300 RA Leiden, Netherlands. RP Gao, ZG (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM zg21o@nih.gov; kajacobs@helix.nih.gov RI Ye, Kai/B-3640-2012; Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Zweemer, Annelien/0000-0002-3539-3129; IJzerman, Ad/0000-0002-1182-2259; Verzijl, Dennis/0000-0002-7716-9838 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Dutch Top Institute Pharma [D1-105] FX This research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. The financial contribution of the Dutch Top Institute Pharma is also gratefully acknowledged (project D1-105). NR 42 TC 27 Z9 27 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD SEP 15 PY 2011 VL 82 IS 6 BP 658 EP 668 DI 10.1016/j.bcp.2011.06.017 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 810CV UT WOS:000294103900008 PM 21718691 ER PT J AU Sterling, TR Lau, B Zhang, JB Freeman, A Bosch, RJ Brooks, JT Deeks, SG French, A Gange, S Gebo, KA Gill, MJ Horberg, MA Jacobson, LP Kirk, GD Kitahata, MM Klein, MB Martin, JN Rodriguez, B Silverberg, MJ Willig, JH Eron, JJ Goedert, JJ Hogg, RS Justice, AC McKaig, RG Napravnik, S Thorne, J Moore, RD AF Sterling, Timothy R. Lau, Bryan Zhang, Jinbing Freeman, Aimee Bosch, Ronald J. Brooks, John T. Deeks, Steven G. French, Audrey Gange, Stephen Gebo, Kelly A. Gill, M. John Horberg, Michael A. Jacobson, Lisa P. Kirk, Gregory D. Kitahata, Mari M. Klein, Marina B. Martin, Jeffrey N. Rodriguez, Benigno Silverberg, Michael J. Willig, James H. Eron, Joseph J. Goedert, James J. Hogg, Robert S. Justice, Amy C. McKaig, Rosemary G. Napravnik, Sonia Thorne, Jennifer Moore, Richard D. CA N American AIDS Cohort Collaborati TI Risk Factors for Tuberculosis After Highly Active Antiretroviral Therapy Initiation in the United States and Canada: Implications for Tuberculosis Screening SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HIV-INFECTED PATIENTS; IMMUNE RECONSTITUTION; TREATMENT OUTCOMES; RECURRENCE; RELAPSE; COHORT; AIDS; REINFECTION; MORTALITY; COUNTRIES AB Background. Screening for tuberculosis prior to highly active antiretroviral therapy (HAART) initiation is not routinely performed in low-incidence settings. Identifying factors associated with developing tuberculosis after HAART initiation could focus screening efforts. Methods. Sixteen cohorts in the United States and Canada contributed data on persons infected with human immunodeficiency virus (HIV) who initiated HAART December 1995-August 2009. Parametric survival models identified factors associated with tuberculosis occurrence. Results. Of 37 845 persons in the study, 145 were diagnosed with tuberculosis after HAART initiation. Tuberculosis risk was highest in the first 3 months of HAART (20 cases; 215 cases per 100 000 person-years; 95% confidence interval [CI]: 131-333 per 100 000 person-years). In a multivariate Weibull proportional hazards model, baseline CD4(+) lymphocyte count,200, black race, other nonwhite race, Hispanic ethnicity, and history of injection drug use were independently associated with tuberculosis risk. In addition, in a piece-wise Weibull model, increased baseline HIV-1 RNA was associated with increased tuberculosis risk in the first 3 months; male sex tended to be associated with increased risk. Conclusions. Screening for active tuberculosis prior to HAART initiation should be targeted to persons with baseline CD4 <200 lymphocytes/mm(3) or increased HIV-1 RNA, persons of nonwhite race or Hispanic ethnicity, history of injection drug use, and possibly male sex. C1 [Sterling, Timothy R.] Vanderbilt Univ, Sch Med, Div Infect Dis, Dept Med, Nashville, TN 37232 USA. [Lau, Bryan; Gebo, Kelly A.; Thorne, Jennifer; Moore, Richard D.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Lau, Bryan; Zhang, Jinbing; Freeman, Aimee; Gange, Stephen; Jacobson, Lisa P.; Kirk, Gregory D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Brooks, John T.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Deeks, Steven G.; Martin, Jeffrey N.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [French, Audrey] Rush Univ, Med Ctr, Dept Med, Chicago, IL 60612 USA. [Gill, M. John] Univ Calgary, Dept Med, Calgary, AB T2N 1N4, Canada. [Horberg, Michael A.; Silverberg, Michael J.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Kitahata, Mari M.] Univ Washington, Dept Med, Seattle, WA USA. [Klein, Marina B.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Klein, Marina B.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Willig, James H.] Univ Alabama Birmingham, Dept Internal Med, Birmingham, AL USA. [Eron, Joseph J.; Napravnik, Sonia] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Goedert, James J.; McKaig, Rosemary G.] NIH, Bethesda, MD 20892 USA. [Hogg, Robert S.] BC Ctr Excellence & HIV AIDS, Vancouver, BC, Canada. [Hogg, Robert S.] Simon Fraser Univ, Vancouver, BC, Canada. [Justice, Amy C.] Yale Univ, Dept Med, New Haven, CT 06520 USA. [Justice, Amy C.] VA Connecticut Healthcare Syst, New Haven, CT USA. RP Sterling, TR (reprint author), Vanderbilt Univ, Sch Med, Div Infect Dis, Dept Med, A2209 Med Ctr N,1161 21st Ave S, Nashville, TN 37232 USA. EM timothy.sterling@vanderbilt.edu RI Hogg, Robert/B-2783-2012; Rodriguez, Benigno/C-3365-2009; Gill, John/G-7083-2016; OI Rodriguez, Benigno/0000-0001-9736-7957; Gill, John/0000-0002-8546-8790; Gange, Stephen/0000-0001-7842-512X; Hogg, Robert/0000-0003-3463-5488 FU Pfizer; Bristol-Myers Squibb; GlaxoSmithKline; Roche; Gilead; Boehringer-Ingelheim; Merck; Abbott; Tibotec; Canadian Institutes of Health Research; Canadian Institutes of Health Research/Fonds de la Recherche en Sante du Quebec; Canadian HIV Trials Network; Ontario HIV Treatment Network; Schering Plough Canada; Gilead Sciences; National Institutes of Health [U01-AI069918, U01-AA013566, U01-AI-35042, 5-MO1-RR-00052 [GCRC], U01-AI-35043, U01-AI-35039, U01-AI-35040, U01-AI-35041, U01-AI38855: ALLRT, U01-AI38858, U01-AI68634, U01-AI68636, AI-69432, AI-69434, U01-AI-35004, U01-AI-31834]; Centers for Disease Control [CDC 200-2006-18797]; Canadian Institutes for Health Research (CIHR) [TGF-96118, HCP-97105, CBR-86906, CBR-94036, KRS-86251, 169621]; Canadian Trials Network [242] FX T. R. S. reports receiving grant support from Pfizer and Bristol-Myers Squibb. S. G. D. reports receiving consulting fees from GlaxoSmithKline, Roche, Gilead, and Boehringer-Ingelheim and grant support from Merck, Gilead, Bristol-Myers Squibb, and Pfizer. M. J. G. reports receiving consulting fees from Gilead, Abbott, Merck, Boehringer-Ingelheim, Tibotec, and Pfizer and grant support from GlaxoSmithKline, Abbott, Canadian Institutes of Health Research, Tibotec, and Pfizer. M. B. K. reports receiving consulting fees from GlaxoSmithKline, Abbott, Pfizer, and Boehringer-Ingelheim; lecture fees from Abbott, Gilead, Tibotec, Bristol-Myers Squibb, and GlaxoSmithKline; and research support from Canadian Institutes of Health Research/Fonds de la Recherche en Sante du Quebec, Canadian HIV Trials Network, Ontario HIV Treatment Network, and Schering Plough Canada. B. R. reports receiving consulting fees from Gilead and Bristol-Myers Squibb, lecture fees from Bristol-Myers Squibb, and grant support from STERIS. J. H. W. reports receiving consulting fees and/or research funding from Bristol-Myers Squibb, Gilead Sciences, Merck and Tibotec. R. D. M. reports receiving consulting fees from Bristol-Myers Squibb and GlaxoSmithKline, lecture fees from Gilead, and grant support from Pfizer, Merck, Gilead, and Agency for Healthcare Research and Quality. All other authors: no conflicts.; This work was supported by the National Institutes of Health (U01-AI069918, U01-AA013566, U01-AI-35042, 5-MO1-RR-00052 [GCRC], U01-AI-35043, U01-AI-35039, U01-AI-35040, U01-AI-35041, U01-AI38855: ALLRT; U01-AI38858; U01-AI68634; U01-AI68636; AI-69432; AI-69434, U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993, and U01-AI-42590, U01-HD-32632, UL1-RR024131, P30-AI27757; K23-AI-61-0320, P30-AI27767, P30-AI50410; RR025747, P30-AI54999, R01-DA04334; R01-DA12568, R01-MH54907, R24-AI067039, N02-CP55504; Z01-CP010176, AHQ290-01-0012, K01-AI071754, K24-00432; R01-DA11602, K01-AI071725, R01-AG026250: Kelly Gebo). This work was also supported by the Centers for Disease Control (CDC 200-2006-18797); the Canadian Institutes for Health Research (CIHR: TGF-96118; HCP-97105; CBR-86906; CBR-94036; KRS-86251; 169621); and the Canadian Trials Network (project number 242). NR 34 TC 16 Z9 16 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2011 VL 204 IS 6 BP 893 EP 901 DI 10.1093/infdis/jir421 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 809QJ UT WOS:000294071500012 PM 21849286 ER PT J AU Kobayashi, SD Malachowa, N Whitney, AR Braughton, KR Gardner, DJ Long, D BubeckWardenburg, J Schneewind, O Otto, M DeLeo, FR AF Kobayashi, Scott D. Malachowa, Natalia Whitney, Adeline R. Braughton, Kevin R. Gardner, Donald J. Long, Dan BubeckWardenburg, Juliane Schneewind, Olaf Otto, Michael DeLeo, Frank R. TI Comparative Analysis of USA300 Virulence Determinants in a Rabbit Model of Skin and Soft Tissue Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; STAPHYLOCOCCUS-AUREUS DISEASE; ALPHA-HEMOLYSIN; TOXIN AB Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are frequently associated with strains harboring genes encoding Panton-Valentine leukocidin (PVL). The role of PVL in the success of the epidemic CA-MRSA strain USA300 remains unknown. Here we developed a skin and soft tissue infection model in rabbits to test the hypothesis that PVL contributes to USA300 pathogenesis and compare it with well-established virulence determinants: alpha-hemolysin (Hla), phenol-soluble modulin-alpha peptides (PSM alpha), and accessory gene regulator (Agr). The data indicate that Hla, PSM alpha, and Agr contribute to the pathogenesis of USA300 skin infections in rabbits, whereas a role for PVL could not be detected. C1 [Kobayashi, Scott D.; Malachowa, Natalia; Whitney, Adeline R.; Braughton, Kevin R.; Otto, Michael; DeLeo, Frank R.] NIAID, Rocky Mt Labs, NIH, Vet Branch, Hamilton, MT 59840 USA. [Gardner, Donald J.; Long, Dan] NIAID, Rocky Mt Labs, NIH, Vet Branch, Bethesda, MD USA. [Kobayashi, Scott D.; Malachowa, Natalia; Braughton, Kevin R.; Otto, Michael; DeLeo, Frank R.] NIAID, NIH, Lab Human Bacterial Pathogenesis, Hamilton, MT USA. [Kobayashi, Scott D.; Malachowa, Natalia; Whitney, Adeline R.; Braughton, Kevin R.; Otto, Michael; DeLeo, Frank R.] NIAID, NIH, Lab Human Bacterial Pathogenesis, Bethesda, MD 20892 USA. [BubeckWardenburg, Juliane; Schneewind, Olaf] Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA. [BubeckWardenburg, Juliane] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. RP DeLeo, FR (reprint author), NIAID, Rocky Mt Labs, NIH, Vet Branch, 903 S 4th St, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516; Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); Region V Great Lakes Regional Center of Excellence (RCE) (NIH) [2-U54-AI-057153] FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). J. B. W. and O. S. acknowledge membership in and support from the Region V Great Lakes Regional Center of Excellence (RCE) (NIH award 2-U54-AI-057153). NR 17 TC 120 Z9 121 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2011 VL 204 IS 6 BP 937 EP 941 DI 10.1093/infdis/jir441 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 809QJ UT WOS:000294071500017 PM 21849291 ER PT J AU Huang, WW Huang, RL Attene-Ramos, MS Sakamuru, S Englund, EE Inglese, J Austin, CP Xia, MH AF Huang, Wenwei Huang, Ruili Attene-Ramos, Matias S. Sakamuru, Srilatha Englund, Erika E. Inglese, James Austin, Christopher P. Xia, Menghang TI Synthesis and evaluation of quinazolin-4-ones as hypoxia-inducible factor-1 alpha inhibitors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Hypoxia-inducible factor-1 alpha; Quinazolin-4-ones; Parallel synthesis ID SIGNALING PATHWAY; TARGETING HYPOXIA; CELL-GROWTH; HIF-1-ALPHA; CANCER; IDENTIFICATION; ANGIOGENESIS; DERIVATIVES; THERAPY; BIOLOGY AB Quinazolin-4-one 1 was identified as an inhibitor of the HIF-1 alpha transcriptional factor from a high-throughput screen. HIF-1 alpha up-regulation is common in many cancer cells. In this Letter, we describe an efficient one-pot sequential reaction for the synthesis of quinazolin-4-one 1 analogues. The structure-activity relationship (SAR) study led to the 5-fold more potent analogue, 16. Published by Elsevier Ltd. C1 [Huang, Wenwei; Huang, Ruili; Attene-Ramos, Matias S.; Sakamuru, Srilatha; Englund, Erika E.; Inglese, James; Austin, Christopher P.; Xia, Menghang] NHGRI, NIH Chem Genom Ctr, NIH, Rockville, MD 20850 USA. RP Huang, WW (reprint author), NHGRI, NIH Chem Genom Ctr, NIH, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM huangwe@mail.nih.gov FU Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research, National Institutes of Health FX We thank Paul Shinn and Danielle Van Leer for compound management, William Leister and Jeremy Smith for analytical chemistry. This research was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research, National Institutes of Health. NR 26 TC 4 Z9 4 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 15 PY 2011 VL 21 IS 18 BP 5239 EP 5243 DI 10.1016/j.bmcl.2011.07.043 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 809KB UT WOS:000294051800022 PM 21831635 ER PT J AU Bogatcheva, E Hanrahan, C Nikonenko, B de los Santos, G Reddy, V Chen, P Barbosa, F Einck, L Nacy, C Protopopova, M AF Bogatcheva, Elena Hanrahan, Colleen Nikonenko, Boris de los Santos, Gladys Reddy, Venkata Chen, Ping Barbosa, Francis Einck, Leo Nacy, Carol Protopopova, Marina TI Identification of SQ609 as a lead compound from a library of dipiperidines SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Dipiperidine scaffold; (Piperidin-4-ylmethyl)piperidine; Tuberculosis; Combinatorial library ID MYCOBACTERIUM-TUBERCULOSIS; SCAFFOLDS AB We recently reported that compounds created around a dipiperidine scaffold demonstrated activity against Mycobacterium tuberculosis (Mtb) (Bogatcheva, E.; Hanrahan, C.; Chen, P.; Gearhart, J.; Sacksteder, K.; Einck, L.; Nacy, C.; Protopopova, M. Bioorg. Med. Chem. Lett. 2010, 20, 201). To optimize the dipiperidine compound series and to select a lead compound to advance into preclinical studies, we evaluated the structure-activity relationship (SAR) of our proprietary libraries. The (piperidin-4-ylmethyl) piperidine scaffold was an essential structural element required for antibacterial activity. Based on SAR, we synthesized a focused library of 313 new dipiperidines to delineate additional structural features responsible for antitubercular activity. Thirty new active compounds with MIC 10-20 mu g/ml on Mtb were identified, but none was better than the original hits of this series, SQ609, SQ614, and SQ615. In Mtb-infected macrophages in vitro, SQ609 and SQ614 inhibited more than 90% of intracellular bacterial growth at 4 mu g/ml; SQ615 was toxic to these cells. In mice infected with Mtb, weight loss was completely prevented by SQ609, but not SQ614, and SQ609 had a prolonged therapeutic effect, extended by 10-15 days, after cessation of therapy. Based on in vitro and in vivo antitubercular activity, SQ609 was identified as the best-in-class dipiperidine compound in the series. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Bogatcheva, Elena; Nikonenko, Boris; Reddy, Venkata; Einck, Leo; Nacy, Carol; Protopopova, Marina] Sequella Inc, Rockville, MD 20850 USA. [Hanrahan, Colleen] Johns Hopkins Sch Med, Baltimore, MD USA. [Hanrahan, Colleen] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. [Chen, Ping] NIAID, NIH, Bethesda, MD 20892 USA. [Barbosa, Francis] Sibley Hosp, Washington, DC 20016 USA. [de los Santos, Gladys] Ctr Invest Quim Aplicada, Saltillo 25250, Coahuila, Mexico. RP Bogatcheva, E (reprint author), Sequella Inc, 9610 Med Ctr Dr,Suite 200, Rockville, MD 20850 USA. EM elenabogatcheva@sequella.com FU NIH NIAID [UC1A149514, 1R43AI060250] FX This work was supported by NIH NIAID UC1A149514 and 1R43AI060250. We would like to thank Mr. Gardner of the Research Triangle Institute for acquiring mass spectra. NR 13 TC 27 Z9 29 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 15 PY 2011 VL 21 IS 18 BP 5353 EP 5357 DI 10.1016/j.bmcl.2011.07.015 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 809KB UT WOS:000294051800047 PM 21807506 ER PT J AU Wang, XH Meyers, C Guo, M Zheng, ZM AF Wang, Xiaohong Meyers, Craig Guo, Ming Zheng, Zhi-Ming TI Upregulation of p18Ink4c expression by oncogenic HPV E6 via p53-miR-34a pathway SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE human papillomaviruses; microRNAs; p53; cell cycle control; p18ink4c ID KINASE INHIBITOR P18(INK4C); TUMOR-SUPPRESSIVE MIR-34A; PAPILLOMAVIRUS TYPE-16 E7; SQUAMOUS-CELL CARCINOMA; CERVICAL-CANCER; GENE-EXPRESSION; G1 CYCLIN; APOPTOSIS; ONCOPROTEIN; ACTIVATION AB Binding of p53 to miR-34a promoter activates the expression of tumor-suppressive miR-34a. Oncogenic human papillomavirus (HPV) infection downregulates miR-34a expression through viral E6 degradation of p53. In our report, we found that miR-34a specifically targets p18Ink4c, a CDK4 and CDK6 inhibitor induced by E2F transactivation. HPV18(+) HeLa cells with ectopic miR-34a expression or by E6 siRNA knockdown-induced expression of endogenous miR-34a exhibited a substantial reduction of p18Ink4c in a dose-dependent manner, but had no effect on p16Ink4a, another member of CDK4/6 inhibitor family. In contrast, de novo infection by oncogenic HPVs of human keratinocyte-derived raft tissues increased p18Ink4c expression. Suppression of endogenous miR-34a in cell lines with a miR-34a inhibitor also increased p18Ink4c. We found that miR-34a suppresses the expression of p18Ink4c by binding to a specific seed match in the 5' UTR of p18Ink4c. Further investigation found remarkable increase of p18Ink4c in cervical precancer lesions and cervical cancer. Immunohistochemical staining of cervical tissue arrays showed increased expression of p18Ink4c in 68% of cervical cancer, 8.3% of chronic cervical inflammation and 4.8% of normal cervix. Although p18Ink4c inhibits cell proliferation in general and regulates E2F1 expression in HCT116 cells, it appears not to function as a tumor suppressor in cervical cancer cells lacking an intact G1 checkpoint because of viral E7 degradation of pRB. In summary, our study demonstrates an intimate connection among oncogenic HPV E6, p53, miR-34a and p18Ink4c and identifies p18Ink4c as a possible biomarker for cervical cancer. C1 [Wang, Xiaohong; Zheng, Zhi-Ming] NCI, Tumor Virus RNA Biol Sect, HIV & AIDS Malignancy Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Meyers, Craig] Penn State Univ, Sch Med, Dept Microbiol & Immunol, Hershey, PA USA. [Guo, Ming] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. RP Zheng, ZM (reprint author), 10 Ctr Dr,Rm 6N106, Bethesda, MD 20892 USA. EM zhengt@exchange.nih.gov FU US National Institutes of Health [AI057988]; National Institutes of Health; National Cancer Institute; Center for Cancer Research FX Grant sponsor: US National Institutes of Health; Grant number: AI057988; Grant sponsors: Intramural Research Program of the National Institutes of Health, the National Cancer Institute and the Center for Cancer Research NR 50 TC 30 Z9 34 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2011 VL 129 IS 6 BP 1362 EP 1372 DI 10.1002/ijc.25800 PG 11 WC Oncology SC Oncology GA 798XP UT WOS:000293245800011 PM 21128241 ER PT J AU Shen, GP Pan, QH Hong, MH Qin, HD Xu, YF Chen, LZ Feng, QS Jorgensen, TJ Shugart, YY Zeng, YX Jia, WH AF Shen, Guo-Ping Pan, Qing-Hua Hong, Ming-Huang Qin, Hai-De Xu, Ya-Fei Chen, Li-Zhen Feng, Qi-Sheng Jorgensen, Timothy J. Shugart, Yin Yao Zeng, Yi-Xin Jia, Wei-Hua TI Human genetic variants of homologous recombination repair genes first found to be associated with Epstein-Barr virus antibody titers in healthy Cantonese SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Epstein-Barr virus; antiviral capsid antigen; homologous recombination repair; single nucleotide polymorphism; nasopharyngeal carcinoma ID DNA-DAMAGE RESPONSE; CYCLE-CONTROL GENES; NASOPHARYNGEAL CARCINOMA; VIRAL REPLICATION; MASS SURVEY; P53; INFECTION; 53BP1; CELLS; GENOME AB Epstein-Barr virus (EBV) infection is a major risk factor for nasopharyngeal carcinoma (NPC). Despite high prevalence of infection among the general population worldwide, only a small proportion of infected individuals presents with seropositivity for EBV-specific IgA antibodies. This seropositive subgroup of EBV carriers has an elevated cumulative risk for NPC during their lifetime. Previous studies reported that the host homologous recombination repair (HRR) system participates in EBV lytic replication, suggesting a potential mechanism to influence EBV reactivation status and thus seropositivity. To investigate whether genetic variants of HRR genes are associated with the serostatus in a healthy population, we investigated the association between seropositivity for anti-VCA-IgA and 156 tagging SNPs in 35 genes connected with HRR in an observational study among 755 healthy Cantonese speakers in southern China. Six variant alleles of MDC1, RAD54L, TP53BP1, RPA1, LIG3 and RFC1 exhibited associations with seropositivity (p(trend) from 0.0085 to 0.00027). Our study provides evidence that genetic variation within the HRR might affect an individual's propensity for EBV seropositive status of anti-VCA IgA antibody. C1 [Shen, Guo-Ping; Pan, Qing-Hua; Hong, Ming-Huang; Qin, Hai-De; Xu, Ya-Fei; Chen, Li-Zhen; Feng, Qi-Sheng; Zeng, Yi-Xin; Jia, Wei-Hua] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol So China, Guangzhou 510060, Guangdong, Peoples R China. [Shen, Guo-Ping; Hong, Ming-Huang] Sun Yat Sen Univ, Ctr Canc, Clin Dept Nasopharyngeal Carcinoma, Guangzhou 510060, Guangdong, Peoples R China. [Pan, Qing-Hua; Qin, Hai-De; Xu, Ya-Fei; Chen, Li-Zhen; Feng, Qi-Sheng; Zeng, Yi-Xin; Jia, Wei-Hua] Sun Yat Sen Univ, Ctr Canc, Dept Expt Res, Guangzhou 510060, Guangdong, Peoples R China. [Hong, Ming-Huang] Sun Yat Sen Univ, Ctr Canc, Clin Trials Ctr, Guangzhou 510060, Guangdong, Peoples R China. [Hong, Ming-Huang] Sun Yat Sen Univ, Ctr Canc, Inst Drug Clin Trials, Guangzhou 510060, Guangdong, Peoples R China. [Jorgensen, Timothy J.] Georgetown Univ, Jess & Mildred Fisher Ctr Familial Canc Res, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Jorgensen, Timothy J.; Shugart, Yin Yao] NIMH, Genom Res Branch, Div Neurosci Ctr, NIH, Bethesda, MD 20892 USA. RP Jia, WH (reprint author), Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol So China, Guangzhou 510060, Guangdong, Peoples R China. EM jiaweih@mail.sysu.edu.cn FU National Natural Science Foundation of China [30671798, 30471487, 81000925]; National Science and Technology Support Program of China [2006BAI02A11]; National Major Basic Research Program of China [863:2006AA02A404, 973:2006CB910104, 973:2011CB504303]; Program for Changjiang Scholars and Innovative Research Team in University [IRT0663] FX Grant sponsor: National Natural Science Foundation of China; Grant numbers: 30671798, 30471487, 81000925; Grant sponsor: National Science and Technology Support Program of China; Grant number: 2006BAI02A11; Grant sponsor: National Major Basic Research Program of China; Grant numbers: 863:2006AA02A404, 973:2006CB910104, 973:2011CB504303; Grant sponsor: Program for Changjiang Scholars and Innovative Research Team in University; Grant number: IRT0663. NR 46 TC 9 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2011 VL 129 IS 6 BP 1459 EP 1466 DI 10.1002/ijc.25759 PG 8 WC Oncology SC Oncology GA 798XP UT WOS:000293245800022 PM 21792882 ER PT J AU O'Doherty, MG Cantwell, MM Murray, LJ Anderson, LA Abnet, CC AF O'Doherty, Mark G. Cantwell, Marie M. Murray, Liam J. Anderson, Lesley A. Abnet, Christian C. CA FINBAR Study Grp TI Dietary fat and meat intakes and risk of reflux esophagitis, Barrett's esophagus and esophageal adenocarcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE adenocarcinoma; Barrett's esophagus; dietary fat; epidemiology; meat ID N-NITROSO COMPOUNDS; GASTRIC CARDIA; CANCER-RISK; PROCESSED MEAT; TRACT CANCER; RAT MODEL; IRON; STOMACH; HEME; RED AB The aim of our study was to investigate whether dietary fat and meat intakes are associated with reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). In this all-Ireland case-control study, dietary intake data were collected using a food frequency questionnaire in 219 RE patients, 220 BE patients, 224 EAC patients and 256 frequency-matched controls between 2002 and 2005. Unconditional multiple logistic regression analysis was used to examine the association between dietary variables and disease risk using quartiles of intake, to attain odds ratios (ORs) and 95% confidence intervals (95% CIs), while adjusting for potential confounders. Patients in the highest quartile of total fat intake had a higher risk of RE (OR = 3.54; 95% CI = 1.32-9.46) and EAC (OR = 5.44; 95% CI = 2.08-14.27). A higher risk of RE and EAC was also reported for patients in the highest quartile of saturated fat intake (OR = 2.79; 95% CI = 1.11-7.04; OR = 2.41; 95% CI = 1.14-5.08, respectively) and monounsaturated fat intake (OR = 2.63; 95% CI = 1.01-6.86; OR = 5.35; 95% CI = 2.14-13.34, respectively). Patients in the highest quartile of fresh red meat intake had a higher risk of EAC (OR = 3.15; 95% CI = 1.38-7.20). Patients in the highest category of processed meat intake had a higher risk of RE (OR = 4.67; 95% CI = 1.71-12.74). No consistent associations were seen for BE with either fat or meat intakes. Further studies investigating the association between dietary fat and food sources of fat are needed to confirm these results. C1 [O'Doherty, Mark G.] Queens Univ Belfast, Canc Epidemiol Hlth Serv Res Grp, Ctr Publ Hlth, Inst Clin Sci, Belfast BT12 6BA, Antrim, North Ireland. [Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD USA. RP O'Doherty, MG (reprint author), Queens Univ Belfast, Canc Epidemiol Hlth Serv Res Grp, Ctr Publ Hlth, Inst Clin Sci, Block B,Grosvenor Rd, Belfast BT12 6BA, Antrim, North Ireland. EM m.odoherty@qub.ac.uk RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; Anderson, Lesley/0000-0002-1000-3649 FU Health and Social Care Research & Development Office (Belfast, Northern Ireland); National Institutes of Health, National Cancer Institute (Bethesda, MD, USA) (All-Ireland National Cancer Institute Cancer Consortium); Health Research Board (Dublin, Ireland); Ulster Cancer Foundation (Belfast, Northern Ireland) FX Grant sponsors: Health and Social Care Research & Development Office (Belfast, Northern Ireland) and the Intramural Research Program of the National Institutes of Health, National Cancer Institute (Bethesda, MD, USA) (All-Ireland National Cancer Institute Cancer Consortium Joint Research Project in Cancer), Health Research Board (Dublin, Ireland), Ulster Cancer Foundation (Belfast, Northern Ireland). NR 49 TC 24 Z9 24 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2011 VL 129 IS 6 BP 1493 EP 1502 DI 10.1002/ijc.26108 PG 10 WC Oncology SC Oncology GA 798XP UT WOS:000293245800026 PM 21455992 ER PT J AU Parsons, HM Tuttle, TM Kuntz, KM Begun, JW McGovern, PM Virnig, BA AF Parsons, Helen M. Tuttle, Todd M. Kuntz, Karen M. Begun, James W. McGovern, Patricia M. Virnig, Beth A. TI Association Between Lymph Node Evaluation for Colon Cancer and Node Positivity Over the Past 20 Years SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID COLORECTAL-CANCER; RECTAL-CANCER; SURVIVAL; POPULATION; MICROMETASTASES; RESECTION; SURGERY; NUMBER; STAGE; ADENOCARCINOMA AB Context Among patients surgically treated for colon cancer, better survival has been demonstrated in those with more lymph nodes evaluated. The presumed mechanism behind this association suggests that a more extensive lymph node evaluation reduces the risk of understaging, leading to improved survival. Objective To further evaluate the mechanism behind lymph node evaluation and survival by examining the association between more extensive lymph node evaluation, identification of lymph node-positive cancers, and hazard of death. Design Observational cohort study. Setting Surveillance, Epidemiology, and End Results (SEER) program data from 1988 through 2008. Patients 86 394 patients surgically treated for colon cancer. Main Outcome Measure We examined the relationship between lymph node evaluation and node positivity using Cochran-Armitage tests and multivariate logistic regression. The association between lymph node evaluation and hazard of death was evaluated using Cox proportional hazards modeling. Results The number of lymph nodes evaluated increased from 1988 to 2008 but did not result in a significant overall increase in lymph node positivity. During 1988-1990, 34.6% of patients (3875/11 200) had 12 or more lymph nodes evaluated, increasing to 73.6% (9798/13 310) during 2006-2008 (P<.001); however, the proportion of node-positive cancers did not change with time (40% in 1988-1990, 42% in 2006-2008, P=.53). Although patients with high levels of lymph node evaluation were only slightly more likely to be node positive (adjusted odds ratio for 30-39 nodes vs 1-8 nodes, 1.11; 95% CI, 1.02-1.20), these patients experienced significantly lower hazard of death compared with those with fewer nodes evaluated (adjusted hazard ratio for 30-39 nodes vs 1-8 nodes, 0.66; 95% CI, 0.62-0.71; unadjusted 5-year mortality, 35.3%). Conclusion The number of lymph nodes evaluated for colon cancer has markedly increased in the past 2 decades but was not associated with an overall shift toward higher-staged cancers, questioning the upstaging mechanism as the primary basis for improved survival in patients with more lymph nodes evaluated. JAMA. 2011;306(10):1089-1097 www.jama.com C1 [Parsons, Helen M.] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Tuttle, Todd M.] Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. [Kuntz, Karen M.; Begun, James W.; Virnig, Beth A.] Univ Minnesota, Div Hlth Policy & Management, Minneapolis, MN 55455 USA. [McGovern, Patricia M.] Univ Minnesota, Div Environm Hlth Sci, Minneapolis, MN 55455 USA. [Tuttle, Todd M.; Virnig, Beth A.] Masonic Canc Ctr, Minneapolis, MN USA. RP Parsons, HM (reprint author), NCI, Appl Res Program, Execut Plaza N,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM helen.parsons@nih.gov NR 32 TC 79 Z9 82 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 14 PY 2011 VL 306 IS 10 BP 1089 EP 1097 DI 10.1001/jama.2011.1285 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 819DS UT WOS:000294806200022 PM 21917579 ER PT J AU Lorieau, JL Louis, JM Bax, A AF Lorieau, Justin L. Louis, John M. Bax, Ad TI Whole-Body Rocking Motion of a Fusion Peptide in Lipid Bilayers from Size-Dispersed N-15 NMR Relaxation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MODEL-FREE APPROACH; MAGNETIC-RESONANCE RELAXATION; INFLUENZA HEMAGGLUTININ; MEMBRANE-PROTEINS; STATE NMR; ROTATIONAL DIFFUSION; MOLECULAR-DYNAMICS; ORIENTATION; VIRUS; SPECTROSCOPY AB Biological membranes present a highly fluid environment, and integration of proteins within such membranes is itself highly dynamic: proteins diffuse laterally within the plane of the membrane and rotationally about the normal vector of this plane. We demonstrate that whole-body motions of proteins within a lipid bilayer can be determined from NMR N-15 relaxation rates collected for different-sized bicelles. The importance of membrane integration and interaction is particularly acute for proteins and peptides that function on the membrane itself, as is the case for pore-forming and fusion-inducing proteins. For the influenza hemagglutinin fusion peptide, which lies on the surface of membranes and catalyzes the fusion of membranes and vesicles, we found large-amplitude, rigid-body wobbling motions on the nanosecond time scale relative to the lipid bilayer. This behavior complements prior analyses where data were commonly interpreted in terms of a static oblique angle of insertion for the fusion peptide with respect to the membrane. Quantitative disentanglement of the relative motions of two interacting objects by systematic variation of the size of one is applicable to a wide range of systems beyond protein-membrane interactions. C1 [Lorieau, Justin L.; Louis, John M.; Bax, Ad] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM bax@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); Office of the Director, NIH FX We thank Annie Aniana and Jane Sayer for help with protein expression, purification, and mass spectrometry and Dennis Torchia and Attila Szabo for many helpful discussions. This work was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. NR 42 TC 19 Z9 21 U1 1 U2 16 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 SEP 14 PY 2011 VL 133 IS 36 BP 14184 EP 14187 DI 10.1021/ja2045309 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 824HT UT WOS:000295193700010 PM 21848255 ER PT J AU Gong, B Klein, DJ Ferre-D'Amare, AR Carey, PR AF Gong, Bo Klein, Daniel J. Ferre-D'Amare, Adrian R. Carey, Paul R. TI The glmS Ribozyme Tunes the Catalytically Critical pK(a) of Its Coenzyme Glucosamine-6-phosphate SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID DELTA VIRUS RIBOZYME; ACTIVE-SITE ADENINE; HAIRPIN RIBOZYME; RAMAN CRYSTALLOGRAPHY; CATALYSIS; RIBOSWITCH; MECHANISM; ACTIVATION; NEUTRALITY; COFACTOR AB The glmS ribozyme riboswitch is the first known natural catalytic RNA that employs a small-molecule cofactor. Binding of glucosamine-6-phosphate (GlcN6P) uncovers the latent self-cleavage activity of the RNA, which adopts a catalytically competent conformation that is nonetheless inactive in the absence of GlcN6P. Structural and analogue studies suggest that the amine of GlcN6P functions as a general acid-base catalyst, while its phosphate is important for binding affinity. However, the solution pK(a) of the amine is 8.06 +/- 0.05, which is not optimal for proton transfer. Here we used Raman crystallography directly to determine the pK(a)'s of GlcN6P bound to the glmS ribozyme. Binding to the RNA lowers the pK(a) of the amine of GlcN6P to 7.26 +/- 0.09 and raises the pK(a) of its phosphate to 6.35 +/- 0.09. Remarkably, the pK(a)'s of these two functional groups are unchanged from their values for free GlcN6P (8.06 +/- 0.05 and 5.98 +/- 0.05, respectively) when GlcN6P binds to the catalytically inactive but structurally unperturbed G40A mutant of the ribozyme, thus implicating the ribozyme active site guanine in pK(a) tuning. This is the first demonstration that a ribozyme can tune the pK(a) of a small-molecule ligand. Moreover, the anionic glmS ribozyme in effect stabilizes the neutral amine of GlcN6P by lowering its pK(a). This is unprecedented and illustrates the chemical sophistication of ribozyme active sites. C1 [Ferre-D'Amare, Adrian R.] NHLBI, Lab RNA Biophys & Cellular Physiol, Bethesda, MD 20892 USA. [Gong, Bo; Carey, Paul R.] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. [Klein, Daniel J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, Lab RNA Biophys & Cellular Physiol, 50 South Dr, Bethesda, MD 20892 USA. EM ferrea@mail.nih.gov; paul.carey@case.edu RI Gong, Bo /E-8870-2010 FU National Institutes of Health [GM84976, GM63576, GM84120]; W. M. Keck Foundation; National Heart, Lung, and Blood Institute FX We thank M. Lau and H. Xiao for help in preparation of glmS crystals. This work was supported in part by grants from the National Institutes of Health (GM84976 to D.J.K, GM63576 to A.R.F., and GM84120 to P.R.C.), the W. M. Keck Foundation (A.R.F.), and the intramural program of the National Heart, Lung, and Blood Institute (A.R.F.) NR 28 TC 24 Z9 24 U1 0 U2 15 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 SEP 14 PY 2011 VL 133 IS 36 BP 14188 EP 14191 DI 10.1021/ja205185g PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 824HT UT WOS:000295193700011 PM 21848325 ER PT J AU Basu, SK Malik, R Huggins, CJ Lee, S Sebastian, T Sakchaisri, K Quinones, OA Alvord, WG Johnson, PF AF Basu, Sandip K. Malik, Radek Huggins, Christopher J. Lee, Sook Sebastian, Thomas Sakchaisri, Krisada Quinones, Octavio A. Alvord, W. Gregory Johnson, Peter F. TI 3 ' UTR elements inhibit Ras-induced C/EBP beta post-translational activation and senescence in tumour cells SO EMBO JOURNAL LA English DT Article DE C/EBP beta; mRNA trafficking; oncogene-induced senescence; Ras signalling; 3 ' UTR ID BINDING-PROTEIN-BETA; ONCOGENE-INDUCED SENESCENCE; POSTTRANSCRIPTIONAL GENE-REGULATION; MESSENGER-RNA STABILITY; AU-RICH ELEMENTS; CELLULAR SENESCENCE; UNTRANSLATED REGION; CYCLE ARREST; DNA-BINDING; IN-VIVO AB C/EBP beta is an auto-repressed protein that becomes post-translationally activated by Ras-MEK-ERK signalling. C/EBP beta is required for oncogene-induced senescence (OIS) of primary fibroblasts, but also displays pro-oncogenic functions in many tumour cells. Here, we show that C/EBP beta activation by H-Ras(V12) is suppressed in immortalized/transformed cells, but not in primary cells, by its 30 untranslated region (3'UTR). 3'UTR sequences inhibited Ras-induced cytostatic activity of C/EBP beta, DNA binding, transactivation, phosphorylation, and homodimerization, without significantly affecting protein expression. The 3'UTR suppressed induction of senescence-associated C/EBP beta target genes, while promoting expression of genes linked to cancers and TGF beta signalling. An AU-rich element (ARE) and its cognate RNA-binding protein, HuR, were required for 3'UTR inhibition. These components also excluded the Cebpb mRNA from a perinuclear cytoplasmic region that contains activated ERK1/2, indicating that the site of C/EBP beta translation controls de-repression by Ras signalling. Notably, 3'UTR inhibition and Cebpb mRNA compartmentalization were absent in primary fibroblasts, allowing Ras-induced C/EBP beta activation and OIS to proceed. Our findings reveal a novel mechanism whereby non-coding mRNA sequences selectively regulate C/EBP beta activity and suppress its anti-oncogenic functions. The EMBO Journal (2011) 30, 3714-3728. doi: 10.1038/emboj.2011.250; Published online 29 July 2011 C1 [Basu, Sandip K.; Malik, Radek; Huggins, Christopher J.; Lee, Sook; Sebastian, Thomas; Sakchaisri, Krisada; Johnson, Peter F.] NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Quinones, Octavio A.; Alvord, W. Gregory] NCI, Data Management Serv, Frederick, MD 21701 USA. RP Johnson, PF (reprint author), NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Bldg 539,Rm 122, Frederick, MD 21701 USA. EM johnsope@mail.nih.gov RI Johnson, Peter/A-1940-2012; Malik, Radek/G-3578-2014 OI Johnson, Peter/0000-0002-4145-4725; FU NIH, National Cancer Institute, Center for Cancer Research FX We thank M Gorospe for HuR vectors, K Kosick for the GFP reporter/mRNA visualization system, F Rauscher for the MT inducible vector, X Wu for assistance with microarrays, K Peifley and S Lockett for confocal microscopy support, J Hao for generating the pWZL-ER:RasV12 construct, and J Wada for preparation of figures. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 55 TC 20 Z9 20 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD SEP 14 PY 2011 VL 30 IS 18 BP 3714 EP 3728 DI 10.1038/emboj.2011.250 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 821UK UT WOS:000294999700006 PM 21804532 ER PT J AU Li, XC Wei, L Zhang, GQ Bai, ZL Hu, YY Zhou, P Bai, SH Chai, Z Lakatta, EG Hao, XM Wang, SQ AF Li, Xiao-Chen Wei, Ling Zhang, Guang-Qin Bai, Zai-Ling Hu, Ying-Ying Zhou, Peng Bai, Shu-Hua Chai, Zhen Lakatta, Edward G. Hao, Xue-Mei Wang, Shi-Qiang TI Ca2+ Cycling in Heart Cells from Ground Squirrels: Adaptive Strategies for Intracellular Ca2+ Homeostasis SO PLOS ONE LA English DT Article ID VENTRICULAR-FIBRILLATION; SARCOPLASMIC-RETICULUM; HIBERNATING CHIPMUNKS; CARDIAC-HYPERTROPHY; CALCIUM; RAT; HYPOTHERMIA; CHANNEL; MYOCARDIUM; RYANODINE AB Heart tissues from hibernating mammals, such as ground squirrels, are able to endure hypothermia, hypoxia and other extreme insulting factors that are fatal for human and nonhibernating mammals. This study was designed to understand adaptive mechanisms involved in intracellular Ca2+ homeostasis in cardiomyocytes from the mammalian hibernator, ground squirrel, compared to rat. Electrophysiological and confocal imaging experiments showed that the voltage-dependence of L-type Ca2+ current (I-Ca) was shifted to higher potentials in ventricular myocytes from ground squirrels vs. rats. The elevated threshold of I-Ca did not compromise the Ca2+-induced Ca2+ release, because a higher depolarization rate and a longer duration of action potential compensated the voltage shift of I-Ca. Both the caffeine-sensitive and caffeine-resistant components of cytosolic Ca2+ removal were more rapid in ground squirrels. Ca2+ sparks in ground squirrels exhibited larger amplitude/size and much lower frequency than in rats. Due to the high I-Ca threshold, low SR Ca2+ leak and rapid cytosolic Ca2+ clearance, heart cells from ground squirrels exhibited better capability in maintaining intracellular Ca2+ homeostasis than those from rats and other nonhibernating mammals. These findings not only reveal adaptive mechanisms of hibernation, but also provide novel strategies against Ca2+ overload-related heart diseases. C1 [Li, Xiao-Chen; Wei, Ling; Bai, Zai-Ling; Hu, Ying-Ying; Zhou, Peng; Bai, Shu-Hua; Chai, Zhen; Hao, Xue-Mei; Wang, Shi-Qiang] Peking Univ, Coll Life Sci, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China. [Zhang, Guang-Qin] China Pharmaceut Univ, Res Div Pharmacol, Nanjing 210009, Peoples R China. [Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Li, XC (reprint author), Peking Univ, Coll Life Sci, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China. EM wsq@pku.edu.cn RI Zhou, Peng/M-3917-2013 FU 973 Major State Basic Research Development Program of China [2011CB809101]; 863 Program [2007AA02Z457]; National Natural Science Foundation of China [30730013]; National Institutes of Health, USA [NIH R01 TW007269]; National Institute on Aging, NIH FX This work was supported by the 973 Major State Basic Research Development Program of China (2011CB809101); the 863 Program (2007AA02Z457); the National Natural Science Foundation of China (30730013); the National Institutes of Health, USA (NIH R01 TW007269); and the Intramural Research Program of the National Institute on Aging, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 11 Z9 14 U1 1 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 14 PY 2011 VL 6 IS 9 AR e24787 DI 10.1371/journal.pone.0024787 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822JC UT WOS:000295039700048 PM 21935466 ER PT J AU Luo, ZC Volkow, ND Heintz, N Pan, YT Du, CW AF Luo, Zhongchi Volkow, Nora D. Heintz, Nathaniel Pan, Yingtian Du, Congwu TI Acute Cocaine Induces Fast Activation of D1 Receptor and Progressive Deactivation of D2 Receptor Striatal Neurons: In Vivo Optical Microprobe [Ca2+](i) Imaging SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SOMATOSENSORY CORTICAL-NEURONS; BASAL GANGLIA DISORDERS; CENTRAL-NERVOUS-SYSTEM; CEREBRAL-CORTEX; MULTIPHOTON MICROSCOPY; DOPAMINE D-1; ADULT-RAT; BRAIN; BEHAVIOR; ANTAGONISTS AB Cocaine induces fast dopamine increases in brain striatal regions, which are recognized to underlie its rewarding effects. Both dopamine D1 and D2 receptors are involved in cocaine's reward but the dynamic downstream consequences of cocaine effects in striatum are not fully understood. Here we used transgenic mice expressing EGFP under the control of either the D1 receptor (D1R) or the D2 receptor (D2R) gene and microprobe optical imaging to assess the dynamic changes in intracellular calcium ([Ca2+](i)) responses (used as marker of neuronal activation) to acute cocaine in vivo separately for D1R-versus D2R-expressing neurons in striatum. Acute cocaine (8 mg/kg, i. p.) rapidly increased [Ca2+](i) in D1R-expressing neurons (10.6 +/- 3.2%) in striatum within 8.3 +/- 2.3 min after cocaine administration after which the increases plateaued; these fast [Ca2+](i) increases were blocked by pretreatment with a D1R antagonist (SCH23390). In contrast, cocaine induced progressive decreases in [Ca2+](i) in D2R-expressing neurons (10.4 +/- 5.8%) continuously throughout the 30 min that followed cocaine administration; these slower [Ca2+](i) decreases were blocked by pretreatment with a D2R antagonist (raclopride). Since activation of striatal D1R-expressing neurons (direct-pathway) enhances cocaine reward, whereas activation of D2R-expressing neurons suppresses it (indirect-pathway) (Lobo et al., 2010), this suggests that cocaine's rewarding effects entail both its fast stimulation of D1R(resulting in abrupt activation of direct-pathway neurons) and a slower stimulation of D2R(resulting in longer-lasting deactivation of indirect-pathway neurons). We also provide direct in vivo evidence of D2R and D1R interactions in the striatal responses to acute cocaine administration. C1 [Du, Congwu] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Luo, Zhongchi; Pan, Yingtian] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Du, Congwu] SUNY Stony Brook, Dept Anesthesiol, Stony Brook, NY 11794 USA. [Volkow, Nora D.] NIAAA, NIH, Bethesda, MD 20892 USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. [Heintz, Nathaniel] Rockefeller Univ, Howard Hughes Med Inst, Mol Biol Lab, New York, NY 10065 USA. RP Du, CW (reprint author), Brookhaven Natl Lab, Dept Med, Bldg 490,Bell Ave, Upton, NY 11973 USA. EM yinpan@notes.cc.sunysb.edu; congwu@bnl.gov FU NIH [K25-DA021200, 2R01-DK059265, 1RC1DA028534]; Brookhaven National Laboratory [LDRD 10-023]; Department of Energy; NIAAA FX This work was supported in part by NIH Grants K25-DA021200 (C. D.), 2R01-DK059265 (Y.P.), and 1RC1DA028534 (C. D., Y.P.), and by the Brookhaven National Laboratory (LDRD 10-023, C. D.), the Department of Energy, and the NIAAA Intramural Research Program (N.D.V.). We thank Dr. Paul Greengard of the Rockefeller University for kindly providing DrD2-EGFP mouse breeders and Dr. Myriam Heiman for suggestions on managing the colony. NR 51 TC 25 Z9 26 U1 0 U2 7 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 SEP 14 PY 2011 VL 31 IS 37 BP 13180 EP 13190 DI 10.1523/JNEUROSCI.2369-11.2011 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 819QA UT WOS:000294841900017 PM 21917801 ER PT J AU Turtzo, LC Siegel, C McCullough, LD AF Turtzo, L. Christine Siegel, Chad McCullough, Louise D. TI X Chromosome Dosage and the Response to Cerebral Ischemia SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ESTROGEN PLUS PROGESTIN; TURNER-SYNDROME; SEX-DIFFERENCES; EXPERIMENTAL STROKE; MALE-MICE; POSTMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; TABBY SYNDROME; BRAIN-INJURY; MOUSE MODEL AB Gonadal hormones contribute to ischemic neuroprotection, but cannot fully explain the observed sexual dimorphism in stroke outcomes seen during life stages with low sex steroid hormones. Sex chromosomal complement (XX in females; XY in males) may also contribute to ischemic sexual dimorphism. A transient middle cerebral artery occlusion model was used to investigate the role of X chromosome dosage in female XX and XO littermates of two mouse strains (Paf and Eda(Ta)). Cohorts of XX and XO gonadally intact, ovariectomized, and ovariectomized females supplemented with estrogen were examined. Infarct sizes were equivalent between ovariectomized XX and XO mice, between intact XX and XO mice, and between estrogen-supplemented ovariectomized XX and XO mice. This is the first study to investigate the role of sex chromosome dosage in the response to cerebral ischemia. Neither the number of X chromosomes nor the parent of origin of the remaining X chromosome had a significant effect on the degree of cerebral infarction after experimental stroke in adult female mice. Estrogen was protective against cerebral ischemia in both XX and XO mice. C1 [Turtzo, L. Christine; Siegel, Chad; McCullough, Louise D.] Univ Connecticut, Dept Neurol, Ctr Hlth, Farmington, CT 06030 USA. [Turtzo, L. Christine; Siegel, Chad; McCullough, Louise D.] Univ Connecticut, Dept Neurosci, Ctr Hlth, Farmington, CT 06030 USA. [Turtzo, L. Christine] Henry M Jackson Fdn, Ctr Neurosci & Regenerat Med, Rockville, MD 20852 USA. [Turtzo, L. Christine] NIH, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. RP McCullough, LD (reprint author), Univ Connecticut, Dept Neurol, Ctr Hlth, 263 Farmington Ave,MC1840, Farmington, CT 06030 USA. EM lmccullough@uchc.edu FU National Institutes of Health [1R01-NS055215, 5F31-NS062608] FX We thank the National Institutes of Health for funding support (L. D. M.: 1R01-NS055215 and 5F31-NS062608). We also thank Matthew Siegel for technical assistance in the blinding of images for the infarct size analysis. NR 48 TC 9 Z9 9 U1 0 U2 3 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 SEP 14 PY 2011 VL 31 IS 37 BP 13255 EP 13259 DI 10.1523/JNEUROSCI.0621-11.2011 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 819QA UT WOS:000294841900024 PM 21917808 ER PT J AU Chakir, K Depry, C Dimaano, VL Zhu, WZ Vanderheyden, M Bartunek, J Abraham, TP Tomaselli, GF Liu, SB Xiang, YK Zhang, ML Takimoto, E Dulin, N Xiao, RP Zhang, J Kass, DA AF Chakir, Khalid Depry, Charlene Dimaano, Veronica L. Zhu, Wei-Zhong Vanderheyden, Marc Bartunek, Jozef Abraham, Theodore P. Tomaselli, Gordon F. Liu, Shu-bai Xiang, Yang K. Zhang, Manling Takimoto, Eiki Dulin, Nickolai Xiao, Rui Ping Zhang, Jin Kass, David A. TI G alpha(s)-Biased beta(2)-Adrenergic Receptor Signaling from Restoring Synchronous Contraction in the Failing Heart SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CARDIAC-RESYNCHRONIZATION THERAPY; BETA-ADRENERGIC-RECEPTOR; PROTEIN-KINASE-C; ADENYLYL-CYCLASE; GENE-EXPRESSION; RGS PROTEINS; FAILURE; MYOCYTES; ACTIVATION; MICE AB Cardiac resynchronization therapy (CRT), in which both ventricles are paced to recoordinate contraction in hearts that are dyssynchronous from conduction delay, is the only heart failure (HF) therapy to date to clinically improve acute and chronic function while also lowering mortality. CRT acutely enhances chamber mechanical efficiency but chronically alters myocyte signaling, including improving beta-adrenergic receptor reserve. We speculated that the latter would identify unique CRT effects that might themselves be effective for HF more generally. HF was induced in dogs by 6 weeks of atrial rapid pacing with (HFdys, left bundle ablated) or without (HFsyn) dyssynchrony. We used dyssynchronous followed by resynchronized tachypacing (each 3 weeks) for CRT. Both HFdys and HFsyn myocytes had similarly depressed rest and beta-adrenergic receptor sarcomere and calcium responses, particularly the beta(2)-adrenergic response, whereas cells subjected to CRT behaved similarly to those from healthy controls. CRT myocytes exhibited suppressed G alpha(i) signaling linked to increased regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling (RGS2, RGS3), yielding G alpha(s)-biased beta(2)-adrenergic responses. This included increased adenosine cyclic AMP responsiveness and activation of sarcoplasmic reticulum-localized protein kinase A. Human CRT responders also showed up-regulated myocardial RGS2 and RGS3. Inhibition of G alpha(i) (with pertussis toxin, RGS3, or RGS2 transfection), stimulation with a G alpha(s)-biased beta(2) agonist (fenoterol), or transient (2-week) exposure to dyssynchrony restored beta-adrenergic receptor responses in HFsyn to the values obtained after CRT. These results identify a key pathway that is triggered by restoring contractile synchrony and that may represent a new therapeutic approach for a broad population of HF patients. C1 [Chakir, Khalid; Dimaano, Veronica L.; Abraham, Theodore P.; Tomaselli, Gordon F.; Zhang, Manling; Takimoto, Eiki; Kass, David A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Depry, Charlene; Zhang, Jin] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Zhu, Wei-Zhong; Xiao, Rui Ping] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Vanderheyden, Marc; Bartunek, Jozef] Onze Lieve Vrouw Hosp, Ctr Cardiovasc, B-9300 Aalst, Belgium. [Liu, Shu-bai; Xiang, Yang K.] Univ Illinois, Mol & Integrat Physiol & Neurosci Program, Urbana, IL 61820 USA. [Dulin, Nickolai] Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Kass, DA (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. EM dkass@jhmi.edu FU Public Health Service [PO1-HL077180, RO1-HL-089297, T32-HL0072, RO1-DK073368, DP1OD006419, F31-GM087079, RO1-GM085058, RO1-HL-053432]; American Heart Association; Fondation Leducq; Peter Belfer Laboratory; GE Healthcare FX Supported by Public Health Service grants PO1-HL077180, RO1-HL-089297, and T32-HL0072 (D. A. K., K. C., and M.Z.); RO1-DK073368 and DP1OD006419 (J.Z.); F31-GM087079 (C. D.); RO1-GM085058 (N.D.); and RO1-HL-053432 (E. T.); American Heart Association fellowship award (M.Z.); and Fondation Leducq, Peter Belfer Laboratory, and Abraham and Virginia Weiss Professorship (D.A.K.).; D.A.K. is a paid consultant for St. Jude Medical. T. P. A. has received honoraria and research funding from GE Healthcare, which manufactures ultrasound equipment and analysis software used in this study. The other authors declare that they have no competing interests. A provisional patent has been filed through Johns Hopkins University regarding the use of temporary dyssynchrony pacing to improve cardiac function in failing hearts. NR 44 TC 21 Z9 23 U1 0 U2 13 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD SEP 14 PY 2011 VL 3 IS 100 AR 100ra88 DI 10.1126/scitranslmed.3001909 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 819PX UT WOS:000294841400003 PM 21918105 ER PT J AU Sheetlin, S Park, Y Spouge, JL AF Sheetlin, Sergey Park, Yonil Spouge, John L. TI Objective method for estimating asymptotic parameters, with an application to sequence alignment SO PHYSICAL REVIEW E LA English DT Article ID GUMBEL SCALE PARAMETER; LOCAL ALIGNMENT; DIRECTED POLYMERS; RANDOM IMPURITIES; PSI-BLAST; STATISTICS; SEARCH; MODEL; REGRESSION; DYNAMICS AB Sequence alignment is an indispensable computational tool in modern molecular biology. The model underlying biological sequence alignment is of interest to physicists because it approximates the statistical mechanics of DNA and protein annealing, while bearing an intimate relationship to models of directed polymers in random media. Recent methods for determining the statistics of random sequence alignments have reduced the computation time to less than 1 s, opening up some interesting possibilities for online computation with biological search engines. Before implementation, however, the methods required an objective technique for computing regression coefficients pertinent to an asymptotic regime. Typically, physicists estimate parameters pertinent to an asymptotic regime subjectively: They eyeball their data; estimate the asymptotic regime where the regression model holds with reasonable accuracy; and then regress data only within the estimated asymptotic regime. Our publicly available computer program ARRP replaces the subjective assessment of the asymptotic regime with an objective change-point detection method, increasing confidence in the scientific objectivity of the parameter estimates. Asymptotic regression has potential applications across most of physics. C1 [Sheetlin, Sergey; Park, Yonil; Spouge, John L.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Sheetlin, S (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM spouge@ncbi.nlm.nih.gov FU NIH, NLM FX The authors would like to acknowledge helpful discussions with Yi-Kuo Yu. This research was supported by the Intramural Research Program of the NIH, NLM. NR 49 TC 0 Z9 0 U1 1 U2 7 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD SEP 13 PY 2011 VL 84 IS 3 AR 031914 DI 10.1103/PhysRevE.84.031914 PN 1 PG 8 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 841DH UT WOS:000296492200010 PM 22060410 ER PT J AU Zanettini, C Panlilio, LV Alicki, M Goldberg, SR Haller, J Yasar, S AF Zanettini, Claudio Panlilio, Leigh V. Alicki, Mano Goldberg, Steven R. Haller, Jozsef Yasar, Sevil TI Effects of endocannabinoid system modulation on cognitive and emotional behavior SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Article DE endocannabinoids; cognition; anxiety; depression; learning; memory; animal models ID ACID AMIDE HYDROLASE; CANNABINOID CB1 RECEPTOR; ANXIETY-LIKE BEHAVIOR; CONTEXTUAL FEAR MEMORY; SHORT-TERM-MEMORY; EXTRACELLULAR ACETYLCHOLINE CONCENTRATION; ANTIDEPRESSANT-LIKE ACTIVITY; MEDIAL PREFRONTAL CORTEX; SPATIAL WORKING-MEMORY; D-2 DOPAMINE-RECEPTORS AB Cannabis has long been known to produce cognitive and emotional effects. Research has shown that cannabinoid drugs produce these effects by driving the brain's endogenous cannabinoid system and that this system plays a modulatory role in many cognitive and emotional processes. This review focuses on the effects of endocannabinoid system modulation in animal models of cognition (learning and memory) and emotion (anxiety and depression). We review studies in which natural or synthetic cannabinoid agonists were administered to directly stimulate cannabinoid receptors or, conversely, where cannabinoid antagonists were administered to inhibit the activity of cannabinoid receptors. Inaddition, studies are reviewed that involved genetic disruption of cannabinoid receptors or genetic or pharmacological manipulation of the endocannabinoid-degrading enzyme, fatty acid amide hydrolase (FAAH). Endocannabinoids affect the function of many neurotransmitter systems, some of which play opposing roles. The diversity of cannabinoid roles and the complexity of task-dependent activation of neuronal circuits may lead to the effects of endocannabinoid system modulation being strongly dependent on environmental conditions. Recent findings are reviewed that raise the possibility that endocannabinoid signaling may change the impact of environmental influences on emotional and cognitive behavior rather than selectively affecting any specific behavior. C1 [Zanettini, Claudio; Panlilio, Leigh V.; Goldberg, Steven R.] Natl Inst Drug Abuse, Dept Hlth & Human Serv, Preclinical Pharmacol Sect, Behav Neurosci Branch,Intramural Res Program,NIH, Baltimore, MD USA. [Alicki, Mano; Haller, Jozsef] Hungarian Acad Sci, Inst Expt Med, Dept Behav Neurobiol, Budapest, Hungary. [Yasar, Sevil] Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. RP Yasar, S (reprint author), Johns Hopkins Sch Med, Dept Med, Div Geriatr Med & Gerontol, 5505 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM syasar@jhmi.edu OI Haller, Jozsef/0000-0002-1953-3726 FU National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA; Institute of Experimental Medicine, Budapest, Hungary; Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USA FX This study was supported in part by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA; by the Institute of Experimental Medicine, Budapest, Hungary and by the Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. NR 158 TC 68 Z9 70 U1 1 U2 25 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD SEP 13 PY 2011 VL 5 AR 57 DI 10.3389/fnbeh.2011.00057 PG 21 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 827YJ UT WOS:000295466000001 PM 21949506 ER PT J AU Burks, SR Ziadloo, A Hancock, HA Chaudhry, A Dean, DD Lewis, BK Frenkel, V Frank, JA AF Burks, Scott R. Ziadloo, Ali Hancock, Hilary A. Chaudhry, Aneeka Dean, Dana D. Lewis, Bobbi K. Frenkel, Victor Frank, Joseph A. TI Investigation of Cellular and Molecular Responses to Pulsed Focused Ultrasound in a Mouse Model SO PLOS ONE LA English DT Article ID SKELETAL-MUSCLE INJURY; ENDOTHELIAL-CELLS; IN-VITRO; SOLID TUMORS; BLOOD; HIFU; MECHANOTRANSDUCTION; DELIVERY; CANCER; MRI AB Continuous focused ultrasound (cFUS) has been widely used for thermal ablation of tissues, relying on continuous exposures to generate temperatures necessary to induce coagulative necrosis. Pulsed FUS (pFUS) employs non-continuous exposures that lower the rate of energy deposition and allow cooling to occur between pulses, thereby minimizing thermal effects and emphasizing effects created by non-thermal mechanisms of FUS (i.e., acoustic radiation forces and acoustic cavitation). pFUS has shown promise for a variety of applications including drug and nanoparticle delivery; however, little is understood about the effects these exposures have on tissue, especially with regard to cellular pro-homing factors (growth factors, cytokines, and cell adhesion molecules). We examined changes in murine hamstring muscle following pFUS or cFUS and demonstrate that pFUS, unlike cFUS, has little effect on the histological integrity of muscle and does not induce cell death. Infiltration of macrophages was observed 3 and 8 days following pFUS or cFUS exposures. pFUS increased expression of several cytokines (e. g., IL-1 alpha, IL-1 beta, TNF alpha, INF gamma, MIP-1 alpha, MCP-1, and GMCSF) creating a local cytokine gradient on days 0 and 1 post-pFUS that returns to baseline levels by day 3 post-pFUS. pFUS exposures induced upregulation of other signaling molecules (e.g., VEGF, FGF, PlGF, HGF, and SDF-1 alpha) and cell adhesion molecules (e. g., ICAM-1 and VCAM-1) on muscle vasculature. The observed molecular changes in muscle following pFUS may be utilized to target cellular therapies by increasing homing to areas of pathology. C1 [Burks, Scott R.; Ziadloo, Ali; Chaudhry, Aneeka; Dean, Dana D.; Lewis, Bobbi K.; Frank, Joseph A.] NIH, Frank Lab, Ctr Clin, Bethesda, MD 20892 USA. [Hancock, Hilary A.; Frenkel, Victor] NIH, Mol Imaging Lab, Ctr Clin, Bethesda, MD 20892 USA. [Burks, Scott R.] Ctr Clin, Imaging Sci Training Program, Bethesda, MD USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Program, NIH, Bethesda, MD USA. RP Burks, SR (reprint author), NIH, Frank Lab, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM scott.burks@nih.gov FU Intramural Research Program at the Clinical Center; National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health FX This work was supported by the Intramural Research Program at the Clinical Center and National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 18 Z9 19 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 13 PY 2011 VL 6 IS 9 AR e24730 DI 10.1371/journal.pone.0024730 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825ZV UT WOS:000295321800056 PM 21931834 ER PT J AU Kim, PS Woods, C Dutcher, L Georgoff, P Rosenberg, A Mican, JAM Kopp, JB Smith, MA Hadigan, C AF Kim, Peter S. Woods, Christian Dutcher, Lauren Georgoff, Patrick Rosenberg, Alice Mican, Jo Ann M. Kopp, Jeffrey B. Smith, Margo A. Hadigan, Colleen TI Increased Prevalence of Albuminuria in HIV-Infected Adults with Diabetes SO PLOS ONE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; REVERSE-TRANSCRIPTASE INHIBITORS; MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; URINARY ALBUMIN; RISK-FACTORS; MICROALBUMINURIA; NEPHROPATHY; COHORT; ASSOCIATION AB Objective: HIV and type 2 diabetes are known risk factors for albuminuria, but no previous reports have characterized albuminuria in HIV-infected patients with diabetes. Research Design and Methods: We performed a cross-sectional study including 73 HIV-infected adults with type 2 diabetes, 82 HIV-infected non-diabetics, and 61 diabetic control subjects without HIV. Serum creatinine > 1.5 mg/dL was exclusionary. Albuminuria was defined as urinary albumin/creatinine ratio > 30 mg/g. Results: The prevalence of albuminuria was significantly increased among HIV-infected diabetics (34% vs. 13% of HIV nondiabetic vs. 16% diabetic control, p = 0.005). HIV status and diabetes remained significant predictors of albuminuria after adjusting for age, race, BMI, and blood pressure. Albumin/creatinine ratio correlated significantly with HIV viral load (r = 0.28, p = 0.0005) and HIV-infected subjects with albuminuria had significantly greater cumulative exposure to abacavir (p = 0.01). In an adjusted multivariate regression analysis of HIV-infected subjects, the diagnosis of diabetes (p = 0.003), higher HIV viral load (p = 0.03) and cumulative exposure to abacavir (p = 0.0009) were significant independent predictors of albuminuria. Conclusions: HIV and diabetes appear to have additive effects on albuminuria which is also independently associated with increased exposure to abacavir and HIV viral load. Future research on the persistence, progression and management of albuminuria in this unique at-risk population is needed. C1 [Kim, Peter S.; Rosenberg, Alice; Mican, Jo Ann M.; Hadigan, Colleen] NIAID, NIH, Bethesda, MD 20892 USA. [Woods, Christian; Smith, Margo A.] Washington Hosp Ctr, Dept Infect Dis, Washington, DC 20010 USA. [Dutcher, Lauren; Georgoff, Patrick] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Kopp, Jeffrey B.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Kim, PS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hadiganc@niaid.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; Washington Hospital Center, Department of Infectious Diseases FX The study was funded and conducted by the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Programs and the Washington Hospital Center, Department of Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 9 Z9 10 U1 0 U2 1 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 SEP 13 PY 2011 VL 6 IS 9 AR e24610 DI 10.1371/journal.pone.0024610 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825ZV UT WOS:000295321800038 PM 21931772 ER PT J AU Potts, RC Zhang, PS Wurster, AL Precht, P Mughal, MR Wood, WH Zhang, YQ Becker, KG Mattson, MP Pazin, MJ AF Potts, Rebecca Casaday Zhang, Peisu Wurster, Andrea L. Precht, Patricia Mughal, Mohamed R. Wood, William H., III Zhang, Yonqing Becker, Kevin G. Mattson, Mark P. Pazin, Michael J. TI CHD5, a Brain-Specific Paralog of Mi2 Chromatin Remodeling Enzymes, Regulates Expression of Neuronal Genes SO PLOS ONE LA English DT Article ID TUMOR-SUPPRESSOR; HISTONE DEACETYLASE; SYNAPTIC PLASTICITY; MI-2/NURD COMPLEX; CANCER; FAMILY; NEUROBLASTOMAS; DIVERSE; MEMORY; HYPERMETHYLATION AB CHD5 is frequently deleted in neuroblastoma and is a tumor suppressor gene. However, little is known about the role of CHD5 other than it is homologous to chromatin remodeling ATPases. We found CHD5 mRNA was restricted to the brain; by contrast, most remodeling ATPases were broadly expressed. CHD5 protein isolated from mouse brain was associated with HDAC2, p66 beta, MTA3 and RbAp46 in a megadalton complex. CHD5 protein was detected in several rat brain regions and appeared to be enriched in neurons. CHD5 protein was predominantly nuclear in primary rat neurons and brain sections. Microarray analysis revealed genes that were upregulated and downregulated when CHD5 was depleted from primary neurons. CHD5 depletion altered expression of neuronal genes, transcription factors, and brain-specific subunits of the SWI/SNF remodeling enzyme. Expression of gene sets linked to aging and Alzheimer's disease were strongly altered by CHD5 depletion from primary neurons. Chromatin immunoprecipitation revealed CHD5 bound to these genes, suggesting the regulation was direct. Together, these results indicate that CHD5 protein is found in a NuRD-like multi-protein complex. CHD5 expression is restricted to the brain, unlike the closely related family members CHD3 and CHD4. CHD5 regulates expression of neuronal genes, cell cycle genes and remodeling genes. CHD5 is linked to regulation of genes implicated in aging and Alzheimer's disease. C1 [Potts, Rebecca Casaday; Wurster, Andrea L.; Precht, Patricia; Pazin, Michael J.] Natl Inst Aging Intramural Res Program, Lab Mol Biol & Immunol, NIH, Baltimore, MD USA. [Zhang, Peisu; Mughal, Mohamed R.; Mattson, Mark P.] Natl Inst Aging Intramural Res Program, Neurosci Lab, NIH, Baltimore, MD USA. [Wood, William H., III; Zhang, Yonqing; Becker, Kevin G.] Natl Inst Aging Intramural Res Program, Res Resources Branch, NIH, Baltimore, MD USA. RP Potts, RC (reprint author), US Pharmacopeia, Rockville, MD USA. EM pazinm@mail.nih.gov RI Mattson, Mark/F-6038-2012; OI Becker, Kevin/0000-0002-6794-6656; Pazin, Michael/0000-0002-7561-3640 FU National Institutes of Health (NIH), National Institute on Aging [Z01AG000378] FX This research was supported entirely by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging (http://www.grc.nia.nih.gov/), grant Z01AG000378. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 37 Z9 40 U1 1 U2 8 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 SEP 13 PY 2011 VL 6 IS 9 AR e24515 DI 10.1371/journal.pone.0024515 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825ZV UT WOS:000295321800029 PM 21931736 ER PT J AU Xu, WP Trepel, J Neckers, L AF Xu, Wanping Trepel, Jane Neckers, Len TI Ras, ROS and Proteotoxic Stress: A Delicate Balance SO CANCER CELL LA English DT Editorial Material ID PATHWAY AB Ras-deregulated cells require reactive oxygen species for proliferation. They survive the resultant proteotoxic stress by maintaining sufficient levels of reduced glutathione and optimally functioning stress response machinery. In this issue of Cancer Cell, De Raedt et al. identify a novel strategy that utilizes this dependency to cause cell death. C1 [Xu, Wanping; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Trepel, Jane] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM neckers@nih.gov FU Intramural NIH HHS [ZIA SC010074-14, Z01 SC010074-12, ZIA SC010074-15, Z99 CA999999] NR 10 TC 19 Z9 21 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD SEP 13 PY 2011 VL 20 IS 3 BP 281 EP 282 DI 10.1016/j.ccr.2011.08.020 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 824MJ UT WOS:000295205700002 PM 21907917 ER PT J AU Tong, WH Sourbier, C Kovtunovych, G Jeong, SY Vira, M Ghosh, M Romero, VV Sougrat, R Vaulont, S Viollet, B Kim, YS Lee, S Trepe, J Srinivasan, R Bratslavsky, G Yang, YF Linehan, WM Rouault, TA AF Tong, Wing-Hang Sourbier, Carole Kovtunovych, Gennady Jeong, Suh Young Vira, Manish Ghosh, Manik Romero, Vladimir Valera Sougrat, Rachid Vaulont, Sophie Viollet, Benoit Kim, Yeong-Sang Lee, Sunmin Trepe, Jane Srinivasan, Ramaprasad Bratslavsky, Gennady Yang, Youfeng Linehan, W. Marston Rouault, Tracey A. TI The Glycolytic Shift in Fumarate-Hydratase-Deficient Kidney Cancer Lowers AMPK Levels, Increases Anabolic Propensities and Lowers Cellular Iron Levels SO CANCER CELL LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1; HEREDITARY LEIOMYOMATOSIS; SUCCINATE-DEHYDROGENASE; REGULATORY PROTEINS; GLUCOSE-METABOLISM; RENAL-CANCER; COMPLEX-II; CARCINOMA; GROWTH; CELLS AB Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1 alpha, but not HIF-2 alpha. Silencing of HIF-1 alpha or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1 alpha and AMPK contribute to the oncogenic growth of FH-deficient cells. C1 [Tong, Wing-Hang; Kovtunovych, Gennady; Jeong, Suh Young; Ghosh, Manik; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Program Mol Med, Bethesda, MD USA. [Sourbier, Carole; Romero, Vladimir Valera; Srinivasan, Ramaprasad; Bratslavsky, Gennady; Yang, Youfeng; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Vira, Manish] Albert Einstein Coll Med, New York, NY USA. [Sougrat, Rachid] King Abdullah Univ Sci & Technol, Thuwal, Saudi Arabia. [Vaulont, Sophie; Viollet, Benoit] Univ Paris 05, CNRS, Inst Cochin, UMR8104, Paris, France. [Vaulont, Sophie; Viollet, Benoit] INSERM, U1016, Paris, France. [Kim, Yeong-Sang; Lee, Sunmin; Trepe, Jane] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Program Mol Med, Bethesda, MD USA. EM WML@nih.gov; rouault@mail.nih.gov OI Sougrat, Rachid/0000-0001-6476-1886; Jeong, Suh Young/0000-0002-6376-7001 FU National Institute of Child Health and Human Development; National Cancer Institute FX The authors thank our colleagues and thank the intramural programs of the National Institute of Child Health and Human Development and the National Cancer Institute for support. NR 61 TC 71 Z9 71 U1 1 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD SEP 13 PY 2011 VL 20 IS 3 BP 315 EP 327 DI 10.1016/j.ccr.2011.07.018 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 824MJ UT WOS:000295205700008 PM 21907923 ER PT J AU Medina, DL Fraldi, A Bouche, V Annunziata, F Mansueto, G Spampanato, C Puri, C Pignata, A Martina, JA Sardiello, M Palmieri, M Polishchuk, R Puertollano, R Ballabio, A AF Medina, Diego L. Fraldi, Alessandro Bouche, Valentina Annunziata, Fabio Mansueto, Gelsomina Spampanato, Carmine Puri, Claudia Pignata, Antonella Martina, Jose A. Sardiello, Marco Palmieri, Michela Polishchuk, Roman Puertollano, Rosa Ballabio, Andrea TI Transcriptional Activation of Lysosomal Exocytosis Promotes Cellular Clearance SO DEVELOPMENTAL CELL LA English DT Article ID MUCOLIPIDOSIS TYPE-IV; STORAGE DISORDERS; SECRETORY LYSOSOMES; EPITHELIAL-CELLS; MEMBRANE REPAIR; CALCIUM; BIOGENESIS; AUTOPHAGY; IDENTIFICATION; INFLAMMATION AB Lysosomes are cellular organelles primarily involved in degradation and recycling processes. During lysosomal exocytosis, a Ca2+-regulated process, lysosomes are docked to the cell surface and fuse with the plasma membrane (PM), emptying their content outside the cell. This process has an important role in secretion and PM repair. Here we show that the transcription factor EB (TFEB) regulates lysosomal exocytosis. TFEB increases the pool of lysosomes in the proximity of the PM and promotes their fusion with PM by raising intracellular Ca2+ levels through the activation of the lysosomal Ca2+ channel MCOLN1. Induction of lysosomal exocytosis by TFEB overexpression rescued pathologic storage and restored normal cellular morphology both in vitro and in vivo in lysosomal storage diseases (LSDs). Our data indicate that lysosomal exocytosis may directly modulate cellular clearance and suggest an alternative therapeutic strategy for disorders associated with intracellular storage. C1 [Medina, Diego L.; Fraldi, Alessandro; Bouche, Valentina; Annunziata, Fabio; Mansueto, Gelsomina; Spampanato, Carmine; Puri, Claudia; Pignata, Antonella; Polishchuk, Roman; Ballabio, Andrea] TIGEM, I-80131 Naples, Italy. [Martina, Jose A.; Puertollano, Rosa] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Sardiello, Marco; Ballabio, Andrea] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Sardiello, Marco; Palmieri, Michela; Ballabio, Andrea] Texas Children Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA. [Ballabio, Andrea] Univ Naples Federico II, Dept Pediat, I-80131 Naples, Italy. RP Ballabio, A (reprint author), TIGEM, Via P Castellino 111, I-80131 Naples, Italy. EM ballabio@tigem.it RI Annunziata, Fabio/D-5074-2016; di Ronza, Alberto/H-7674-2016; OI Annunziata, Fabio/0000-0001-8598-5459; di Ronza, Alberto/0000-0002-9813-5143; BALLABIO, Andrea/0000-0003-1381-4604; Medina, Diego L./0000-0002-7347-2645 FU Italian Telethon Foundation; European Research Council [250154]; European Commission [HEALTH-2007-A-201678]; Beyond Batten Disease Foundation; MPS Society; NIH, National Heart, Lung, and Blood Institute (NHLBI) FX We thank P. Barba, J. Cancino, P. Colella, F. Donaudy, L. Pisapia, and A. Luciani for technical assistance. We thank E. Neufeld, B. Davidson, N. Andrews, C. Tam, and P. De Camilli for helpful discussions. We would like to acknowledge Elena Polishchuk and Anastasia Egorova for help in execution of microscopy experiments as well as Telethon Electron Microscopy Core Facility (IBP, CNR, Naples) and Integrated Microscopy Facility (IGB, CNR, Naples) for EM support. We also thank B. Lelouvier and the NHLBI Light Microscopy Core Facility for their help with the calcium experiments. We also thank G. Diez-Roux, G. Parenti, A. Luini, and A. De Matteis for comments on the manuscript. We acknowledge the support of the Italian Telethon Foundation (D.L.M., A.F., V.B., F.A., G.M., C.S., A.P., and A.B); the European Research Council Advanced Investigator grant number # 250154 (AR); the European Commission under the FP7 EUCLYD project (Grant No. HEALTH-2007-A-201678); the Beyond Batten Disease Foundation (M.S and A.B); MPS Society (D.L.M, A.F. and A.B.). J.M. and R.P. are supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute (NHLBI). In addition, we would like to thank the TIGEM AAV vector core for virus production. NR 45 TC 151 Z9 156 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD SEP 13 PY 2011 VL 21 IS 3 BP 421 EP 430 DI 10.1016/j.devcel.2011.07.016 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 822PA UT WOS:000295060900008 PM 21889421 ER PT J AU Redheuil, A Yu, WC Mousseaux, E Harouni, AA Kachenoura, N Wu, CO Bluemke, D Lima, JAC AF Redheuil, Alban Yu, Wen-Chung Mousseaux, Elie Harouni, Ahmed A. Kachenoura, Nadjia Wu, Colin O. Bluemke, David Lima, Joao A. C. TI Age-Related Changes in Aortic Arch Geometry Relationship With Proximal Aortic Function and Left Ventricular Mass and Remodeling SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aging; aortic geometry; elasticity; left ventricular remodeling; magnetic resonance imaging ID CONTRAST MR-IMAGES; ARTERIAL STIFFNESS; CARDIOVASCULAR EVENTS; CLINICAL-APPLICATIONS; DISEASE; RISK; ATHEROSCLEROSIS; VALIDATION; DIAMETER; STRAIN AB Objectives We sought to define age-related geometric changes of the aortic arch and determine their relationship to central aortic stiffness and left ventricular (LV) remodeling. Background The proximal aorta has been shown to thicken, enlarge in diameter, and lengthen with aging in humans. However, no systematic study has described age-related longitudinal and transversal remodeling of the aortic arch and their relationship with LV mass and remodeling. Methods We studied 100 subjects (55 women, 45 men, average age 46 +/- 16 years) free of overt cardiovascular disease using magnetic resonance imaging to determine aortic arch geometry (length, diameters, height, width, and curvature), aortic arch function (local aortic distensibility and arch pulse wave velocity [PWV]), and LV volumes and mass. Radial tonometry was used to calculate central blood pressure. Results Aortic diameters and arch length increased significantly with age. The ascending aorta length increased most, with age leading to aortic arch widening and decreased curvature. These geometric changes of the aortic arch were significantly related to decreased ascending aortic distensibility, increased aortic arch PWV (p < 0.001), and increased central blood pressures (p < 0.001). Increased ascending aortic diameter, lengthening, and decreased curvature of the aortic arch (unfolding) were all significantly associated with increased LV mass and concentric remodeling independently of age, sex, body size, and central blood pressure (p < 0.01). Conclusions Age-related unfolding of the aortic arch is related to increased proximal aortic stiffness in individuals without cardiovascular disease and associated with increased LV mass and mass-to-volume ratio independent of age, body size, central pressure, and cardiovascular risk factors. (J Am Coll Cardiol 2011;58:1262-70) (C) 2011 by the American College of Cardiology Foundation C1 [Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 21287 USA. [Wu, Colin O.] NHLBI, Bethesda, MD 20892 USA. [Bluemke, David] Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth Clin Ctr, Bethesda, MD USA. [Redheuil, Alban; Mousseaux, Elie; Kachenoura, Nadjia] Univ Paris 05, Georges Pompidou European Hosp, APHP, Paris, France. [Redheuil, Alban; Mousseaux, Elie; Kachenoura, Nadjia] INSERM, U678, Paris, France. [Yu, Wen-Chung] Natl Yang Ming Univ, Taipei Vet Gen Hosp, Div Cardiol, Taipei 112, Taiwan. RP Lima, JAC (reprint author), Johns Hopkins Univ, Sch Med, Div Cardiol, 600 Wolfe St,Blalock 524, Baltimore, MD 21287 USA. EM jlima@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU Federation and Societe Francaise de Cardiologie; Societe Francaise de Radiologie FX Dr. Redheuil received partial grant support from Federation and Societe Francaise de Cardiologie and Societe Francaise de Radiologie. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Michael O'Rourke, MD, served as Guest Editor for this paper. NR 29 TC 75 Z9 78 U1 1 U2 6 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 SEP 13 PY 2011 VL 58 IS 12 BP 1262 EP 1270 DI 10.1016/j.jacc.2011.06.012 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 816NP UT WOS:000294609400013 PM 21903061 ER PT J AU Volkow, ND Wang, GJ Fowler, JS Tomasi, D Telang, F AF Volkow, Nora D. Wang, Gene-Jack Fowler, Joanna S. Tomasi, Dardo Telang, Frank TI Addiction: Beyond dopamine reward circuitry SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE prefrontal cortex; dorsal striatum; substance use disorders; stimulant drugs; brain imaging ID HUMAN BRAIN; RECEPTOR AVAILABILITY; ORBITOFRONTAL CORTEX; COCAINE ADDICTION; NUCLEUS-ACCUMBENS; RELEASE; METABOLISM; STRIATUM; METHAMPHETAMINE; METHYLPHENIDATE AB Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction is much less clear. This review focuses on studies that used PET to characterize the brain DA system in addicted subjects. These studies have corroborated in humans the relevance of drug-induced fast DA increases in striatum [including nucleus accumbens (NAc)] in their rewarding effects but have unexpectedly shown that in addicted subjects, drug-induced DA increases (as well as their subjective reinforcing effects) are markedly blunted compared with controls. In contrast, addicted subjects show significant DA increases in striatum in response to drug-conditioned cues that are associated with self-reports of drug craving and appear to be of a greater magnitude than the DA responses to the drug. We postulate that the discrepancy between the expectation for the drug effects (conditioned responses) and the blunted pharmacological effects maintains drug taking in an attempt to achieve the expected reward. Also, whether tested during early or protracted withdrawal, addicted subjects show lower levels of D2 receptors in striatum (including NAc), which are associated with decreases in baseline activity in frontal brain regions implicated in salience attribution (orbitofrontal cortex) and inhibitory control (anterior cingulate gyrus), whose disruption results in compulsivity and impulsivity. These results point to an imbalance between dopaminergic circuits that underlie reward and conditioning and those that underlie executive function (emotional control and decision making), which we postulate contributes to the compulsive drug use and loss of control in addiction. C1 [Volkow, Nora D.] Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. [Volkow, Nora D.; Tomasi, Dardo; Telang, Frank] NIAAA, NIH, Bethesda, MD 20892 USA. [Wang, Gene-Jack; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov RI Tomasi, Dardo/J-2127-2015 NR 44 TC 238 Z9 253 U1 13 U2 76 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 SEP 13 PY 2011 VL 108 IS 37 BP 15037 EP 15042 DI 10.1073/pnas.1010654108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819DF UT WOS:000294804900016 PM 21402948 ER PT J AU Choi, KY Chang, K Pickel, JM Badger, JD Roche, KW AF Choi, Kyu Yeong Chang, Kai Pickel, James M. Badger, John D., II Roche, Katherine W. TI Expression of the metabotropic glutamate receptor 5 (mGluR5) induces melanoma in transgenic mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Gq; mGluR1; melanin ID SIGNAL-REGULATED KINASE; LONG-TERM DEPRESSION; IN-VIVO; CANCER GROWTH; CELLS; PHOSPHORYLATION; ACTIVATION; PATHWAY; GLUTAMATE-RECEPTOR-1; STIMULATION AB Glutamate is the major excitatory neurotransmitter in the mammalian CNS and mediates fast synaptic transmission upon activation of glutamate-gated ion channels. In addition, glutamate modulates a variety of other synaptic responses and intracellular signaling by activating metabotropic glutamate receptors (mGluRs), which are G protein-coupled receptors. The mGluRs are also expressed in nonneuronal tissues and are implicated in a variety of normal biological functions as well as diseases. To study mGluR-activated calcium signaling in neurons, we generated mGluR5 transgenic animals using a Thy1 promoter to drive expression in the forebrain, and one founder unexpectedly developed melanoma. To directly investigate the role of mGluR5 in melanoma formation, we generated mGluR5 transgenic lines under a melanocyte-specific promoter, tyrosinase-related protein 1. A majority of the founders showed a severe phenotype with early onset. Hyperpigmentation of the pinnae and tail could be detected as early as 3-5 d after birth for most of the mGluR5 transgene-positive mice. There was 100% penetrance in the progeny from the tyrosinase-related protein 1-mGluR5 lines generated from founders that developed melanoma. Expression of mGluR5 was detected in melanoma samples by RT-PCR, immunoblotting, and immunohistochemistry. We evaluated the expression of several cancer-related proteins in tumor samples and observed a dramatic increase in the phosphorylation of ERK, implicating ERK as a downstream effector of mGluR5 signaling in tumors. Our findings show that mGluR5-mediated glutamatergic signaling can trigger melanoma in vivo. The aggressive growth and severe phenotype make these mouse lines unique and a potentially powerful tool for therapeutic studies. C1 [Choi, Kyu Yeong; Chang, Kai; Badger, John D., II; Roche, Katherine W.] Natl Inst Neurol Disorders & Stroke, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. [Pickel, James M.] NIMH, Transgen Core Facil, NIH, Bethesda, MD 20892 USA. RP Roche, KW (reprint author), Natl Inst Neurol Disorders & Stroke, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. EM rochek@ninds.nih.gov OI Roche, Katherine/0000-0001-7282-6539 FU National Institute of Neurological Disorders and Stroke FX We thank Michael Spencer and Bill Branson (National Institutes of Health Medical Art) for assistance with high-resolution photography; James Nagle and Debbie Kauffman (National Institute of Neurological Disorders and Stroke Sequencing Facility) for DNA sequence analysis; and the animal care staff of the Porter Neuroscience Center. The National Institute of Neurological Disorders and Stroke Intramural Research Program supported this work. NR 40 TC 33 Z9 36 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 SEP 13 PY 2011 VL 108 IS 37 BP 15219 EP 15224 DI 10.1073/pnas.1107304108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819DF UT WOS:000294804900049 PM 21896768 ER PT J AU Andreu-Perez, P Esteve-Puig, R de Torre-Minguela, C Lopez-Fauqued, M Bech-Serra, JJ Tenbaum, S Garcia-Trevijano, ER Canals, F Merlino, G Avila, MA Recio, JA AF Andreu-Perez, Pedro Esteve-Puig, Rosaura de Torre-Minguela, Carlos Lopez-Fauqued, Marta Josep Bech-Serra, Joan Tenbaum, Stephan Garcia-Trevijano, Elena R. Canals, Francesc Merlino, Glenn Avila, Matias A. Recio, Juan A. TI Protein Arginine Methyltransferase 5 Regulates ERK1/2 Signal Transduction Amplitude and Cell Fate Through CRAF SO SCIENCE SIGNALING LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; MAP KINASE CASCADE; LYSINE METHYLATION; MAMMALIAN-CELLS; RAT HEPATOCYTES; PC12 CELLS; IN-VITRO; B-RAF; ACTIVATION; PATHWAY AB The RAS to extracellular signal-regulated kinase (ERK) signal transduction cascade is crucial to cell proliferation, differentiation, and survival. Although numerous growth factors activate the RAS-ERK pathway, they can have different effects on the amplitude and duration of the ERK signal and, therefore, on the biological consequences. For instance, nerve growth factor, which elicits a larger and more sustained increase in ERK phosphorylation in PC12 cells than does epidermal growth factor (EGF), stimulates PC12 cell differentiation, whereas EGF stimulates PC12 cell proliferation. Here, we show that protein arginine methylation limits the ERK1/2 signal elicited by particular growth factors in different cell types from various species. We found that this restriction in ERK1/2 phosphorylation depended on methylation of RAF proteins by protein arginine methyltransferase 5 (PRMT5). PRMT5-dependent methylation enhanced the degradation of activated CRAF and BRAF, thereby reducing their catalytic activity. Inhibition of PRMT5 activity or expression of RAF mutants that could not be methylated not only affected the amplitude and duration of ERK phosphorylation in response to growth factors but also redirected the response of PC12 cells to EGF from proliferation to differentiation. This additional level of regulation within the RAS pathway may lead to the identification of new targets for therapeutic intervention. C1 [Andreu-Perez, Pedro; Esteve-Puig, Rosaura; de Torre-Minguela, Carlos; Lopez-Fauqued, Marta; Recio, Juan A.] Vall dHebron Res Inst, Dept Anat Pathol, Mouse Models & Canc Lab, Barcelona 08035, Spain. [Josep Bech-Serra, Joan; Canals, Francesc] Vall dHebron Res Inst VHIO, Med Oncol Res Program, Prote Lab, Barcelona 08035, Spain. [Tenbaum, Stephan] Vall dHebron Res Inst VHIO, Med Oncol Res Program, Canc Stem Cells Lab, Barcelona 08035, Spain. [Garcia-Trevijano, Elena R.; Avila, Matias A.] Univ Navarra, Ctr Appl Med Res, Div Hepatol & Gene Therapy, Pamplona 31008, Spain. [Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Recio, JA (reprint author), Vall dHebron Res Inst, Dept Anat Pathol, Mouse Models & Canc Lab, Barcelona 08035, Spain. EM juan.recio@vhir.org OI Esteve-Puig, Rosaura/0000-0003-0547-1752; Recio, Juan Angel/0000-0002-7320-3832 FU Intramural NIH HHS NR 54 TC 37 Z9 44 U1 0 U2 9 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 SEP 13 PY 2011 VL 4 IS 190 AR ra58 DI 10.1126/scisignal.2001936 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819HZ UT WOS:000294817300001 PM 21917714 ER PT J AU Koblin, BA Casapia, M Morgan, C Qin, L Wang, ZM Defawe, OD Baden, L Goepfert, P Tomaras, GD Montefiori, DC McElrath, MJ Saavedra, L Lau, CY Graham, BS AF Koblin, Beryl A. Casapia, Martin Morgan, Cecilia Qin, Li Wang, Zhixue Maggie Defawe, Olivier D. Baden, Lindsey Goepfert, Paul Tomaras, Georgia D. Montefiori, David C. McElrath, M. Juliana Saavedra, Lilian Lau, Chuen-Yen Graham, Barney S. CA NIAID HIV Vaccine Trials Network TI Safety and Immunogenicity of an HIV Adenoviral Vector Boost after DNA Plasmid Vaccine Prime by Route of Administration: A Randomized Clinical Trial SO PLOS ONE LA English DT Article ID STANDARD INTRAMUSCULAR VACCINATION; CELL-MEDIATED-IMMUNITY; CANDIDATE VACCINE; PHASE-1 SAFETY; HEALTHY-ADULTS; T-CELLS; RESPONSES; ANTIBODY; ASSAY; IMMUNIZATION AB Background: In the development of HIV vaccines, improving immunogenicity while maintaining safety is critical. Route of administration can be an important factor. Methodology/Principal Findings: This multicenter, open-label, randomized trial, HVTN 069, compared routes of administration on safety and immunogenicity of a DNA vaccine prime given intramuscularly at 0, 1 and 2 months and a recombinant replication-defective adenovirus type 5 (rAd5) vaccine boost given at 6 months by intramuscular (IM), intradermal (ID), or subcutaneous (SC) route. Randomization was computer-generated by a central data management center; participants and staff were not blinded to group assignment. The outcomes were vaccine reactogenicity and humoral and cellular immunogenicity. Ninety healthy, HIV-1 uninfected adults in the US and Peru, aged 18-50 were enrolled and randomized. Due to the results of the Step Study, injections with rAd5 vaccine were halted; thus 61 received the booster dose of rAd5 vaccine (IM: 20; ID: 21; SC: 20). After the rAd5 boost, significant differences by study arm were found in severity of headache, pain and erythema/induration. Immune responses (binding and neutralizing antibodies, IFN-gamma ELISpot HIV-specific responses and CD4+ and CD8+ T-cell responses by ICS) at four weeks after the rAd5 booster were not significantly different by administration route of the rAd5 vaccine boost (Binding antibody responses: IM: 66.7%; ID: 70.0%; SC: 77.8%; neutralizing antibody responses: IM: 11.1%; ID: 0.0%; SC 16.7%; ELISpot responses: IM: 46.7%; ID: 35.3%; SC: 44.4%; CD4+ T-cell responses: IM: 29.4%; ID: 20.0%; SC: 35.3%; CD8+ T-cell responses: IM: 29.4%; ID: 16.7%; SC: 50.0%.) Conclusions/Significance: This study was limited by the reduced sample size. The higher frequency of local reactions after ID and SC administration and the lack of sufficient evidence to show that there were any differences in immunogenicity by route of administration do not support changing route of administration for the rAd5 boost. C1 [Koblin, Beryl A.] New York Blood Ctr, Lab Infect Dis Prevent, New York, NY 10021 USA. [Casapia, Martin; Saavedra, Lilian] Asociac Civil Selva Amazon, Iquitos, Peru. [Morgan, Cecilia; Qin, Li; Wang, Zhixue Maggie; Defawe, Olivier D.; McElrath, M. Juliana] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Baden, Lindsey] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Goepfert, Paul] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Tomaras, Georgia D.; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Lau, Chuen-Yen] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Koblin, BA (reprint author), New York Blood Ctr, Lab Infect Dis Prevent, New York, NY 10021 USA. EM bkoblin@nybloodcenter.org RI Tomaras, Georgia/J-5041-2016 FU Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), United States National Institutes of Health (NIH); NIAID FX The study was sponsored by the Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), United States National Institutes of Health (NIH) and conducted through the NIAID-funded HIV Vaccine Trials Network (HVTN). Study vaccine and placebo were provided by the Dale and Betty Bumpers Vaccine Research Center (VRC), NIAID, NIH. VRC and HVTN both contributed to the study design, decision to publish, and preparation of the manuscript. The clinical trial and data analyses were conducted by HVTN and the Statistical Center for HIV/AIDS Research and Prevention (SCHARP). NR 40 TC 25 Z9 25 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 SEP 12 PY 2011 VL 6 IS 9 AR e24517 DI 10.1371/journal.pone.0024517 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CO UT WOS:000294803200024 PM 21931737 ER PT J AU Munk, R Ghosh, P Ghosh, MC Saito, T Xu, M Carter, A Indig, F Taub, DD Longo, DL AF Munk, Rachel Ghosh, Paritosh Ghosh, Manik C. Saito, Takeshi Xu, Mai Carter, Arnell Indig, Fred Taub, Dennis D. Longo, Dan L. TI Involvement of mTOR in CXCL12 Mediated T Cell Signaling and Migration SO PLOS ONE LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; MAMMALIAN TARGET; PROTEIN-KINASE; CHEMOKINE; PATHWAY; ACTIVATION; RECEPTOR; LYMPHOCYTES; SDF-1-ALPHA AB Background: CXCL12 is a pleiotropic chemokine involved in multiple different processes such as immune regulation, inflammatory responses, and cancer development. CXCL12 is also a potent chemokine involved in chemoattraction of T cells to the site of infection or inflammation. Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that modulates different cellular processes, such as metabolism, nutrient sensing, protein translation, and cell growth. The role of mTOR in CXCL12-mediated resting T cell migration has yet to be elucidated. Methodology/Principal Findings: Rapamycin, an inhibitor of mTOR, significantly inhibits CXCL12 mediated migration of both primary human resting T cells and human T cell leukemia cell line CEM. p70(S6K1), an effector molecule of mTOR signaling pathway, was knocked down by shRNA in CEM cells using a lentiviral gene transfer system. Using p70(S6K1) knock down cells, we demonstrate the role of mTOR signaling in T cell migration both in vitro and in vivo. Conclusions: Our data demonstrate a new role for mTOR in CXCL12-induced T cell migration, and enrich the current knowledge regarding the clinical use of rapamycin. C1 [Munk, Rachel; Ghosh, Paritosh; Ghosh, Manik C.; Saito, Takeshi; Longo, Dan L.] NIA, Lymphocyte Cell Biol Unit, NIH, Baltimore, MD 21224 USA. [Xu, Mai; Carter, Arnell; Taub, Dennis D.] NIA, Clin Immunol Sect, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Indig, Fred] NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. RP Munk, R (reprint author), NIA, Lymphocyte Cell Biol Unit, NIH, Baltimore, MD 21224 USA. EM ghoshp@grc.nia.nih.gov FU National Institutes of Health (NIH), National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging. There is no current external funding source for this study. The research was conducted as a part of the official duty of an employee in the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 12 Z9 12 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 SEP 12 PY 2011 VL 6 IS 9 AR e24667 DI 10.1371/journal.pone.0024667 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CO UT WOS:000294803200036 PM 21931802 ER PT J AU Li, Q Lei, H Liu, AJ Yang, YL Su, DF Liu, X AF Li, Qi Lei, Hong Liu, Aijun Yang, Yili Su, Dingfeng Liu, Xia TI The antishock effect of anisodamine requires the upregulation of alpha 7 nicotine acetylcholine receptors by IL-10 SO LIFE SCIENCES LA English DT Article DE Anisodamine; IL-10; alpha 7 nAChR; Cholinergic anti-inflammatory pathway; Septic shock ID ANTIINFLAMMATORY PATHWAY; VAGUS NERVE; SEPSIS; EXPRESSION; CELLS; INFLAMMATION; ENDOTOXEMIA; SHOCK; ACTIVATION; RESPONSES AB Aims: Although anisodamine, a muscarinic acetylcholine receptor antagonist, has been used in China for treating various shocks for many years, the mechanisms are not well understood. Our previous studies have demonstrated anisodamine exerts its cholinergic anti-inflammatory action through indirectly activating alpha 7 nicotinic acetylcholine receptors (alpha 7 nAChR). Because IL-10 is a critical anti-inflammatory factor, we investigated its potential role in the antishock action of anisodamine. Main methods: C57BL/6 and IL-10-/- mice were intraperitoneally administered LPS and/or anisodamine, and the 24 h survival rate, cytokine production and alpha 7 nAChR expression were examined. In addition, RAW264.7 cells were stimulated with LPS, anisodamine and/or IL-10, and cytokine production and alpha 7 nAChR expression were investigated. Key findings: Anisodamine dose-dependently increased the 24 h survival rate of C57BL/6 mice treated with LPS. The antishock role of anisodamine was significantly attenuated in IL-10-/- mice. Anisodamine significantly decreased TNF-alpha and IL-1 beta production in LPS-treated RAW264.7 cells and C57BL/6 mice. However, it did not increase the level of IL-10 in the same experiments. In RAW264.7 cells, IL-10 treatment increased alpha 7 nAChR expression, which was further augmented in the presence of anisodamine. Spleens from IL-10-/- mice expressed significantly lower alpha 7 nAChRs levels compared to IL-10+/+ mice. Although anisodamine markedly increased the expression of alpha 7 nAChRs in spleens from LPS-treated IL-10+/+ mice, it only induced a marginal increase of the receptor in spleens from LPS-treated IL-10-/- mice. Significance: These findings demonstrate that IL-10 plays an important role in the antishock action of anisodamine. It acts through upregulating alpha 7nAChR synergistically with anisodamine. Crown Copyright (C) 2011 Published by Elsevier Inc. All rights reserved. C1 [Li, Qi; Lei, Hong; Liu, Aijun; Su, Dingfeng; Liu, Xia] Second Mil Med Univ, Sch Pharm, Dept Pharmacol, Shanghai 200433, Peoples R China. [Yang, Yili] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. RP Su, DF (reprint author), Second Mil Med Univ, Sch Pharm, Dept Pharmacol, 325 Guo He Rd, Shanghai 200433, Peoples R China. EM dfsu2008@gmail.com; lxflying@yahoo.com.cn FU National Natural Science Foundation of China [30973525]; National Science and Technology Major Project [2009ZX09303-002] FX This work was supported by grants from the National Natural Science Foundation of China (No. 30973525, to Xia Liu) and the National Science and Technology Major Project (2009ZX09303-002, to Dingfeng Su). NR 40 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 0024-3205 EI 1879-0631 J9 LIFE SCI JI Life Sci. PD SEP 12 PY 2011 VL 89 IS 11-12 BP 395 EP 401 DI 10.1016/j.lfs.2011.07.008 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 813VH UT WOS:000294397800007 PM 21798271 ER PT J AU Coutellier, L Usdin, TB AF Coutellier, Laurence Usdin, Ted B. TI Enhanced long-term fear memory and increased anxiety and depression-like behavior after exposure to an aversive event in mice lacking TIP39 signaling SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE TIP39 signaling; Fear memory; Anxiety; Depression-like behavior ID POSTTRAUMATIC-STRESS-DISORDER; TUBEROINFUNDIBULAR PEPTIDE; 39 RESIDUES; EXTINCTION; MODULATION; NEURONS; BRAIN; MODEL AB Exaggerated recall for fear-provoking events leads to abnormal behaviors. We hypothesized that tuberoinfundibular-peptide-of-39-residues (TIP39) modulates fear memory by limiting long-term consequences of aversive experiences. We now show that mice lacking TIP39 signaling display enhanced fear-recall, anxiety and depression-like behavior 2 weeks after a traumatic event. We suggest that TIP39 modulates long-term fear recall and that mice lacking TIP39 or its receptor are tools for investigating fear-related psychopathologies. Published by Elsevier B.V. C1 [Coutellier, Laurence; Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, NIH, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), NIMH, Sect Fundamental Neurosci, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov FU NIH, National Institute of Mental Health FX This research was supported by the Intramural Program of the NIH, National Institute of Mental Health. We thank Milan Rusnak for mouse management. The authors declare that there are no potential conflicts of interest. NR 21 TC 3 Z9 3 U1 1 U2 5 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 SEP 12 PY 2011 VL 222 IS 1 BP 265 EP 269 DI 10.1016/j.bbr.2011.02.043 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 774WV UT WOS:000291418400032 PM 21382418 ER PT J AU Li, YF Ramdhan, DH Naito, H Yamagishi, N Ito, Y Hayashi, Y Yanagiba, Y Okamura, A Tamada, H Gonzalez, FJ Nakajima, T AF Li, Yufei Ramdhan, Doni Hikmat Naito, Hisao Yamagishi, Nozomi Ito, Yuki Hayashi, Yumi Yanagiba, Yukie Okamura, Ai Tamada, Hazuki Gonzalez, Frank J. Nakajima, Tamie TI Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPAR alpha SO TOXICOLOGY LETTERS LA English DT Article DE Perfluorooctanoic acid; Peroxisome proliferator-activated receptor alpha; Reproductive toxicity; Testosterone ID ACTIVATED-RECEPTOR-ALPHA; ACUTE REGULATORY PROTEIN; PEROXISOME-PROLIFERATOR; LEYDIG-CELLS; MITOCHONDRIAL-MEMBRANE; STEROIDOGENIC ENZYMES; UNCOUPLING PROTEIN-2; TARGETED DISRUPTION; HORMONAL-REGULATION; FATTY-ACIDS AB Perfluorooctanoate, a peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist, has the potential to lower testosterone levels as a result of testicular toxicity. To elucidate the mechanism and impact of PPAR alpha on this reproductive toxicity, ammonium pertluorooctanoate (APFO) at doses of 0, 1.0 (low) mg/kg/day, or 5.0 (high) mg/kg/day was orally given daily to 129/sv wild-type (mPPAR alpha), Ppar alpha-null and PPAR alpha-humanized (hPPAR alpha) mice for 6 weeks. Both low- and high-dose APFO significantly reduced plasma testosterone concentrations in mPPAR alpha and hPPAR alpha mice, respectively. These decreases may, in part, be associated with decreased expression of mitochondrial cytochrome P450 side-chain cleavage enzyme, steroidogenic acute regulatory protein or peripheral benzodiazepine receptor as well as microsomal cytochrome P450(17 alpha) involved in the steroidogenesis. Additionally, both doses increased abnormalities in sperm morphology and vacuolated cells in the seminiferous tubules of both mouse lines. In contrast, APFO caused only a marginal effect either on the testosterone synthesis system or sperm and testis morphology in Ppar alpha-null mice. These results suggest that APFO may disrupt testosterone biosynthesis by lowering the delivery of cholesterol into the mitochondria and decreasing the conversion of cholesterol to pregnenolone and androstandione in the testis of mPPAR alpha and hPPAR alpha mice, which may, in part, be related to APFO-induced mitochondrial damage. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Li, Yufei; Ramdhan, Doni Hikmat; Naito, Hisao; Yamagishi, Nozomi; Ito, Yuki; Hayashi, Yumi; Yanagiba, Yukie; Okamura, Ai; Tamada, Hazuki; Nakajima, Tamie] Nagoya Univ, Grad Sch Med, Dept Occupat & Environm Hlth, Showa Ku, Aichi 4668550, Japan. [Li, Yufei] Xi An Jiao Tong Univ, Coll Med, Fac Publ Hlth, Xian 710061, Shaanxi, Peoples R China. [Ramdhan, Doni Hikmat] Univ Indonesia, Fac Publ Hlth, Dept Occupat Hlth & Safety, Depok 16424, Jawa Barat, Indonesia. [Ito, Yuki] Nagoya City Univ, Grad Sch Med, Dept Occupat & Environm Hlth, Nagoya, Aichi 4678601, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Nakajima, T (reprint author), Nagoya Univ, Grad Sch Med, Dept Occupat & Environm Hlth, Showa Ku, 65 Tsurumai Cho, Aichi 4668550, Japan. EM tnasu23@med.nagoya-u.ac.jp RI Ito, Yuki/C-3698-2008 NR 45 TC 12 Z9 13 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP 10 PY 2011 VL 205 IS 3 BP 265 EP 272 DI 10.1016/j.toxlet.2011.06.015 PG 8 WC Toxicology SC Toxicology GA 816DI UT WOS:000294578500006 PM 21712084 ER PT J AU Madlala, P Gijsbers, R Christ, F Hombrouck, A Werner, L Mlisana, K An, P Karim, SSA Winkler, CA Debyser, Z Ndung'u, T AF Madlala, Paradise Gijsbers, Rik Christ, Frauke Hombrouck, Anneleen Werner, Lise Mlisana, Koleka An, Ping Karim, Salim S. Abdool Winkler, Cheryl A. Debyser, Zeger Ndung'u, Thumbi TI Association of polymorphisms in the LEDGF/p75 gene (PSIP1) with susceptibility to HIV-1 infection and disease progression SO AIDS LA English DT Article DE disease progression; HIV-1; HIV-1 integrase; Lens epithelium-derived growth factor/p75 (LEDGF/p75); PC4 or SFRS1 interacting protein 1 gene (PSIP1); single nucleotide polymorphisms; susceptibility to infection ID HUMAN-IMMUNODEFICIENCY-VIRUS; STRESS-RELATED GENES; SOUTH-AFRICA; HUMAN-CELLS; VIRAL LOAD; IN-VITRO; INTEGRASE; REPLICATION; PROTEINS; BINDING AB Objective: LEDGF/p75, encoded by the PSIP1 gene, interacts with HIV-1 integrase and targets HIV-1 integration into active genes. We investigated the influence of polymorphisms in PSIP1 on HIV-1 acquisition and disease progression in black South Africans. Methods: Integrase binding domain of LEDGF/p75 was sequenced in 126 participants. Four haplotype tagging SNPs rs2277191, rs1033056, rs12339417 and rs10283923 referred to as SNP1, SNP2, SNP3 and SNP4, respectively, and one exonic SNP rs61744944 (SNP5, Q472L) were genotyped in 195 HIV-1 seronegative, 52 primary and 403 chronically infected individuals using TaqMan assays. LEDGF/p75 expression was quantified by real-time RT-PCR. The impact of Q472L mutation on the interaction with HIV_1 IN was measured by AlphaScreen. Results: rs2277191 (SNP1) A was more frequent among seropositives (P=0.06, Fisher's exact test). Among individuals followed longitudinally SNP1A trended towards association with higher likelihood of HIV-1 acquisition [relative hazard (RH)=2.21, P=0.08; Cox model] and it was also associated with rapid disease progression (RH=5.98, P=0.04; Cox model) in the recently infected (primary infection) cohort. rs12339417 (SNP3) C was associated with slower decline of CD4(+) T cells (P=0.02) and lower messenger RNA (mRNA) levels of LEDGF/p75 (P < 0.01). Seroconverters had higher preinfection mRNA levels of LEDGF/p75 (P < 0.01) and these levels decreased after HIV-1 infection (P=0.02). Conclusions: Genetic variants of PSIP1 may affect HIV-1 outcomes. Further studies are needed to confirm the effect of genetic variation of PSIP1 on HIV-1 pathogenesis in different cohorts. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Madlala, Paradise; Ndung'u, Thumbi] Univ KwaZulu Natal, HIV Pathogenesis Programme, Durban, South Africa. [Madlala, Paradise] Univ KwaZulu Natal, Dept Genet, Pietermaritzburg, South Africa. [Gijsbers, Rik; Christ, Frauke; Hombrouck, Anneleen; Debyser, Zeger] Katholieke Univ Leuven, Louvain, Flanders, Belgium. [Werner, Lise; Mlisana, Koleka; Karim, Salim S. Abdool; Ndung'u, Thumbi] Univ KwaZulu Natal, Ctr AIDS Programme Res S Africa CAPRISA, Durban, South Africa. [An, Ping; Winkler, Cheryl A.] NCI, Basic Res Lab, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. RP Ndung'u, T (reprint author), Private Bag 7,Congella 4013,DDMRI Level 1,Room 11, ZA-4001 Durban, South Africa. EM ndungu@ukzn.ac.za RI Abdool Karim, Salim Safurdeen/N-5947-2013; OI Abdool Karim, Salim Safurdeen/0000-0002-4986-2133; debyser, zeger/0000-0002-3982-1565; Mlisana, Koleka/0000-0002-8436-3268; Ndung'u, Thumbi/0000-0003-2962-3992 FU National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH) [R01-AI067073, N01-AI-15422, HHSN261200800001E]; US Department of Health and Human Services [U19 AI 51794]; European commission [HEALTH-F3- 2008-201032]; South African Department of Science and Technology/National Research Foundation Research Chairs Initiative; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX We thank Taryn Page, Yuchun Zhou, Beth Binns-Roemer, Sofie Vets and Nam Joo Van der Veken for excellent technical support. We acknowledge the participants and their clinicians who participated in the CAPRISA AI 002 and Sinikithemba studies. The CAPRISA 002 study was supported by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), US Department of Health and Human Services (grant U19 AI 51794). The Sinikithemba cohort was supported by a grant from the NIH (grant R01-AI067073, contract N01-AI-15422). This study was funded by the seventh framework program (FP7) of the European commission (THINC, HEALTH-F3- 2008-201032). Additional funding was provided by the South African Department of Science and Technology/National Research Foundation Research Chairs Initiative. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does it mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 36 TC 17 Z9 17 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 10 PY 2011 VL 25 IS 14 BP 1711 EP 1719 DI 10.1097/QAD.0b013e328349c693 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 814AT UT WOS:000294415200004 PM 21681054 ER PT J AU Matthews, GV Manzini, P Hu, ZH Khabo, P Maja, P Matchaba, G Sangweni, P Metcalf, J Pool, N Orsega, S Emery, S AF Matthews, Gail V. Manzini, Prince Hu, Zonghui Khabo, Paul Maja, Patrick Matchaba, Gugu Sangweni, Phumele Metcalf, Julie Pool, Nicholaas Orsega, Susan Emery, Sean CA PHIDISA II Study Team TI Impact of lamivudine on HIV and hepatitis B virus-related outcomes in HIV/hepatitis B virus individuals in a randomized clinical trial of antiretroviral therapy in southern Africa SO AIDS LA English DT Article DE hepatitis B; HIV; lamivudine; mortality; randomized controlled trial; South Africa ID HUMAN-IMMUNODEFICIENCY-VIRUS; STAGE LIVER-DISEASE; INFECTED PATIENTS; DISOPROXIL FUMARATE; C VIRUS; COHORT; COINFECTION; TENOFOVIR; NAIVE; PREVALENCE AB Objective: To examine HIV and hepatitis B virus (HBV)-related outcomes in HIV/HBV-coinfected participants in the PHIDISA II study by use of HBV-active vs. non-HBV-active antiretroviral therapy (ART). Design and methods: PHIDISA II was a randomized study of ART therapy in HIV-infected adults employing zidovudine along with didanosine, or lamivudine along with stavudine in a factorial 2x2 design. HIV/HBV-coinfected participants by randomization received HBV-active or non-HBV-active ART. The following outcomes of interest were examined: immunological recovery and HIV RNA suppression; hepatic flare; HBV DNA suppression; and mortality. Results: HIV/HBV coinfection was present in 106 of 1771 (6%) of participants. Participants with HIV/HBV coinfection were more likely to be men, and have higher baseline alanine aminotransferase, lower albumin, and lower platelets than those with HIV monoinfection. Median CD4 cell gain and HIV RNA suppression was similar across all groups. Hepatic flare was observed in 9.4% of coinfected and 0.02% monoinfected participants. HBV DNA suppression (<55 IU/ml) at week 48 was observed in only 33% of those on lamivudine vs. 13% in those on no HBV-active drugs (P 0.13). Mortality over follow-up was significantly greater in coinfected (17%) than monoinfected (11%) participants (P=0.04). Conclusion: In summary, the use of lamivudine-containing ART in HIV/HBV participants in PHIDISA II resulted in little additional benefit over that of ART itself and failed to impact on the greater mortality in this group. These data provide strong support for recent guidelines advocating the use of tenofovir in all HIV-HBV-coinfected individuals initiating ART. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Matthews, Gail V.; Emery, Sean] Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW 2010, Australia. [Manzini, Prince; Khabo, Paul; Maja, Patrick; Matchaba, Gugu; Sangweni, Phumele] S African Natl Def Force, S African Mil Hlth Serv, Project PHIDISA, Centurion, South Africa. [Hu, Zonghui; Metcalf, Julie; Orsega, Susan] NIAID, NIH, Bethesda, MD 20892 USA. [Pool, Nicholaas] Bioanalyt Res Corp PTY LTD, Johannesburg, South Africa. RP Matthews, GV (reprint author), Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Cnr W & Boundary St, Sydney, NSW 2010, Australia. EM gmatthews@kirby.unsw.edu.au RI Emery, Sean/H-4920-2013 OI Emery, Sean/0000-0001-6072-8309 FU United States Department of Defense (US DoD); United States Department of Health and Human Services (HHS) through the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); BMS; Roche; MSD; Merck Labs FX Funding was provided by the United States Department of Defense (US DoD) and the United States Department of Health and Human Services (HHS) through the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). The Government of the United States through the US DOD and HHS, and the Government of Republic of South Africa (RSA) through its Department of Defence, signed a cooperative agreement, also known as joint research agreement, to conduct this research project.; G.M. has received payment for educational materials from BMS, Roche, and MSD and traveling expenses from MSD.; S.E. has received travel/accommodation expenses from Merck Labs. NR 30 TC 22 Z9 22 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 10 PY 2011 VL 25 IS 14 BP 1727 EP 1735 DI 10.1097/QAD.0b013e328349bbf3 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 814AT UT WOS:000294415200006 PM 21716078 ER PT J AU Kulkarni, V Jalah, R Ganneru, B Bergamaschi, C Alicea, C von Gegerfelt, A Patel, V Zhang, GM Chowdhury, B Broderick, KE Sardesai, NY Valentin, A Rosati, M Felber, BK Pavlakis, GN AF Kulkarni, Viraj Jalah, Rashmi Ganneru, Brunda Bergamaschi, Cristina Alicea, Candido von Gegerfelt, Agneta Patel, Vainav Zhang, Gen-Mu Chowdhury, Bhabadeb Broderick, Kate E. Sardesai, Niranjan Y. Valentin, Antonio Rosati, Margherita Felber, Barbara K. Pavlakis, George N. TI Comparison of immune responses generated by optimized DNA vaccination against SIV antigens in mice and macaques SO VACCINE LA English DT Article DE DNA vaccine; Electroporation; Immune response; Mice; Macaque; SIV; HIV; Antibody; Cellular immune responses ID IMMUNODEFICIENCY-VIRUS TYPE-1; ELECTROPORATION IN-VIVO; HERPES-SIMPLEX-VIRUS; RHESUS MACAQUES; GENE-TRANSFER; PLASMID DNA; THERAPEUTIC VACCINATION; REVERSE-TRANSCRIPTASE; CANDIDATE VACCINE; INFECTED MACAQUES AB Optimized DNA vectors were constructed comprising the proteome of Sly including the structural, enzymatic, regulatory, and accessory proteins. In addition to native antigens as produced by the virus, fusion proteins and modified antigens with altered secretion, cellular localization and stability characteristics were generated. The DNA vectors were tested for expression upon transfection in human cells. In addition, the vectors were tested either alone or in combinations in mice and macaques, which provided an opportunity to compare immune responses in two animal models. DNA only immunization using intramuscular injection in the absence or presence of in vivo electroporation did not alter the phenotype of the induced T cell responses in mice. Although several fusion proteins induced immune responses to all the components of a polyprotein, we noted fusion proteins that abrogated immune response to some of the components. Since the expression levels of such fusion proteins were not affected, these data suggest that the immune recognition of certain components was altered by the fusion. Testing different DNA vectors in mice and macaques revealed that a combination of DNAs producing different forms of the same antigen generated more balanced immune responses, a desirable feature for an optimal AIDS vaccine. Published by Elsevier Ltd. C1 [Ganneru, Brunda; Bergamaschi, Cristina; von Gegerfelt, Agneta; Patel, Vainav; Zhang, Gen-Mu; Chowdhury, Bhabadeb; Valentin, Antonio; Rosati, Margherita; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Kulkarni, Viraj; Jalah, Rashmi; Alicea, Candido; Zhang, Gen-Mu; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Broderick, Kate E.; Sardesai, Niranjan Y.] Inovio Pharmaceut, Blue Bell, PA 19422 USA. RP Pavlakis, GN (reprint author), NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Ft Detrick, MD 21702 USA. EM pavlakig@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; National Center for Research Resources, NIH [RR-00169] FX We are grateful to D. Weiss, J. Treece, I. Kalisz, V. Kalyanaraman, S. Orndorff, P. Markham and staff at Advanced BioScience Laboratories, Inc., Kensington, for their expert help. We thank the AIDS Research and Reagent Program (NIH) for antibodies, K. Nagashima for electron microscopy, D. Hazuda (Merck) for the integrase inhibitor, J. Bear for technical assistance, and T. Jones for editorial assistance. This research was supported by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. Part of this work was supported by the grant RR-00169 from the National Center for Research Resources, NIH, to the California National Primate Research Center. NR 63 TC 19 Z9 19 U1 0 U2 3 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 SEP 9 PY 2011 VL 29 IS 39 SI SI BP 6742 EP 6754 DI 10.1016/j.vaccine.2010.12.056 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 828JL UT WOS:000295497200005 PM 21195080 ER PT J AU Wilcock, DM Morgan, D Gordon, MN Taylor, TL Ridnour, LA Wink, DA Colton, CA AF Wilcock, Donna M. Morgan, Dave Gordon, Marcia N. Taylor, Tiffany L. Ridnour, Lisa A. Wink, David A. Colton, Carol A. TI Activation of matrix metalloproteinases following anti-A beta immunotherapy; implications for microhemorrhage occurrence SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Immunotherapy; matrix metalloproteinases; inflammation; microhemorrhage; amyloid; cerebral amyloid angiopathy; transgenic mouse; Alzheimer?'?s disease ID CEREBRAL AMYLOID ANGIOPATHY; ALZHEIMERS-DISEASE; MICROGLIAL ACTIVATION; TRANSGENIC MICE; FOCAL ISCHEMIA; MATRIX-METALLOPROTEINASE-9 MMP-9; MOUSE MODELS; DEPOSITION; HEMORRHAGE; RELEASE AB Background: Anti-A beta immunotherapy is a promising approach to the prevention and treatment of Alzheimer's disease (AD) currently in clinical trials. There is extensive evidence, both in mice and humans that a significant adverse event is the occurrence of microhemorrhages. Also, vasogenic edema was reported in phase 2 of a passive immunization clinical trial. In order to overcome these vascular adverse effects it is critical that we understand the mechanism(s) by which they occur. Methods: We have examined the matrix metalloproteinase (MMP) protein degradation system in two previously published anti-A beta immunotherapy studies. The first was a passive immunization study in which we examined 22 month old APPSw mice that had received anti-A beta antibodies for 1, 2 or 3 months. The second is an active vaccination study in which we examined 16 month old APPSw/NOS2-/- mice treated with A beta vaccination for 4 months. Results: There is a significant activation of the MMP2 and MMP9 proteinase degradation systems by anti-A beta immunotherapy, regardless of whether this is delivered through active vaccination or passive immunization. We have characterized this activation by gene expression, protein expression and zymography assessment of MMP activity. Conclusions: Since the MMP2 and MMP9 systems are heavily implicated in the pathophysiology of intracerbral hemorrhage, these data may provide a potential mechanism of microhemorrhage due to immunotherapy. Increased activity of the MMP system, therefore, is likely to be a major factor in increased microhemorrhage occurrence. C1 [Wilcock, Donna M.; Taylor, Tiffany L.] Univ Kentucky, Sanders Brown Ctr Aging, Dept Physiol, Lexington, KY 40536 USA. [Wilcock, Donna M.; Colton, Carol A.] Duke Univ, Med Ctr, Dept Med, Div Neurol, Durham, NC 27710 USA. [Morgan, Dave; Gordon, Marcia N.] Univ S Florida, Dept Mol Pharmacol & Physiol, Tampa, FL 33612 USA. [Ridnour, Lisa A.; Wink, David A.] NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Wilcock, DM (reprint author), Univ Kentucky, Sanders Brown Ctr Aging, Dept Physiol, Lexington, KY 40536 USA. EM donna.wilcock@uky.edu RI Morgan, David/J-5989-2012; Gordon, Marcia N./K-2420-2012; Wilcock, Donna/J-7517-2016 OI Gordon, Marcia N./0000-0002-4051-9283; FU NIH [AG030942, AG15490, AG18478, AG031845, AG19740]; Alzheimer's Association [IIRG-07-59802, NIRG-09-13302] FX These studies were funded by NIH grants AG030942 (DMW), AG15490 (MNG), AG18478 (DM), AG031845 (CAC), AG19740 (CAC), Alzheimer's Association grant IIRG-07-59802 (CAC) and Alzheimer's Association grant NIRG-09-13302 (DMW). NR 52 TC 20 Z9 20 U1 1 U2 2 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 SEP 9 PY 2011 VL 8 AR 115 DI 10.1186/1742-2094-8-115 PG 13 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 828PL UT WOS:000295514300001 PM 21906275 ER PT J AU Bot, A Obrocea, M Marincola, FM AF Bot, Adrian Obrocea, Mihail Marincola, Francesco M. TI Cancer vaccines at an inflexion point: what next? SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material ID HUMAN-MELANOMA AB With the approval of the first therapeutic cancer vaccines for veterinarian and human use, the field reached a significant milestone after a considerable interval of tumultuous research and development marked by numerous ups and downs. As the mechanism of action and clinical benefit afforded by this class of agents are starkly different from that of conventional or small targeted therapies for cancer, there are still numerous hurdles that need to be overcome to fully unleash their potential. These challenges and efforts are illustrated in a book just published on this subject, a non-exhaustive yet representative synopsis of the latest advances in cancer vaccine technologies in various stages of development. Major lessons resulting from clinical testing of cancer vaccines and other immune interventions, are being integrated in novel, cutting edge platform technologies that blur the distinction between passive and active immunotherapies as well as carry the promise of fundamentally changing and improving the management of patients with cancer. C1 [Bot, Adrian] Kite Pharma Inc, Los Angeles, CA 90024 USA. [Obrocea, Mihail] Abbott Labs, Global Pharmaceut Res & Dev, Redwood City, CA 94063 USA. [Marincola, Francesco M.] NIH, Trans NIH, CHI, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, IDIS, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM FMarincola@mail.cc.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD SEP 9 PY 2011 VL 9 AR 148 DI 10.1186/1479-5876-9-148 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 822NN UT WOS:000295055300001 PM 21906272 ER PT J AU Bhatia, G Patterson, N Pasaniuc, B Zaitlen, N Genovese, G Pollack, S Mallick, S Myers, S Tandon, A Spencer, C Palmer, CD Adeyemo, AA Akylbekova, EL Cupples, LA Divers, J Fornage, M Kao, WHL Lange, L Li, MY Musani, S Mychaleckyj, JC Ogunniyi, A Papanicolaou, G Rotimi, CN Rotter, JI Ruczinski, I Salako, B Siscovick, DS Tayo, BO Yang, Q McCarro, S Sabeti, P Lettre, G De Jager, P Hirschhorn, J Zhu, XF Cooper, R Reich, D Wilson, JG Price, AL AF Bhatia, Gaurav Patterson, Nick Pasaniuc, Bogdan Zaitlen, Noah Genovese, Giulio Pollack, Samuela Mallick, Swapan Myers, Simon Tandon, Arti Spencer, Chris Palmer, Cameron D. Adeyemo, Adebowale A. Akylbekova, Ermeg L. Cupples, L. Adrienne Divers, Jasmin Fornage, Myriam Kao, W. H. Linda Lange, Leslie Li, Mingyao Musani, Solomon Mychaleckyj, Josyf C. Ogunniyi, Adesola Papanicolaou, George Rotimi, Charles N. Rotter, Jerome I. Ruczinski, Ingo Salako, Babatunde Siscovick, David S. Tayo, Bamidele O. Yang, Qiong McCarro, Steve Sabeti, Pardis Lettre, Guillaume De Jager, Phil Hirschhorn, Joel Zhu, Xiaofeng Cooper, Richard Reich, David Wilson, James G. Price, Alkes L. TI Genome-wide Comparison of African-Ancestry Populations from CARe and Other Cohorts Reveals Signals of Natural Selection SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID RECENT POSITIVE SELECTION; GENETIC-VARIATION; HAPLOTYPE MAP; ASSOCIATION ANALYSIS; HIGH-ALTITUDE; MALARIA; HUMANS; HLA; DIFFERENTIATION; SUSCEPTIBILITY AB The study of recent natural selection in human populations has important applications to human history and medicine. Positive natural selection drives the increase in beneficial alleles and plays a role in explaining diversity across human populations. By discovering traits subject to positive selection, we can better understand the population level response to environmental pressures including infectious disease. Our study examines unusual population differentiation between three large data sets to detect natural selection. The populations examined, African Americans, Nigerians, and Gambians, are genetically close to one another (F(ST) < 0.01 for all pairs), allowing us to detect selection even with moderate changes in allele frequency. We also develop a tree-based method to pinpoint the population in which selection occurred, incorporating information across populations. Our genome-wide significant results corroborate loci previously reported to be under selection in Africans including HBB and CD36. At the HLA locus on chromosome 6, results suggest the existence of multiple, independent targets of population-specific selective pressure. In addition, we report a genome-wide significant (p = 1.36 x 10(-11)) signal of selection in the prostate stem cell antigen (PSCA) gene. The most significantly differentiated marker in our analysis, rs2920283, is highly differentiated in both Africa and East Asia and has prior genome-wide significant associations to bladder and gastric cancers. C1 [Bhatia, Gaurav] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Bhatia, Gaurav; Patterson, Nick; Pasaniuc, Bogdan; Zaitlen, Noah; Pollack, Samuela; Mallick, Swapan; Tandon, Arti; Palmer, Cameron D.; McCarro, Steve; De Jager, Phil; Hirschhorn, Joel; Reich, David; Price, Alkes L.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Pasaniuc, Bogdan; Zaitlen, Noah; Pollack, Samuela; Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Pasaniuc, Bogdan; Zaitlen, Noah; Pollack, Samuela; Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Genovese, Giulio] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. [Genovese, Giulio] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Mallick, Swapan; Tandon, Arti; McCarro, Steve; Reich, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Myers, Simon] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Spencer, Chris] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Palmer, Cameron D.; Hirschhorn, Joel] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Palmer, Cameron D.; Hirschhorn, Joel] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Palmer, Cameron D.; Hirschhorn, Joel] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Adeyemo, Adebowale A.] NHGRI, NIH, Intramural Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Akylbekova, Ermeg L.] Jackson State Univ, Jackson Heart Study, Jackson, MS 39213 USA. [Cupples, L. Adrienne; Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat & Epidemiol, Boston, MA 02218 USA. [Divers, Jasmin] Wake Forest Univ, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Epidemiol, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Inst Mol Med, Houston, TX 77030 USA. [Kao, W. H. Linda; Ruczinski, Ingo] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21205 USA. [Kao, W. H. Linda] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Lange, Leslie] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Li, Mingyao] Univ Penn, Philadelphia, PA 19104 USA. [Musani, Solomon; Wilson, James G.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Mychaleckyj, Josyf C.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22902 USA. [Ogunniyi, Adesola; Salako, Babatunde] Univ Ibadan, Dept Med, Ibadan 5017, Nigeria. [Papanicolaou, George] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Tayo, Bamidele O.; Cooper, Richard] Loyola Univ Chicago, Stritch Sch Med, Dept Prevent Med & Epidemiol, Maywood, IL 60153 USA. [Sabeti, Pardis] Harvard Univ, Cambridge, MA 02138 USA. [Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Lettre, Guillaume] Univ Montreal, Dept Med, Montreal, PQ H3T 3J7, Canada. [De Jager, Phil] Brigham & Womens Hosp, Ctr Neurol Dis, Div Mol Immunol, Boston, MA 02115 USA. [De Jager, Phil] Partners Ctr Personalized Genet Med, Boston, MA 02115 USA. [Zhu, Xiaofeng] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. RP Bhatia, G (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM gbhatia@mit.edu; aprice@hsph.harvard.edu RI Pasaniuc, Bogdan/E-9310-2012; Yang, Qiong/G-5438-2014; Myers, Simon/A-6792-2015; OI Adeyemo, Adebowale/0000-0002-3105-3231; Myers, Simon/0000-0002-2585-9626; Cupples, L. Adrienne/0000-0003-0273-7965 FU NIH [R01 HG005224, RC1 GM091332, 5T32ES007142-27]; National Human Genome Research Institute (NHGRI) [T32 HG002295]; NIH/NHGRI [U01 HG004726-01]; NHLBI's CARe consortium [HHSN268200960009C]; Grand Challenges in Global Health Initiative FX This work was funded by NIH grants R01 HG005224 (B.P. S.P., A.L.P.), RC1 GM091332 (N.P., D.R., J.G.W.) and by grant T32 HG002295 from the National Human Genome Research Institute (NHGRI) (G.B.) and NIH fellowship 5T32ES007142-27 (N.Z.), and used data from NHLBI's CARe project. C.H., D.R., N.P., and A.T. were supported by NIH/NHGRI grant U01 HG004726-01. We acknowledge the contributions of the participants and investigators of NHLBI's CARe consortium (contract number HHSN268200960009C). Funding information for CARe and its parent cohorts can be found at http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx. This study makes use of data generated by MalariaGEN. A full list of the investigators who contributed to the generation of the data is available from www.MalariaGEN.net. Funding for this project was provided by the Foundation for the National Institutes of Health and the Wellcome Trust. The funding for this project comes through the Grand Challenges in Global Health Initiative. NR 61 TC 33 Z9 33 U1 1 U2 19 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 SEP 9 PY 2011 VL 89 IS 3 BP 368 EP 381 DI 10.1016/j.ajhg.2011.07.025 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 820XQ UT WOS:000294939800002 PM 21907010 ER PT J AU O'hUigin, C Kulkarni, S Xu, YP Deng, ZH Kidd, J Kidd, K Gao, XJ Carrington, M AF O'hUigin, Colm Kulkarni, Smita Xu, Yunping Deng, Zhihui Kidd, Judith Kidd, Kenneth Gao, Xiaojiang Carrington, Mary TI The Molecular Origin and Consequences of Escape from miRNA Regulation by HLA-C Alleles SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID EXPRESSION; DETERMINANTS; POLYMORPHISM; GENOME; HIV-1 AB Differential expression of human leukocyte antigen C (HLA-C) allotypes is mediated by the binding of a microRNA, miR-148a, to the 3' untranslated region of some, but not all, HLA-C alleles. The binding results in lower levels of HLA-C expression, which is associated with higher levels of HIV-1 viral load among infected individuals. The alternative set of HLA-C alleles has several substitutions in the miR-148a binding site that prevent binding and HLA-C downregulation; these high-expression alleles associate with control of HIV-1 viral load. We show that the common ancestor of all extant HLA-C alleles was suppressed by miR-148a. Substitutions that prevent miR-148a binding arose by a sequence exchange event between an HLA-C allele and an HLA-B (MIM 142830) allele of a B*07-like lineage. The event occurred 3-5 million years ago, resulting in an HLA-C variant that escape from miR-148a downregulation. We present evidence suggesting that selection played a role in the successful spread of the HLA-C escape alleles, giving rise to 7 of the 14 extant HLA-C lineages. Notably, critical peptide and KIR binding residues of the escape variants have selectively converged to resemble the sequence of their inhibited counterparts, such that the inhibited and escape groupings differ primarily by their levels of expression. C1 [O'hUigin, Colm; Kulkarni, Smita; Gao, Xiaojiang; Carrington, Mary] NCI Frederick, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Kulkarni, Smita; Gao, Xiaojiang; Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. [Xu, Yunping; Deng, Zhihui] Shenzhen Blood Ctr, Immunogenet Lab, Shenzhen 518035, Guangdong, Peoples R China. [Kidd, Judith; Kidd, Kenneth] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. RP O'hUigin, C (reprint author), NCI Frederick, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. EM ohuiginc@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX We would like to thank members of the Carrington group and Ram Savan for informative discussion. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 23 TC 22 Z9 22 U1 0 U2 5 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 SEP 9 PY 2011 VL 89 IS 3 BP 424 EP 431 DI 10.1016/j.ajhg.2011.07.024 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 820XQ UT WOS:000294939800007 PM 21907013 ER PT J AU Judkowski, V Bunying, A Ge, F Appel, JR Law, K Sharma, A Raja-Gabaglia, C Norori, P Santos, RG Giulianotti, MA Slifka, MK Douek, DC Graham, BS Pinilla, C AF Judkowski, Valeria Bunying, Alcinette Ge, Feng Appel, Jon R. Law, Kingyee Sharma, Atima Raja-Gabaglia, Claudia Norori, Patricia Santos, Radleigh G. Giulianotti, Marc A. Slifka, Mark K. Douek, Daniel C. Graham, Barney S. Pinilla, Clemencia TI GM-CSF Production Allows the Identification of Immunoprevalent Antigens Recognized by Human CD4+T Cells Following Smallpox Vaccination SO PLOS ONE LA English DT Article ID CD4(+) T-CELLS; CYTOKINE EXPRESSION PATTERNS; VACCINIA VIRUS; IMMUNE-RESPONSE; IMMUNOLOGICAL MEMORY; ANTIVIRAL IMMUNITY; ANTIBODY-RESPONSES; BINDING PROTEIN; PEPTIDE LIGANDS; INFECTION AB The threat of bioterrorism with smallpox and the broad use of vaccinia vectors for other vaccines have led to the resurgence in the study of vaccinia immunological memory. The importance of the role of CD4+ T cells in the control of vaccinia infection is well known. However, more CD8+ than CD4+ T cell epitopes recognized by human subjects immunized with vaccinia virus have been reported. This could be, in part, due to the fact that most of the studies that have identified human CD4+ specific protein-derived fragments or peptides have used IFN-gamma production to evaluate vaccinia specific T cell responses. Based on these findings, we reasoned that analyzing a large panel of cytokines would permit us to generate a more complete analysis of the CD4 T cell responses. The results presented provide clear evidence that TNF-alpha is an excellent readout of vaccinia specificity and that other cytokines such as GM-CSF can be used to evaluate the reactivity of CD4+ T cells in response to vaccinia antigens. Furthermore, using these cytokines as readout of vaccinia specificity, we present the identification of novel peptides from immunoprevalent vaccinia proteins recognized by CD4+ T cells derived from smallpox vaccinated human subjects. In conclusion, we describe a "T cell- driven'' methodology that can be implemented to determine the specificity of the T cell response upon vaccination or infection. Together, the single pathogen in vitro stimulation, the selection of CD4+ T cells specific to the pathogen by limiting dilution, the evaluation of pathogen specificity by detecting multiple cytokines, and the screening of the clones with synthetic combinatorial libraries, constitutes a novel and valuable approach for the elucidation of human CD4+ T cell specificity in response to large pathogens. C1 [Judkowski, Valeria; Bunying, Alcinette; Ge, Feng; Appel, Jon R.; Law, Kingyee; Sharma, Atima; Raja-Gabaglia, Claudia; Norori, Patricia; Pinilla, Clemencia] Torrey Pines Inst Mol Studies, San Diego, CA USA. [Santos, Radleigh G.; Giulianotti, Marc A.] Torrey Pines Inst Mol Studies, Port St Lucie, FL USA. [Slifka, Mark K.] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR USA. [Douek, Daniel C.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Judkowski, V (reprint author), Torrey Pines Inst Mol Studies, San Diego, CA USA. EM pinilla@tpims.org FU National Institute of Allergy and Immunology [HHSN266200400080C/N01-AI-40080]; State of Florida, Executive Office of the Governor's Office of Tourism, Trade, and Economic Development; Multiple Sclerosis National Research Institute [UO1 AI082196, R44 AI079898]; Oregon National Primate Research Center [RR00163] FX The work was supported by National Institute of Allergy and Immunology HHSN266200400080C/N01-AI-40080 (C.P.) as well as the State of Florida, Executive Office of the Governor's Office of Tourism, Trade, and Economic Development (M.G. and R.S.); Multiple Sclerosis National Research Institute (C.P. and V.J.), UO1 AI082196 (M.K.S.), R44 AI079898 (M.K.S.); and Oregon National Primate Research Center grant RR00163 (M.K.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 7 Z9 7 U1 0 U2 6 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 SEP 9 PY 2011 VL 6 IS 9 AR e24091 DI 10.1371/journal.pone.0024091 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CN UT WOS:000294803100012 PM 21931646 ER PT J AU Dorjbal, B Derse, D Lloyd, P Soheilian, F Nagashima, K Heidecker, G AF Dorjbal, Batsukh Derse, David Lloyd, Patricia Soheilian, Ferri Nagashima, Kunio Heidecker, Gisela TI The Role of ITCH Protein in Human T-cell Leukemia Virus Type 1 Release SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LATE-BUDDING DOMAINS; NEDD4-LIKE UBIQUITIN LIGASE; INFECTIOUS-ANEMIA VIRUS; IMMUNODEFICIENCY-VIRUS; MULTIVESICULAR BODY; PARTICLE RELEASE; ESCRT MACHINERY; SORTING PATHWAY; MATRIX PROTEIN; HOST PROTEINS AB Human T-cell leukemia virus type 1 (HTLV-1) has two late domain (LD) motifs, PPPY and PTAP, which are important for viral budding. Mutations in the PPPY motif are more deleterious for viral release than changes in the PTAP motif. Several reports have shown that the interaction of PPPY with the WW domains of a Nedd4 (neuronal precursor cell-expressed developmentally down-regulated-4) family ubiquitin ligase (UL) is a critical event in virus release. We tested nine members of the Nedd4 family ULs and found that ITCH is the main contributor to HTLV-1 budding. ITCH overexpression strongly inhibited release and infectivity of wild-type (wt) HTLV-1, but rescued the release of infectious virions with certain mutations in the PPPY motif. Electron microscopy showed either fewer or misshapen virus particles when wt HTLV-1 was produced in the presence of overexpressed ITCH, whereas mutants with changes in the PPPY motif yielded normal looking particles at wt level. The other ULs had significantly weaker or no effects on HTLV-1 release and infectivity except for SMURF-1, which caused enhanced release of wt and all PPPY- mutant particles. These particles were poorly infectious and showed abnormal morphology by electron microscopy. Budding and infectivity defects due to overexpression of ITCH and SMURF-1 were correlated with higher than normal ubiquitination of Gag. Only silencing of ITCH, but not of WWP1, WWP2, and Nedd4, resulted in a reduction of HTLV-1 budding from 293T cells. The binding efficiencies between the HTLV-1 LD and WW domains of different ULs as measured by mammalian two-hybrid interaction did not correlate with the strength of their effect on HTLV-1 budding. C1 [Dorjbal, Batsukh; Derse, David; Heidecker, Gisela] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Lloyd, Patricia] SAIC, Basic Res Program, Frederick, MD 21702 USA. [Soheilian, Ferri; Nagashima, Kunio] SAIC, Image Anal Lab, Frederick, MD 21702 USA. RP Heidecker, G (reprint author), NCI, HIV Drug Resistance Program, POB B,Bldg 535,Rm 111, Frederick, MD 21702 USA. EM heidecke@mail.nih.gov FU National Institutes of Health, NCI, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research. NR 64 TC 9 Z9 9 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 SEP 9 PY 2011 VL 286 IS 36 BP 31092 EP 31104 DI 10.1074/jbc.M111.259945 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 814WI UT WOS:000294487500004 PM 21724848 ER PT J AU Morgan, HP McNae, IW Nowicki, MW Zhong, WH Michels, PAM Auld, DS Fothergill-Gilmore, LA Walkinshaw, MD AF Morgan, Hugh P. McNae, Iain W. Nowicki, Matthew W. Zhong, Wenhe Michels, Paul A. M. Auld, Douglas S. Fothergill-Gilmore, Linda A. Walkinshaw, Malcolm D. TI The Trypanocidal Drug Suramin and Other Trypan Blue Mimetics Are Inhibitors of Pyruvate Kinases and Bind to the Adenosine Site SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOLECULAR-GRAPHICS; BRUCEI; DISCOVERY; ENZYMES; ANALOGS; GLUCOSE; INVIVO; MODEL AB Ehrlich's pioneering chemotherapeutic experiments published in 1904 (Ehrlich, P., and Shiga, K. (1904) Berlin Klin. Wochenschrift 20, 329-362) described the efficacy of a series of dye molecules including trypan blue and trypan red to eliminate trypanosome infections in mice. The molecular structures of the dyes provided a starting point for the synthesis of suramin, which was developed and used as a trypanocidal drug in 1916 and is still in clinical use. Despite the biological importance of these dye-like molecules, the mode of action on trypanosomes has remained elusive. Here we present crystal structures of suramin and three related dyes in complex with pyruvate kinases from Leishmania mexicana or from Trypanosoma cruzi. The phenyl sulfonate groups of all four molecules (suramin, Ponceau S, acid blue 80, and benzothiazole-2,5-disulfonic acid) bind in the position of ADP/ATP at the active sites of the pyruvate kinases (PYKs). The binding positions in the two different trypanosomatid PYKs are nearly identical. We show that suramin competitively inhibits PYKs from humans (muscle, tumor, and liver isoenzymes, K-i = 1.1-17 mu M), T. cruzi (K-i = 108 mu M), and L. mexicana (K-i = 116 mu M), all of which have similar active sites. Synergistic effects were observed when examining suramin inhibition in the presence of an allosteric effector molecule, whereby IC50 values decreased up to 2-fold for both trypanosomatid and human PYKs. These kinetic and structural analyses provide insight into the promiscuous inhibition observed for suramin and into the mode of action of the dye-like molecules used in Ehrlich's original experiments. C1 [Morgan, Hugh P.; McNae, Iain W.; Nowicki, Matthew W.; Zhong, Wenhe; Fothergill-Gilmore, Linda A.; Walkinshaw, Malcolm D.] Univ Edinburgh, Struct Biochem Grp, Inst Struct & Mol Biol, Edinburgh EH9 3JR, Midlothian, Scotland. [Michels, Paul A. M.] Catholic Univ Louvain, Trop Dis Res Unit, Duve Inst, B-1200 Brussels, Belgium. [Michels, Paul A. M.] Catholic Univ Louvain, Biochem Lab, B-1200 Brussels, Belgium. [Auld, Douglas S.] NHGRI, NIH, Chem Genom Ctr, Rockville, MD 20850 USA. RP Walkinshaw, MD (reprint author), Univ Edinburgh, Struct Biochem Grp, Inst Struct & Mol Biol, Kings Bldg,Mayfield Rd, Edinburgh EH9 3JR, Midlothian, Scotland. EM m.walkinshaw@ed.ac.uk RI Michels, Paul/A-5637-2009; OI walkinshaw, malcolm/0000-0001-5955-9325 FU Medical Research Council; European Commission; Wellcome Trust; Biotechnology and Biological Sciences Research Council (BBSRC) FX This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by the Medical Research Council and by the European Commission through its International Cooperation with Developing Countries program.; We thank Professor Hee-won Park, Structural Genomics Consortium, University of Toronto, Canada for the gift of human PYK isoenzymes and Dr. J. Dornan for excellent advice and practical help. We also thank the staff at the synchrotron facilities at the European Synchrotron Radiation Facility (ESRF) and Diamond synchrotron radiation facility and also at the National Institutes of Health, Rockville, MD. The Centre for Translational and Chemical Biology and the Edinburgh Protein Production Facility were funded by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC). NR 51 TC 29 Z9 29 U1 0 U2 8 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 SEP 9 PY 2011 VL 286 IS 36 BP 31232 EP 31240 DI 10.1074/jbc.M110.212613 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 814WI UT WOS:000294487500018 PM 21733839 ER PT J AU Chiluiza, D Bargo, S Callahan, R Rhoads, RE AF Chiluiza, David Bargo, Sharon Callahan, Robert Rhoads, Robert E. TI Expression of Truncated Eukaryotic Initiation Factor 3e (eIF3e) Resulting from Integration of Mouse Mammary Tumor Virus (MMTV) Causes a Shift from Cap-dependent to Cap-independent Translation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTERNAL-RIBOSOME-ENTRY; HEPATITIS-C VIRUS; PROTEIN-SYNTHESIS; MESSENGER-RNAS; MALIGNANT-TRANSFORMATION; BREAST-CANCER; CELL-DEATH; GENE; REVEALS; TUMORIGENESIS AB Integration of mouse mammary tumor virus (MMTV) at the common integration site Int6 occurs in the gene encoding eIF3e, the p48 subunit of translation initiation factor eIF3. Integration is at any of several introns of the Eif3e gene and causes the expression of truncated Eif3e mRNAs. Ectopic expression of the truncated eIF3e protein resulting from integration at intron 5 (3e5) induces malignant transformation, but by an unknown mechanism. Because eIF3e makes up at least part of the binding site for eIF4G, we examined the effects of 3e5 expression on protein synthesis. We developed an NIH3T3 cell line that contains a single copy of the 3e5 sequence at a predetermined genomic site. Co-immunoprecipitation indicated diminished binding of eIF3 to eIF4G, signifying a reduction in recruitment of the mRNA-unwinding machinery to the 43 S preinitiation complex. Cell growth and overall protein synthesis were decreased. Translation driven by the eIF4G-independent hepatitis C virus internal ribosome entry sequence (HCV IRES) in a bicistronic mRNA was increased relative to cap-dependent translation. Endogenous mRNAs encoding XIAP, c-Myc, CYR61, and Pim-1, which are translated in a cap-independent manner, were shifted to heavier polysomes whereas mRNAs encoding GAPDH, actin, L32, and L34, which are translated in a cap-dependent manner, were shifted to lighter polysomes. We propose that expression of 3e5 diminishes eIF4G interaction with eIF3 and causes abnormal gene expression at the translational level. The correlation between up-regulation of cap-independent translation and MMTV-induced tumorigenesis contrasts with the well established model for malignant transformation involving up-regulation of highly cap-dependent translation. C1 [Chiluiza, David; Rhoads, Robert E.] Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Shreveport, LA 71106 USA. [Bargo, Sharon; Callahan, Robert] NCI, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. RP Rhoads, RE (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Shreveport, LA 71130 USA. EM rrhoad@lsuhsc.edu FU NIGMS, National Institutes of Health [R01GM20818] FX This work was supported, in whole or in part, by Grant R01GM20818 from the NIGMS, National Institutes of Health. NR 57 TC 10 Z9 10 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 9 PY 2011 VL 286 IS 36 BP 31288 EP 31296 DI 10.1074/jbc.M111.267294 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 814WI UT WOS:000294487500024 PM 21737453 ER PT J AU Kasiviswanathan, R Copeland, WC AF Kasiviswanathan, Rajesh Copeland, William C. TI Ribonucleotide Discrimination and Reverse Transcription by the Human Mitochondrial DNA Polymerase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID I KLENOW FRAGMENT; ESCHERICHIA-COLI; RNA-POLYMERASE; SIDE-CHAINS; GAMMA; REPLICATION; MUTATIONS; DEPLETION; FIDELITY; PURIFICATION AB During DNA synthesis, DNA polymerases must select against ribonucleotides, present at much higher levels compared with deoxyribonucleotides. Most DNA polymerases are equipped to exclude ribonucleotides from their active site through a bulky side chain residue that can sterically block the 2'-hydroxyl group of the ribose ring. However, many nuclear replicative and repair DNA polymerases incorporate ribonucleotides into DNA, suggesting that the exclusion mechanism is not perfect. In this study, we show that the human mitochondrial DNA polymerase gamma discriminates ribonucleotides efficiently but differentially based on the base identity. Whereas UTP is discriminated by 77,000-fold compared with dTTP, the discrimination drops to 1,100-fold for GTP versus dGTP. In addition, the efficiency of the enzyme was reduced 3-14-fold, depending on the identity of the incoming nucleotide, when it extended from a primer containing a 3'-terminal ribonucleotide. DNA polymerase gamma is also proficient in performing single-nucleotide reverse transcription reactions from both DNA and RNA primer terminus, although its bypass efficiency is significantly diminished with increasing stretches of ribonucleotides in template DNA. Furthermore, we show that the E895A mutant enzyme is compromised in its ability to discriminate ribonucleotides, mainly due to its defects in deoxyribonucleoside triphosphate binding, and is also a poor reverse transcriptase. The potential biochemical defects of a patient harboring a disease mutation in the same amino acid (E895G) are discussed. C1 [Kasiviswanathan, Rajesh; Copeland, William C.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, NIH, 111 TW Alexander Dr,Bldg 101,Rm E316, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov RI Kasiviswanathan, Rajesh/D-2744-2012 FU National Institutes of Health, NIEHS [ES 065078, ES 065080] FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program, NIEHS, Grants ES 065078 and ES 065080. NR 44 TC 27 Z9 27 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 9 PY 2011 VL 286 IS 36 BP 31490 EP 31500 DI 10.1074/jbc.M111.252460 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 814WI UT WOS:000294487500044 PM 21778232 ER PT J AU Lubkowska, L Maharjan, AS Komissarova, N AF Lubkowska, Lucyna Maharjan, Anu S. Komissarova, Natalia TI RNA Folding in Transcription Elongation Complex IMPLICATION FOR TRANSCRIPTION TERMINATION SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PRE-MESSENGER-RNA; ESCHERICHIA-COLI; NASCENT RNA; DNA HYBRID; IN-VIVO; TRANSLATIONAL CONTROL; SECONDARY STRUCTURE; POLYMERASE-II; STEM-LOOP; 3 END AB Intrinsic transcription termination signal in DNA consists of a short inverted repeat followed by a T-rich stretch. Transcription of this sequence by RNA polymerase (RNAP) results in formation of a "termination hairpin" (TH) in the nascent RNA and in rapid dissociation of the transcription elongation complex (EC) at termination points located 7-8 nt downstream of the base of TH stem. RNAP envelops 15 nt of the RNA following RNA growing 3'-end, suggesting that folding of the TH is impeded by a tight protein environment when RNAP reaches the termination points. To monitor TH folding under this constraint, we halted Escherichia coli ECs at various distances downstream from a TH and treated them with single-strand specific RNase T1. The EC interfered with TH formation when halted at 6, 7, and 8, but not 9, nt downstream from the base of the potential stem. Thus, immediately before termination, the downstream arm of the TH is protected from complementary interactions with the upstream arm. This protection makes TH folding extremely sensitive to the sequence context, because the upstream arm easily engages in competing interactions with the rest of the nascent RNA. We demonstrate that by de-synchronizing TH formation and transcription of the termination points, this subtle competition significantly affects the efficiency of transcription termination. This finding can explain previous puzzling observations that sequences far upstream of the TH or point mutations in the terminator that preserve TH stability affect termination. These results can help understand other time sensitive co-transcriptional processes in pro- and eukaryotes. C1 [Lubkowska, Lucyna; Komissarova, Natalia] NCI, Ctr Canc Res, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. [Maharjan, Anu S.; Komissarova, Natalia] NICHD, Program Genom & Differentiat, NIH, Bethesda, MD 20892 USA. [Maharjan, Anu S.] Smith Coll, Northampton, MA 01063 USA. RP Komissarova, N (reprint author), NCI, 37 Convent Dr, Bethesda, MD 20892 USA. EM komissar@mail.nih.gov FU National Cancer Institute, Center for Cancer Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported, in whole or in part, by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 52 TC 5 Z9 5 U1 2 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 9 PY 2011 VL 286 IS 36 BP 31576 EP 31585 DI 10.1074/jbc.M111.249359 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 814WI UT WOS:000294487500052 PM 21730066 ER PT J AU Cavanaugh, NA Beard, WA Batra, VK Perera, L Pedersen, LG Wilson, SH AF Cavanaugh, Nisha A. Beard, William A. Batra, Vinod K. Perera, Lalith Pedersen, Lee G. Wilson, Samuel H. TI Molecular Insights into DNA Polymerase Deterrents for Ribonucleotide Insertion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVE-SITE; STRUCTURAL INSIGHTS; CRYSTAL-STRUCTURE; RNA-POLYMERASE; TRIGGER LOOP; BETA; SUBSTRATE; SUGAR; DISCRIMINATION; PYRIMIDINES AB DNA polymerases can misinsert ribonucleotides that lead to genomic instability. DNA polymerase beta discourages ribonucleotide insertion with the backbone carbonyl of Tyr-271; alanine substitution of Tyr-271, but not Phe-272, resulted in a > 10-fold loss in discrimination. The Y271A mutant also inserted ribonucleotides more efficiently than wild type on a variety of ribonucleoside (rNMP)-containing DNA substrates. Substituting Mn2+ for Mg2+ decreased sugar discrimination for both wild-type and mutant enzymes primarily by increasing the affinity for rCTP. This facilitated crystallization of ternary substrate complexes of both the wild-type and Y271A mutant enzymes. Crystallographic structures of Y271A- and wild type-substrate complexes indicated that rCTP is well accommodated in the active site but that O2' of rCTP and the carbonyl oxygen of Tyr-271 or Ala-271 are unusually close (similar to 2.5 and 2.6 angstrom, respectively). Structure-based modeling indicates that the local energetic cost of positioning these closely spaced oxygens is similar to 2.2 kcal/mol for the wild-type enzyme. Because the side chain of Tyr-271 also hydrogen bonds with the primer terminus, loss of this interaction affects its catalytic positioning. Our results support a model where DNA polymerase beta utilizes two strategies, steric and geometric, with a single protein residue to deter ribonucleotide insertion. C1 [Cavanaugh, Nisha A.; Beard, William A.; Batra, Vinod K.; Perera, Lalith; Pedersen, Lee G.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Pedersen, Lee G.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov RI perera, Lalith/B-6879-2012; Pedersen, Lee/E-3405-2013 OI perera, Lalith/0000-0003-0823-1631; Pedersen, Lee/0000-0003-1262-9861 FU National Institutes of Health [P41 RR-01081, Z01-ES0500158, Z01-ES050161]; NIEHS [1U19CA105010] FX We thank Drs. R. E. London and B. D. Freudenthal for critical reading of this manuscript and E. W. Hou for purification of the F272A mutant. Molecular graphics images were produced using the Chimera package (20) from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by National Institutes of Health Grant P41 RR-01081).; This work was supported, in whole or in part, by National Institutes of Health Research Project Grants Z01-ES0500158 and Z01-ES050161 (to S. H. W.) from the Intramural Research Program, NIEHS, in association with Grant 1U19CA105010. NR 47 TC 25 Z9 25 U1 0 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 SEP 9 PY 2011 VL 286 IS 36 BP 31650 EP 31660 DI 10.1074/jbc.M111.253401 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 814WI UT WOS:000294487500058 PM 21733843 ER PT J AU Ding, YF Winters, A Ding, M Graham, S Akopova, I Muallem, S Wang, YX Hong, JH Gryczynski, Z Yang, SH Birnbaumer, L Ma, R AF Ding, Yanfeng Winters, Ali Ding, Min Graham, Sarabeth Akopova, Irina Muallem, Shmuel Wang, Yanxia Hong, Jeong Hee Gryczynski, Zygmunt Yang, Shao-Hua Birnbaumer, Lutz Ma, Rong TI Reactive Oxygen Species-mediated TRPC6 Protein Activation in Vascular Myocytes, a Mechanism for Vasoconstrictor-regulated Vascular Tone SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLOMERULAR MESANGIAL CELLS; SMOOTH-MUSCLE-CELLS; HYDROGEN-PEROXIDE; CATION CHANNEL; NAD(P)H OXIDASE; RECEPTOR; STIMULATION; EXPRESSION; MODULATION; PATHWAYS AB Both TRPC6 and reactive oxygen species (ROS) play an important role in regulating vascular function. However, their interplay has not been explored. The present study examined whether activation of TRPC6 in vascular smooth muscle cells (VSMCs) by ROS was a physiological mechanism for regulating vascular tone by vasoconstrictors. In A7r5 cells, arginine vasopressin (AVP) evoked a striking Ca2+ entry response that was significantly attenuated by either knocking down TRPC6 using siRNA or inhibition of NADPH oxidases with apocynin or diphenyleneiodonium. Inhibition of TRPC6 or ROS production also decreased AVP-stimulated membrane currents. In primary cultured aortic VSMCs, catalase and diphenyleneiodonium significantly suppressed AVP- and angiotensin II-induced whole cell currents and Ca2+ entry, respectively. In freshly isolated and endothelium-denuded thoracic aortas, hyperforin (an activator of TRPC6), but not its vehicle, induced dose- and time-dependent constriction in TRPC6 wide type (WT) mice. This response was not observed in TRPC6 knock-out (KO) mice. Consistent with the ex vivo study, hyperforin stimulated a robust Ca2+ entry in the aortic VSMCs from WT mice but not from KO mice. Phenylephrine induced a dose-dependent contraction of WT aortic segments, and this response was inhibited by catalase. Moreover, H2O2 itself evoked Ca2+ influx and inward currents in A7r5 cells, and these responses were significantly attenuated by either inhibition of TRPC6 or blocking vesicle trafficking. H2O2 also induced inward currents in primary VSMCs from WT but not from TRPC6 KO mice. Additionally, H2O2 stimulated a dose-dependent constriction of the aortas from WT mice but not from the vessels of KO mice. Furthermore, TIRFM showed that H2O2 triggered membrane trafficking of TRPC6 in A7r5 cells. These results suggest a new signaling pathway of ROS-TRPC6 in controlling vessel contraction by vasoconstrictors. C1 [Ding, Yanfeng; Winters, Ali; Ding, Min; Graham, Sarabeth; Wang, Yanxia; Ma, Rong] Univ N Texas, Hlth Sci Ctr, Dept Integrat Physiol, Ft Worth, TX 76107 USA. [Ding, Yanfeng; Winters, Ali; Ding, Min; Graham, Sarabeth; Wang, Yanxia; Ma, Rong] Univ N Texas, Hlth Sci Ctr, Cardiovasc Res Inst, Ft Worth, TX 76107 USA. [Akopova, Irina; Gryczynski, Zygmunt] Univ N Texas, Hlth Sci Ctr, Dept Mol Biol & Immunol, Ft Worth, TX 76107 USA. [Yang, Shao-Hua] Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Ft Worth, TX 76107 USA. [Muallem, Shmuel; Hong, Jeong Hee] NIDCR, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Birnbaumer, Lutz] NIH, Transmembrane Signaling Grp, Res Triangle Pk, NC 27709 USA. RP Ma, R (reprint author), Univ N Texas, Hlth Sci Ctr, Dept Integrat Physiol, 3500 Camp Bowie Blvd, Ft Worth, TX 76107 USA. EM rong.ma@unthsc.edu RI Yang, Shaohua/D-1738-2013 FU NIDDK [5 RO1 DK079968-01A2, 5R21CA149897-02]; American Heart Association South Central Affiliate [09GRNT2260926] FX This work was supported, in whole or in part, by National Institutes of Health Grants 5 RO1 DK079968-01A2 from NIDDK (to R. M.) and 5R21CA149897-02 (to Z. G.). This work was also supported by Grant-in-aid 09GRNT2260926 from American Heart Association South Central Affiliate (to R. M.). NR 37 TC 36 Z9 37 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 SEP 9 PY 2011 VL 286 IS 36 BP 31799 EP 31809 DI 10.1074/jbc.M111.248344 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 814WI UT WOS:000294487500073 PM 21768109 ER PT J AU Yang, Y Gu, DY Aisa, HA Ito, Y AF Yang, Yi Gu, Dongyu Aisa, Haji Akber Ito, Yoichiro TI Studies on the effect of column angle in figure-8 centrifugal counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 6th International Conference on Countercurrent Chromatography CY JUL 28-30, 2010 CL Univ Lyon, La Doua Campus, Lyon, FRANCE SP French Assoc Separat Sci HO Univ Lyon, La Doua Campus DE Centrifugal counter-current chromatography; Figure-8 column; Angle between column axis and centrifugal force; Retention of the stationary phase; Resolution; Dipeptide; DNP-amino acid ID DESIGN; SPEED AB The performance of the figure-8 column configuration in centrifugal counter-current chromatography was investigated by changing the angle between the column axis (a line through the central post and the peripheral post on which the figure-8 coil is wound) and the centrifugal force. The first series of experiments was performed using a polar two-phase solvent system composed of 1-butanol-acetic acid-water (4:1:5, v/v) to separate two dipeptide samples. Trp-Tyr and Val-Tyr, at a flow rate of 0.05 ml/min at 1000 rpm. When the column angle was changed from 0 degrees (column axis parallel to the centrifugal force) to 45 degrees and 45 degrees to 90 degrees (column axis perpendicular to the centrifugal force), peak resolution (Rs) changed from 1.93 (Sf = 37.8%) to 1.54 (Sf =30.6%), then to 1.31 (Sf = 40.5%) with the lower mobile phase and from 1.21 (Sf = 38.8%) to 1.10 (Sf = 34.4%). then to 0.99 (Sf = 42.2%) with the upper mobile phase, respectively, where the stationary phase retention. SE is given in parentheses. The second series of experiments was similarly performed with a more hydrophobic two-phase solvent system composed of hexane-ethyl acetate-methanol-0.1 M hydrochloric acid (1:1:1:1, v/v) to separate three DNP-amino acids, DNP-glu. DNP-beta-ala and DNP-ala, at a flow rate of 0.05 ml/min at 1000 rpm. When the column angle was altered from 0 degrees to 45 degrees and 45 degrees to 90 degrees, Rs changed from 1.77 (1st peak/2nd peak) and 1.52 (2nd peak/3rd peak) (Sf = 27.3%) to 1.24 and 1.02 (Sf = 35.4%), then to 1.69 and 1.49 (Sf = 42.1%) with the lower mobile phase, and from 1.73 and 0.84 (SF = 41.2%) to 1.44 and 0.73 (Sf = 45.6%), then to 1.21 and 0.63 (Sf = 55.6%) with the upper mobile phase, respectively. The performance of figure-8 column at 0 degrees and 90 degrees was also compared at different flow rates. The results show that Rs was increased with decreased flow rate yielding the highest value at the 0 degrees column angle with lower mobile phase. The overall results of our studies indicated that a 0 degrees column angle for the figure-8 column enhances the mixing of two phases in the column to improve peak resolution while decreasing the stationary phase retention by interrupting the laminar flow of the mobile phase. Published by Elsevier B.V. C1 [Yang, Yi; Gu, Dongyu; Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Yang, Yi; Gu, Dongyu; Aisa, Haji Akber] Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Key Lab Chem Plant Resources Arid Reg, Urumqi 830011, Peoples R China. [Yang, Yi; Gu, Dongyu] Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China. RP Ito, Y (reprint author), NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, 10 Ctr Dr,Bldg 10,Room 8N230, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov FU Intramural NIH HHS [ZIA HL006022-01] NR 18 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD SEP 9 PY 2011 VL 1218 IS 36 BP 6128 EP 6134 DI 10.1016/j.chroma.2010.11.014 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 815JZ UT WOS:000294523200018 PM 21134675 ER PT J AU Weisz, A Ito, Y AF Weisz, Adrian Ito, Yoichiro TI Performance comparison of three types of high-speed counter-current chromatographs for the separation of components of hydrophilic and hydrophobic color additives SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 6th International Conference on Countercurrent Chromatography CY JUL 28-30, 2010 CL Univ Lyon, La Doua Campus, Lyon, FRANCE SP French Assoc Separat Sci HO Univ Lyon, La Doua Campus DE High-speed counter-current chromatography; J-type coil planet centrifuge; Cross-axis coil planet centrifuge; Multilayer-coil column; Spiral-tube assembly column; HPLC; Color additives; FD&C Blue No. 2; D&C Red No. 17; Sudan II ID BLUE NO 2; SUBSIDIARY COLORS; FD; IDENTIFICATION; PURIFICATION; APPARATUS AB The performance of three types of high-speed counter-current chromatography (HSCCC) instruments was assessed for their use in separating components in hydrophilic and hydrophobic dye mixtures. The HSCCC instruments compared were: (i) a J-type coil planet centrifuge (CPC) system with a conventional multilayer-coil column, (ii) a J-type CPC system with a spiral-tube assembly-coil column, and (iii) a cross-axis CPC system with a multilayer-coil column. The hydrophilic dye mixture consisted of a sample of FD&C Blue No. 2 that contained mainly two isomeric components, 5,5'- and 5,7'-disulfonated indigo, in the ratio of similar to 7:1. The hydrophobic dye mixture consisted of a sample of D&C Red No. 17 (mainly Sudan III) and Sudan II in the ratio of similar to 4:1. The two-phase solvent systems used for these separations were 1-butanol/1.3 M HCl and hexane/acetonit rile. Each of the three instruments was used in two experiments for the hydrophilic dye mixture and two for the hydrophobic dye mixture, for a total of 12 experiments. In one set of experiments, the lower phase was used as the mobile phase, and in the second set of experiments, the upper phase was used as the mobile phase. The results suggest that: (a) use of a J-type instrument with either a multilayer-coil column or a spiral-tube assembly column, applying the lower phase as the mobile phase, is preferable for separating the hydrophilic components of FD&C Blue No. 2; and (b) use of a J-type instrument with multilayer-coil column, while applying either the upper phase or the lower phase as the mobile phase, is preferable for separating the hydrophobic dye mixture of D&C Red No. 17 and Sudan II. Published by Elsevier B.V. C1 [Weisz, Adrian] USA Food & Drug Adm, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Ito, Yoichiro] NHLBI, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Weisz, A (reprint author), USA Food & Drug Adm, Off Cosmet & Colors, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM adrian.weisz@fda.hhs.gov FU Intramural NIH HHS [ZIA HL005107-02] NR 26 TC 6 Z9 6 U1 0 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD SEP 9 PY 2011 VL 1218 IS 36 BP 6156 EP 6164 DI 10.1016/j.chroma.2010.12.034 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 815JZ UT WOS:000294523200022 PM 21215406 ER PT J AU Ito, Y Ma, ZY Clary, R Powell, J Knight, M Finn, TM AF Ito, Yoichiro Ma, Zhiyong Clary, Robert Powell, Jimmie Knight, Martha Finn, Thomas M. TI Vortex counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 6th International Conference on Countercurrent Chromatography CY JUL 28-30, 2010 CL Univ Lyon, La Doua Campus, Lyon, FRANCE SP French Assoc Separat Sci HO Univ Lyon, La Doua Campus DE Vortex counter-current chromatography; Type-I coil planet centrifuge; Cylindrical vortex column ID COIL PLANET CENTRIFUGE AB A novel counter-current chromatographic system is developed by mounting a vortex column on a type-I coil planet centrifuge. The column is fabricated from a high-density polyethylene disk (16 cm diameter and 5 cm thick) by making multiple holes of various diameters (3-12.5 mm) each arranged in a circle and connected with narrow transfer ducts. The performance of this vortex column is tested with three different two-phase solvent systems with a broad range in hydrophobicity. The results indicated that the smallest diameter column (3 mm diameter. 120 units with 42.8 ml capacity) yielded the best separation with the height equivalent to a theoretical Plate of 2 cm compared with 20 cm required by the conventional multilayer coil column of high-speed CCC. By avoiding the use of an Archimedean Screw Force, the system shows a low column pressure which would permit safe operation of a large preparative column without a risk of leakage of solvent and column damage. Published by Elsevier B.V. C1 [Ito, Yoichiro; Ma, Zhiyong] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Clary, Robert; Powell, Jimmie] NIH, Bethesda, MD 20892 USA. [Knight, Martha; Finn, Thomas M.] CCBiotech LLC, Rockville, MD USA. [Ma, Zhiyong] Harbin Med Coll, Coll Pharm, Harbin 150081, Peoples R China. RP Ito, Y (reprint author), NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, 10 Ctr Dr,Bldg 10,Room 8N230,MSC 1762, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov OI Knight, Martha/0000-0003-4863-8858 FU Intramural NIH HHS [ZIA HL001060-01] NR 9 TC 7 Z9 7 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD SEP 9 PY 2011 VL 1218 IS 36 BP 6165 EP 6172 DI 10.1016/j.chroma.2010.10.058 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 815JZ UT WOS:000294523200023 PM 21056421 ER PT J AU Hsu, AP Sampaio, EP Khan, J Calvo, KR Lemieux, JE Patel, SY Frucht, DM Vinh, DC Auth, RD Freeman, AF Olivier, KN Uzel, G Zerbe, CS Spalding, C Pittaluga, S Raffeld, M Kuhns, DB Ding, L Paulson, ML Marciano, BE Gea-Banacloche, JC Orange, JS Cuellar-Rodriguez, J Hickstein, DD Holland, SM AF Hsu, Amy P. Sampaio, Elizabeth P. Khan, Javed Calvo, Katherine R. Lemieux, Jacob E. Patel, Smita Y. Frucht, David M. Vinh, Donald C. Auth, Roger D. Freeman, Alexandra F. Olivier, Kenneth N. Uzel, Gulbu Zerbe, Christa S. Spalding, Christine Pittaluga, Stefania Raffeld, Mark Kuhns, Douglas B. Ding, Li Paulson, Michelle L. Marciano, Beatriz E. Gea-Banacloche, Juan C. Orange, Jordan S. Cuellar-Rodriguez, Jennifer Hickstein, Dennis D. Holland, Steven M. TI Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome SO BLOOD LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; MYELOID-LEUKEMIA; HAPLOINSUFFICIENCY AB The syndrome of monocytopenia, B-cell and NK-cell lymphopenia, and mycobacterial, fungal, and viral infections is associated with myelodysplasia, cytogenetic abnormalities, pulmonary alveolar proteinosis, and myeloid leukemias. Both autosomal dominant and sporadic cases occur. We identified 12 distinct mutations in GATA2 affecting 20 patients and relatives with this syndrome, including recur-rent missense mutations affecting the zinc finger-2 domain (R398W and T354M), suggesting dominant interference of gene function. Four discrete insertion/deletion mutations leading to frame shifts and premature termination implicate haploin-sufficiency as a possible mechanism of action as well. These mutations were found in hematopoietic and somatic tissues, and several were identified in families, indicating germline transmission. Thus, GATA2 joins RUNX1 and CEBPA not only as a familial leukemia gene but also as a cause of a complex congenital immunodeficiency that evolves over decades and combines predisposition to infection and myeloid malignancy. (Blood. 2011;118(10):2653-2655) C1 [Hsu, Amy P.; Sampaio, Elizabeth P.; Vinh, Donald C.; Freeman, Alexandra F.; Olivier, Kenneth N.; Uzel, Gulbu; Zerbe, Christa S.; Spalding, Christine; Ding, Li; Paulson, Michelle L.; Marciano, Beatriz E.; Cuellar-Rodriguez, Jennifer; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Khan, Javed] NCI, Oncogen Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Calvo, Katherine R.] Warren Grant Magnuson Clin Canc Ctr, Hematol Sect, Dept Lab Med, Bethesda, MD USA. [Lemieux, Jacob E.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Patel, Smita Y.] Univ Oxford, John Radcliffe Hosp, Oxford OX3 9DU, England. [Frucht, David M.; Auth, Roger D.] Fed Drug Adm, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Pittaluga, Stefania; Raffeld, Mark] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Kuhns, Douglas B.; Paulson, Michelle L.] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Gea-Banacloche, Juan C.; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Orange, Jordan S.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, NIH, CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov RI Calvo, Katherine/A-8109-2009; OI orange, jordan/0000-0001-7117-7725; Calvo, Katherine/0000-0002-0771-4191; VINH, DONALD/0000-0003-1347-7767 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E). NR 18 TC 176 Z9 178 U1 2 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 8 PY 2011 VL 118 IS 10 BP 2653 EP 2655 DI 10.1182/blood-2011-05-356352 PG 3 WC Hematology SC Hematology GA 819BX UT WOS:000294801500008 PM 21670465 ER PT J AU Sokolic, R Maric, I Kesserwan, C Garabedian, E Hanson, IC Dodds, M Buckley, R Issekutz, AC Kamani, N Shaw, K Tan, B Bali, P Hershfield, MS Kohn, DB Wayne, AS Candotti, F AF Sokolic, Robert Maric, Irina Kesserwan, Chimene Garabedian, Elizabeth Hanson, I. Celine Dodds, Margaret Buckley, Rebecca Issekutz, Andrew C. Kamani, Naynesh Shaw, Kit Tan, Ben Bali, Pawan Hershfield, Michael S. Kohn, Donald B. Wayne, Alan S. Candotti, Fabio TI Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase-deficient severe combined immune deficiency SO BLOOD LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; STEM-CELL TRANSPLANTATION; GENE-THERAPY; ADA AB Genetic deficiency of adenosine deaminase (ADA) can cause profound lymphopenia and result in the clinical presentation of severe combined immune deficiency (SCID). However, because of the ubiquitous expression of ADA, ADA-deficient patients often present also with nonimmunologic clinical problems, affecting the skeletal, central nervous, endocrine, and gastrointestinal systems. We now report that myeloid dysplasia features and bone marrow hypocellularity are often found in patients with ADA-SCID. As a clinical correlate to this finding, we have observed vulnerability to antibiotic-induced myelotoxicity and prolonged neutropenia after nonmyeloablative chemotherapy. We have also noted that, in the absence of enzyme replacement therapy, absolute neutrophil counts of patients with ADA deficiency vary inversely with the accumulation of deoxynucleotides. These data have significant implications for the application of standard and investigational therapies to patients with ADA-SCID and support further studies to investigate the possibility that ADA deficiency is associated with a stem cell defect. These trials were registered at www.clinicaltrials.gov as #NCT00018018 and #NCT00006319. (Blood. 2011;118(10):2688-2694) C1 [Sokolic, Robert; Kesserwan, Chimene; Garabedian, Elizabeth; Candotti, Fabio] NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Maric, Irina] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Kesserwan, Chimene; Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Hanson, I. Celine; Dodds, Margaret] Baylor Coll Med, Dept Pediat, Allergy & Immunol Sect, Houston, TX 77030 USA. [Hanson, I. Celine; Dodds, Margaret] Texas Childrens Hosp, Houston, TX 77030 USA. [Buckley, Rebecca] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. [Buckley, Rebecca] Duke Univ, Med Ctr, Div Immunol, Durham, NC 27710 USA. [Issekutz, Andrew C.] Dalhousie Univ, Dept Pediat, Halifax, NS, Canada. [Kamani, Naynesh] George Washington Univ, Dept Immunol, Washington, DC USA. [Kamani, Naynesh] George Washington Univ, Dept Trop Med, Washington, DC USA. [Shaw, Kit; Kohn, Donald B.] Univ Calif Los Angeles, Dept Microbiol, Los Angeles, CA 90024 USA. [Shaw, Kit; Kohn, Donald B.] Univ Calif Los Angeles, Dept Immunol, Los Angeles, CA USA. [Shaw, Kit; Kohn, Donald B.] Univ Calif Los Angeles, Dept Mol Genet, Los Angeles, CA USA. [Tan, Ben] Univ Saskatchewan, Saskatoon, SK, Canada. [Bali, Pawan; Hershfield, Michael S.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Hershfield, Michael S.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. [Kamani, Naynesh] George Washington Univ, Dept Pediat & Microbiol, Washington, DC USA. RP Sokolic, R (reprint author), NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, 10 Ctr Dr,Bldg 10CRC,Rm 6-3330,MSC 1611, Bethesda, MD 20892 USA. EM sokolicr@mail.nih.gov RI Sokolic, Robert/I-6072-2012; Kohn, Donald/N-5085-2016 OI Kohn, Donald/0000-0003-1840-6087 FU National Human Genome Research Institute; NCI Center for Cancer Research; NIH Clinical Center; Enzon Inc; National Institute of Allergy and Infectious Diseases FX This work was supported by the intramural research programs of the National Human Genome Research Institute, the NCI Center for Cancer Research, and the NIH Clinical Center. M.S.H. and P.B. received support from Enzon Inc. I.C.H. was supported by the National Institute of Allergy and Infectious Diseases. NR 17 TC 15 Z9 15 U1 0 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 8 PY 2011 VL 118 IS 10 BP 2688 EP 2694 DI 10.1182/blood-2011-01-329359 PG 7 WC Hematology SC Hematology GA 819BX UT WOS:000294801500013 PM 21725047 ER PT J AU Zhang, DL Senecal, T Ghosh, MC Ollivierre-Wilson, H Tu, T Rouault, TA AF Zhang, De-Liang Senecal, Thomas Ghosh, Manik C. Ollivierre-Wilson, Hayden Tu, Tiffany Rouault, Tracey A. TI Hepcidin regulates ferroportin expression and intracellular iron homeostasis of erythroblasts SO BLOOD LA English DT Article ID HEREDITARY HEMOCHROMATOSIS; RESPONSIVE ELEMENT; POLYCYTHEMIA MICE; BETA-THALASSEMIA; ANEMIA; INFLAMMATION; METABOLISM; ERYTHROPOIESIS; DISORDERS; OVERLOAD AB The iron-regulatory hormone, hepcidin, regulates systemic iron homeostasis by interacting with the iron export protein ferroportin (FPN1) to adjust iron absorption in enterocytes, iron recycling through reticuloendothelial macrophages, and iron release from storage in hepatocytes. We previously demonstrated that FPN1 was highly expressed in erythroblasts, a cell type that consumes most of the serum iron for use in hemoglobin synthesis. Herein, we have demonstrated that FPN1 localizes to the plasma membrane of erythroblasts, and hepcidin treatment leads to decreased expression of FPN1 and a subsequent increase in intracellular iron concentrations in both erythroblast cell lines and primary erythroblasts. Moreover, injection of exogenous hepcidin decreased FPN1 expression in BM erythroblasts in vivo, whereas iron depletion and associated hepcidin reduction led to increased FPN1 expression in erythroblasts. Taken together, hepcidin de-creased FPN1 expression and increased intracellular iron availability of erythroblasts. We hypothesize that FPN1 expression in erythroblasts allows fine-tuning of systemic iron utilization to ensure that erythropoiesis is partially suppressed when nonerythropoietic tissues risk developing iron deficiency. Our results may explain why iron deficiency anemia is the most pronounced early manifestation of mammalian iron deficiency. (Blood. 2011; 118(10): 2868-2877) C1 [Zhang, De-Liang; Senecal, Thomas; Ghosh, Manik C.; Ollivierre-Wilson, Hayden; Tu, Tiffany; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov OI Zhang, Deliang/0000-0001-9478-5344 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 36 TC 30 Z9 32 U1 1 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 8 PY 2011 VL 118 IS 10 BP 2868 EP 2877 DI 10.1182/blood-2011-01-330241 PG 10 WC Hematology SC Hematology GA 819BX UT WOS:000294801500034 PM 21700773 ER PT J AU Pang, K Ryan, JF Baxevanis, AD Martindale, MQ AF Pang, Kevin Ryan, Joseph F. Baxevanis, Andreas D. Martindale, Mark Q. TI Evolution of the TGF-beta Signaling Pathway and Its Potential Role in the Ctenophore, Mnemiopsis leidyi SO PLOS ONE LA English DT Article ID SEA-ANEMONE; AMPHIMEDON-QUEENSLANDICA; EXPRESSION; RECEPTOR; SUPERFAMILY; PROTEINS; ACTIVIN; EMBRYO; CELLS; DIFFERENTIATION AB The TGF-beta signaling pathway is a metazoan-specific intercellular signaling pathway known to be important in many developmental and cellular processes in a wide variety of animals. We investigated the complexity and possible functions of this pathway in a member of one of the earliest branching metazoan phyla, the ctenophore Mnemiopsis leidyi. A search of the recently sequenced Mnemiopsis genome revealed an inventory of genes encoding ligands and the rest of the components of the TGF-beta superfamily signaling pathway. The Mnemiopsis genome contains nine TGF-beta ligands, two TGF-beta-like family members, two BMP-like family members, and five gene products that were unable to be classified with certainty. We also identified four TGF-beta receptors: three Type I and a single Type II receptor. There are five genes encoding Smad proteins (Smad2, Smad4, Smad6, and two Smad1s). While we have identified many of the other components of this pathway, including Tolloid, SMURF, and Nomo, notably absent are SARA and all of the known antagonists belonging to the Chordin, Follistatin, Noggin, and CAN families. This pathway likely evolved early in metazoan evolution as nearly all components of this pathway have yet to be identified in any non-metazoan. The complement of TGF-beta signaling pathway components of ctenophores is more similar to that of the sponge, Amphimedon, than to cnidarians, Trichoplax, or bilaterians. The mRNA expression patterns of key genes revealed by in situ hybridization suggests that TGF-beta signaling is not involved in ctenophore early axis specification. Four ligands are expressed during gastrulation in ectodermal micromeres along all three body axes, suggesting a role in transducing earlier maternal signals. Later expression patterns and experiments with the TGF-beta inhibitor SB432542 suggest roles in pharyngeal morphogenesis and comb row organization. C1 [Pang, Kevin; Martindale, Mark Q.] Univ Hawaii Manoa, Kewalo Marine Lab, Pacific Biomed Res Ctr, Honolulu, HI 96822 USA. [Ryan, Joseph F.; Baxevanis, Andreas D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Pang, K (reprint author), Univ Hawaii Manoa, Kewalo Marine Lab, Pacific Biomed Res Ctr, Honolulu, HI 96822 USA. EM mqmartin@hawaii.edu FU National Science Foundation (NSF); National Human Genome Research Institute, National Institutes of Health (NIH) FX KP was funded by a National Science Foundation (NSF) Graduate Research Fellowship. This work was also supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 36 Z9 37 U1 2 U2 18 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 SEP 8 PY 2011 VL 6 IS 9 AR e24152 DI 10.1371/journal.pone.0024152 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CK UT WOS:000294802800029 PM 21931657 ER PT J AU Young, A Jiang, MS Wang, Y Ahmedli, NB Ramirez, J Reese, BE Birnbaumer, L Farber, DB AF Young, Alejandra Jiang, Meisheng Wang, Ying Ahmedli, Novruz B. Ramirez, John Reese, Benjamin E. Birnbaumer, Lutz Farber, Debora B. TI Specific Interaction of G alpha i3 with the Oa1 G-Protein Coupled Receptor Controls the Size and Density of Melanosomes in Retinal Pigment Epithelium SO PLOS ONE LA English DT Article ID SIGNAL-TRANSDUCTION SYSTEM; HETEROTRIMERIC G-PROTEIN; LINKED OCULAR ALBINISM; TRIMERIC G-PROTEINS; CYTOPLASMIC DOMAINS; GENE-PRODUCT; FUSION; EXPRESSION; BIOGENESIS; ACTIVATION AB Background: Ocular albinism type 1, an X-linked disease characterized by the presence of enlarged melanosomes in the retinal pigment epithelium (RPE) and abnormal crossing of axons at the optic chiasm, is caused by mutations in the OA1 gene. The protein product of this gene is a G-protein-coupled receptor (GPCR) localized in RPE melanosomes. The Oa1-/- mouse model of ocular albinism reproduces the human disease. Oa1 has been shown to immunoprecipitate with the G alpha i subunit of heterotrimeric G proteins from human skin melanocytes. However, the G alpha i subfamily has three highly homologous members, G alpha i1, G alpha i2 and G alpha i3 and it is possible that one or more of them partners with Oa1. We had previously shown by in-vivo studies that G alpha i3-/- and Oa1-/- mice have similar RPE phenotype and decussation patterns. In this paper we analyze the specificity of the Oa1-G alpha i interaction. Methodology: By using the genetic mouse models G alpha i1-/-, G alpha i2-/-, G alpha i3-/- and the double knockout G alpha i1-/-, G alpha i3-/- that lack functional G alpha i1, G alpha i2, G alpha i3, or both G alpha i1 and G alpha i3 proteins, respectively, we show that G alpha i3 is critical for the maintenance of a normal melanosomal phenotype and that its absence is associated with changes in melanosomal size and density. GST-pull-down and immunoprecipitation assays conclusively demonstrate that G alpha i3 is the only G alpha i that binds to Oa1. Western blots show that G alpha i3 expression is barely detectable in the Oa1-/- RPE, strongly supporting a previously unsuspected role for G alpha i3 in melanosomal biogenesis. Conclusion: Our results identify the Oa1 transducer G alpha i3 as the first downstream component in the Oa1 signaling pathway. C1 [Young, Alejandra; Ahmedli, Novruz B.; Ramirez, John; Farber, Debora B.] Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. [Young, Alejandra; Farber, Debora B.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA. [Jiang, Meisheng; Wang, Ying] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA USA. [Reese, Benjamin E.] Univ Calif Santa Barbara, Dept Psychol & Brain Sci, Santa Barbara, CA 93106 USA. [Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Neurobiol Lab, Div Intramural Res, NIH, Res Triangle Pk, NC USA. RP Young, A (reprint author), Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. EM farber@jsei.ucla.edu FU National Institutes of Health (NIH) [EY015141]; Vision of Children Foundation FX This work was supported by the National Institutes of Health (NIH) Grant EY015141 to DBF, BER, and MJ and by The Vision of Children Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 7 Z9 8 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 SEP 8 PY 2011 VL 6 IS 9 AR e24376 DI 10.1371/journal.pone.0024376 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CK UT WOS:000294802800044 PM 21931697 ER PT J AU Zou, ZC Chastain, A Moir, S Ford, J Trandem, K Martinelli, E Cicala, C Crocker, P Arthos, J Sun, PD AF Zou, Zhongcheng Chastain, Ashley Moir, Susan Ford, Jennifer Trandem, Kathryn Martinelli, Elena Cicala, Claudia Crocker, Paul Arthos, James Sun, Peter D. TI Siglecs Facilitate HIV-1 Infection of Macrophages through Adhesion with Viral Sialic Acids SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; GP120 ENVELOPE GLYCOPROTEIN; MYELIN-ASSOCIATED GLYCOPROTEIN; I-TYPE LECTINS; INFLUENZA HEMAGGLUTININ; MANNOSE RECEPTOR; DENDRITIC CELLS; B-LYMPHOCYTES; TYPE-1; PROTEIN AB Background: Human immunodeficiency virus type 1 (HIV-1) infects macrophages effectively, despite relatively low levels of cell surface-expressed CD4. Although HIV-1 infections are defined by viral tropisms according to chemokine receptor usage (R5 and X4), variations in infection are common within both R5- and X4-tropic viruses, indicating additional factors may contribute to viral tropism. Methodology and Principal Findings: Using both solution and cell surface binding experiments, we showed that R5- and X4-tropic HIV-1 gp120 proteins recognized a family of I-type lectin receptors, the Sialic acid-binding immunoglobulin-like lectins (Siglec). The recognition was through envelope-associated sialic acids that promoted viral adhesion to macrophages. The sialic acid-mediated viral-host interaction facilitated both R5-tropic pseudovirus and HIV-1(BaL) infection of macrophages. The high affinity Siglec-1 contributed the most to HIV-1 infection and the variation in Siglec-1 expression on primary macrophages from different donors was associated statistically with sialic acid-facilitated viral infection. Furthermore, envelope-associated sialoglycan variations on various strains of R5-tropic viruses also affected infection. Conclusions and Significance of the Findings: Our study showed that sialic acids on the viral envelope facilitated HIV-1 infection of macrophages through interacting with Siglec receptors, and the expression of Siglec-1 correlated with viral sialic acid-mediated host attachment. This glycan-mediated viral adhesion underscores the importance of viral sialic acids in HIV infection and pathogenesis, and suggests a novel class of antiviral compounds targeting Siglec receptors. C1 [Zou, Zhongcheng; Chastain, Ashley; Ford, Jennifer; Trandem, Kathryn; Sun, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Moir, Susan; Martinelli, Elena; Cicala, Claudia; Arthos, James] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Crocker, Paul] Univ Dundee, Coll Life Sci, Dundee, Scotland. RP Zou, ZC (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM psun@nih.gov OI Chastain, Ashley/0000-0001-9642-9749; Crocker, Paul/0000-0001-6230-0293 FU National Institutes of Health FX The funding is provided by the National Institutes of Health Intramural research funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 36 Z9 36 U1 2 U2 8 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 SEP 8 PY 2011 VL 6 IS 9 AR e24559 DI 10.1371/journal.pone.0024559 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CK UT WOS:000294802800067 PM 21931755 ER PT J AU Flynn, BL Gill, GS Grobelny, DW Chaplin, JH Paul, D Leske, AF Lavranos, TC Chalmers, DK Charman, SA Kostewicz, E Shackleford, DM Morizzi, J Hamel, E Jung, MK Kremmidiotis, G AF Flynn, Bernard L. Gill, Gurmit S. Grobelny, Damian W. Chaplin, Jason H. Paul, Dharam Leske, Annabell F. Lavranos, Tina C. Chalmers, David K. Charman, Susan A. Kostewicz, Edmund Shackleford, David M. Morizzi, Julia Hamel, Ernest Jung, M. Katherine Kremmidiotis, Gabriel TI Discovery of 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a Tubulin Polymerization Inhibitor with Potent Antiproliferative and Tumor Vascular Disrupting Properties SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID COMBRETASTATIN A-4 PHOSPHATE; TARGETING AGENT; ANTICANCER AGENTS; SOLID TUMORS; BIOLOGICAL EVALUATION; ANTITUBULIN AGENTS; ANTITUMOR-ACTIVITY; ENDOTHELIAL-CELLS; COUPLING APPROACH; CONCISE SYNTHESIS AB A structure activity relationship (SAR) guided design of novel tubulin polymerization inhibitors has resulted in a series of benzo[b]furans with exceptional potency toward cancer cells and activated endothelial cells. The potency of early lead compounds has been substantially improved through the synergistic effect of introducing a conformational bias and additional hydrogen bond donor to the pharmacophore. Screening of a focused library of potent tubulin polymerization inhibitors for selectivity against cancer cells and activated endothelial cells over quiescent endothelial cells has afforded 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo-[b]furan (BNC105, 8) as a potent and selective antiproliferative. Because of poor solubility, 8 is administered as its disodium phosphate ester prodrug 9 (BNC105P), which is rapidly cleaved in vivo to return the active 8. 9 exhibits both superior vascular disrupting and tumor growth inhibitory properties compared with the benchmark agent combretastatin A-4 disodium phosphate 5 (CA4P). C1 [Flynn, Bernard L.; Gill, Gurmit S.; Grobelny, Damian W.; Chaplin, Jason H.; Paul, Dharam; Leske, Annabell F.; Lavranos, Tina C.; Kremmidiotis, Gabriel] Bionomics Ltd, Thebarton, SA 5031, Australia. [Charman, Susan A.; Kostewicz, Edmund; Shackleford, David M.; Morizzi, Julia] Monash Univ, Monash Inst Pharmaceut Sci, Ctr Drug Candidate Optimisat, Parkville, Vic 3052, Australia. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Jung, M. Katherine] NIAAA, Div Metab & Hlth Effects, NIH, Bethesda, MD 20892 USA. RP Flynn, BL (reprint author), Bionomics Ltd, 31 Dalgleish St, Thebarton, SA 5031, Australia. EM bernard.flynn@monash.edu RI Chalmers, David/A-4967-2010; Charman, Susan/E-2221-2011; Chalmers, David/L-8533-2013 OI Charman, Susan/0000-0003-1753-8213; Chalmers, David/0000-0003-2366-569X FU Intramural NIH HHS [Z99 CA999999] NR 83 TC 66 Z9 67 U1 0 U2 15 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 SEP 8 PY 2011 VL 54 IS 17 BP 6014 EP 6027 DI 10.1021/jm200454y PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 813RN UT WOS:000294385700005 PM 21774499 ER PT J AU Kiselev, E DeGuire, S Morrell, A Agama, K Dexheimer, TS Pommier, Y Cushmant, M AF Kiselev, Evgeny DeGuire, Sean Morrell, Andrew Agama, Keli Dexheimer, Thomas S. Pommier, Yves Cushmant, Mark TI 7-Azaindenoisoquinolines as Topoisomerase I Inhibitors and Potential Anticancer Agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NITRATED INDENOISOQUINOLINES; CLEAVAGE COMPLEXES; DNA; CAMPTOTHECIN; POISON; 14-AZACAMPTOTHECIN; CYTOTOXICITY; OPTIMIZATION; ORIENTATION; COVALENT AB A series of 7-azaindenoisoquinoline topoisomerase I (Top 1) inhibitors have been prepared to investigate the effect of increased electron affinity of the aromatic system on the ability to stabilize the Top1-DNA cleavage complex. Ab initio calculations suggest that introduction of nitrogen into the aromatic system of the indenoisoquinolines would facilitate charge transfer complex formation with DNA, thus improving the pi-pi stacking interactions. The present study shows that 7-azaindenoisoquinolines demonstrate improved water solubility without any decrease in Top1 inhibitory activity or cytotoxicity. Analysis of the biological results reveals that smaller lactam ring substituents enable intercalation into both free DNA and Top1-DNA cleavage complex, whereas larger substituents only allow binding to the cleavage complex but not free DNA. Free DNA binding suppresses Top1-catalyzed DNA cleavage at high drug concentrations, whereas DNA cleavage and inhibition of religation occurs at low drug concentration. C1 [Kiselev, Evgeny; DeGuire, Sean; Morrell, Andrew; Cushmant, Mark] Purdue Univ, Dept Med Chem & Mol Pharmacol, Coll Pharm, W Lafayette, IN 47907 USA. [Kiselev, Evgeny; DeGuire, Sean; Morrell, Andrew; Cushmant, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Agama, Keli; Dexheimer, Thomas S.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Cushmant, M (reprint author), Purdue Univ, Dept Med Chem & Mol Pharmacol, Coll Pharm, W Lafayette, IN 47907 USA. EM cushman@purdue.edu FU National Institutes of Health (NIH) [UO1 CA89566]; National Cancer Institute, Center for Cancer Research FX This work was made possible by the National Institutes of Health (NIH) through support of this work with Research Grant UO1 CA89566, as well as through support by the Intramural Program of the National Cancer Institute, Center for Cancer Research. NR 37 TC 26 Z9 28 U1 0 U2 11 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 SEP 8 PY 2011 VL 54 IS 17 BP 6106 EP 6116 DI 10.1021/jm200719v PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 813RN UT WOS:000294385700012 PM 21823606 ER PT J AU Liu, F Barsyte-Lovejoy, D Allali-Hassani, A He, YL Herold, JM Chen, X Yates, CM Frye, SV Brown, PJ Huang, J Vedadi, M Arrowsmith, CH Jin, J AF Liu, Feng Barsyte-Lovejoy, Dalia Allali-Hassani, Abdellah He, Yunlong Herold, J. Martin Chen, Xin Yates, Christopher M. Frye, Stephen V. Brown, Peter J. Huang, Jing Vedadi, Masoud Arrowsmith, Cheryl H. Jin, Jian TI Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HISTONE METHYLTRANSFERASES G9A; DNA METHYLATION; CHROMATIN MODIFICATIONS; CHEMICAL PROBE; CANCER-CELLS; GLP; COMPLEX; SUV39H1 AB Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most potent G9a inhibitor to date, via structure-based design and structure-activity relationship (SAR) exploration of the quinazoline scaffold represented by BIX01294 (1). Despite its very high in vitro potency, compound 3 lacks sufficient cellular potency. The design and synthesis of several generations of new analogues aimed at improving cell membrane permeability while maintaining high in vitro potency resulted in the discovery of a number of novel G9a inhibitors such as UNC0646 (6) and UNC0631 (7) with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity. The design, synthesis, and cellular SAR of these potent G9a inhibitors are described. C1 [Liu, Feng; Herold, J. Martin; Chen, Xin; Frye, Stephen V.; Brown, Peter J.; Jin, Jian] Univ N Carolina, UNC Eshelman Sch Pharm, Div Med Chem & Nat Prod, Ctr Integrat Chem Biol & Drug Discovery, Chapel Hill, NC 27599 USA. [Barsyte-Lovejoy, Dalia; Allali-Hassani, Abdellah; Vedadi, Masoud; Arrowsmith, Cheryl H.] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada. [He, Yunlong; Huang, Jing] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Jin, J (reprint author), Univ N Carolina, UNC Eshelman Sch Pharm, Div Med Chem & Nat Prod, Ctr Integrat Chem Biol & Drug Discovery, Chapel Hill, NC 27599 USA. EM jianjin@unc.edu RI Huang, Jing/A-2566-2009; liu, feng/J-4669-2013; He, Yunlong/D-1278-2017 OI Huang, Jing/0000-0002-7163-5156; FU NIH [RC1GM090732]; Carolina Partnership; University of North Carolina at Chapel Hill; Canadian Institutes of Health Research [1097737]; Canada Foundation for Innovation; Genome Canada through the Ontario Genomics Institute; GlaxoSmithKline; Karolinska Institutet; Knut and Alice Wallenberg Foundation; Ontario Innovation Trust; Ontario Ministry for Research and Innovation; Merck Co., Inc; Novartis Research Foundation; Swedish Agency for Innovation Systems; Swedish Foundation for Strategic Research; Wellcome Trust FX We thank Dr. Ryan Trump for helpful discussions, Dr. Cen Gao for ALogP calculation, and Dr. R Bristow for 22RV1 and PC3 cells. The research described here was supported by the grant RC1GM090732 from the NIH, the Carolina Partnership and University Cancer Research Fund from the University of North Carolina at Chapel Hill, and the Structural Genomics Consortium, a registered charity (no. 1097737) that receives funds from the Canadian Institutes of Health Research, the Canada Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc, the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust. NR 38 TC 56 Z9 56 U1 1 U2 20 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 SEP 8 PY 2011 VL 54 IS 17 BP 6139 EP 6150 DI 10.1021/jm200903z PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 813RN UT WOS:000294385700015 PM 21780790 ER PT J AU Ganglee, A Zhao, Y Hamel, E Westbrook, C Mooberry, SL AF Ganglee, Aleem Zhao, Ying Hamel, Ernest Westbrook, Cara Mooberry, Susan L. TI Synthesis and Biological Activities of (R)- and (S)-N-(4-Methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta[d]pyri midin-4-aminium Chloride as Potent Cytotoxic Antitubulin Agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID III BETA-TUBULIN; OVARIAN-CANCER PATIENTS; CELL LUNG-CANCER; COLCHICINE SITE; RESISTANCE; OVEREXPRESSION; CONFIGURATION; DISCOVERY; ANALOGS AB (R,S)-1 is a potent antimitotic compound. (R)-1 center dot HCl and (S)-1 center dot HCl were synthesized from (R)- and (S)-3-methyladipic acid. Both enantiomers were potent inhibitors of cell proliferation and caused cellular microtubule loss and mitotic arrest. They inhibited purified tubulin assembly and the binding of [(3)H]colchicine to tubulin, with (S)-1 being about twice as potent. Cytotoxicity against 60 tumor cell lines, however, indicated that the (S)-isomer was 10- to 88-fold more potent than the (R)-isomer. C1 [Ganglee, Aleem; Zhao, Ying] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Westbrook, Cara; Mooberry, Susan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. RP Ganglee, A (reprint author), Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, 600 Forbes Ave, Pittsburgh, PA 15282 USA. EM gangjee@duq.edu; mooberry@uthscsa.edu FU National Institutes of Health, National Cancer Institute [CA114021]; President's Council; CTRC Cancer Center; CCSG [CA054174]; Duquesne University FX This work was supported in part by the National Institutes of Health, National Cancer Institute Grant CA114021 (A.G.); a President's Council Research Excellence Award (S.L.M.); CTRC Cancer Center Support Grant, CCSG (Grant CA054174) (S.L.M.); and the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (A.G.). NR 22 TC 11 Z9 12 U1 0 U2 2 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 SEP 8 PY 2011 VL 54 IS 17 BP 6151 EP 6155 DI 10.1021/jm2007722 PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 813RN UT WOS:000294385700016 PM 21786793 ER PT J AU Abbott, A Weinberger, D AF Abbott, Alison Weinberger, Daniel TI Q&A Daniel Weinberger A radical approach to mental illness SO NATURE LA English DT News Item C1 [Weinberger, Daniel] NIMH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 8 PY 2011 VL 477 IS 7363 BP 146 EP 146 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 816MC UT WOS:000294603900009 ER PT J AU Johnston, MI Fauci, AS AF Johnston, Margaret I. Fauci, Anthony S. TI HIV Vaccine Development - Improving on Natural Immunity SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Johnston, Margaret I.; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Johnston, MI (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 23 Z9 28 U1 0 U2 9 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 SEP 8 PY 2011 VL 365 IS 10 BP 873 EP 875 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 816JX UT WOS:000294595600001 PM 21899447 ER PT J AU Hatchett, R Coleman, CN Lurie, N AF Hatchett, Richard Coleman, C. Norman Lurie, Nicole TI Health Risks of Accidents at Nuclear Power Plants SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Hatchett, Richard] Biomed Adv Res & Dev Author, Washington, DC USA. [Coleman, C. Norman] NCI, Washington, DC USA. [Lurie, Nicole] Off Assistant Secretary Preparedness & Response, Washington, DC USA. RP Hatchett, R (reprint author), Biomed Adv Res & Dev Author, Washington, DC USA. NR 3 TC 0 Z9 0 U1 0 U2 0 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 SEP 8 PY 2011 VL 365 IS 10 BP 963 EP 964 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 816JX UT WOS:000294595600026 PM 21899465 ER PT J AU Zanotti-Fregonara, P Hindie, E Hatchett, R Coleman, CN Lurie, N AF Zanotti-Fregonara, Paolo Hindie, Elif Hatchett, Richard Coleman, C. Norman Lurie, Nicole TI Health Risks of Accidents at Nuclear Power Plants SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID RADIOIODINES C1 [Zanotti-Fregonara, Paolo] NIMH, Bethesda, MD 20892 USA. [Hindie, Elif] St Louis Hosp, Paris, France. [Hatchett, Richard] Biomed Adv Res & Dev Author, Washington, DC USA. [Coleman, C. Norman] NCI, Washington, DC USA. [Lurie, Nicole] Off Assistant Secretary Preparedness & Response, Washington, DC USA. RP Zanotti-Fregonara, P (reprint author), NIMH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 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 SEP 8 PY 2011 VL 365 IS 10 BP 963 EP 963 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 816JX UT WOS:000294595600025 PM 21899466 ER PT J AU Griffioen, KJ Mattson, MP AF Griffioen, Kathleen J. Mattson, Mark P. TI Playtime Prevents Obesity by Brain-Mediated Fat Browning SO CELL METABOLISM LA English DT Editorial Material ID NEUROTROPHIC FACTOR; EXERCISE; BDNF AB Laboratory animals usually become relatively insulin resistant and obese. In this issue of Cell Metabolism, Cao et al. (2011) find that mice living in a complex environment are resistant to diet-induced obesity because they produce energy-dissipating brown fat cells within white fat depots, a process orchestrated by brain-derived neurotrophic factor. C1 [Griffioen, Kathleen J.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 11 TC 1 Z9 1 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD SEP 7 PY 2011 VL 14 IS 3 BP 287 EP 288 DI 10.1016/j.cmet.2011.08.002 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 830MD UT WOS:000295660200004 PM 21907135 ER PT J AU Xie, XY Gong, ZW Mansuy-Aubert, V Zhou, QL Tatulian, SA Sehrt, D Gnad, F Brill, LM Motamedchaboki, K Chen, Y Czech, MP Mann, M Kruger, M Jiang, ZY AF Xie, Xiangyang Gong, Zhenwei Mansuy-Aubert, Virginie Zhou, Qiong L. Tatulian, Suren A. Sehrt, Daniel Gnad, Florian Brill, Laurence M. Motamedchaboki, Khatereh Chen, Yu Czech, Michael P. Mann, Matthias Krueger, Marcus Jiang, Zhen Y. TI C2 Domain-Containing Phosphoprotein CDP138 Regulates GLUT4 Insertion into the Plasma Membrane SO CELL METABOLISM LA English DT Article ID PROTEIN-KINASE B; INSULIN SIGNALING PATHWAY; GTPASE-ACTIVATING-PROTEIN; GLUT4-CONTAINING VESICLES; GLUCOSE-TRANSPORTER; 3T3-L1 ADIPOCYTES; TRANSLOCATION; PHOSPHORYLATION; FUSION; AKT2 AB The protein kinase B-beta (Akt2) pathway is known to mediate insulin-stimulated glucose transport through increasing glucose transporter GLUT4 translocation from intracellular stores to the plasma membrane (PM). Combining quantitative phosphoproteomics with RNAi-based functional analyses, we show that a previously uncharacterized 138 kDa C2 domain-containing phosphoprotein (CDP138) is a substrate for Akt2, and is required for optimal insulin-stimulated glucose transport, GLUT4 translocation, and fusion of GLUT4 vesicles with the PM in live adipocytes. The purified C2 domain is capable of binding Ca2+ and lipid membranes. CDP138 mutants lacking the Ca2+-binding sites. in the C2 domain or Akt2 phosphorylation site S197 inhibit insulin-stimulated GLUT4 insertion into the PM, a rate-limiting step of GLUT4 translocation. Interestingly, CDP138 is dynamically associated with the PM and GLUT4-containing vesicles in response to insulin stimulation. Together, these results suggest that CDP138 is a key molecule linking the Akt2 pathway to the regulation of GLUT4 vesicle-PM fusion. C1 [Xie, Xiangyang; Gong, Zhenwei; Mansuy-Aubert, Virginie; Sehrt, Daniel; Jiang, Zhen Y.] Sanford Burnham Med Res Inst, Diabet & Obes Res Ctr, Metab Signaling & Dis Program, Orlando, FL 32827 USA. [Zhou, Qiong L.; Czech, Michael P.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Tatulian, Suren A.] Univ Cent Florida, Dept Phys, Orlando, FL 32816 USA. [Gnad, Florian; Mann, Matthias; Krueger, Marcus] Max Planck Inst Biochem, Dept Prote & Signal Transduct, D-82152 Martinsried, Germany. [Brill, Laurence M.; Motamedchaboki, Khatereh] Sanford Burnham Med Res Inst, Prote Core Facil, La Jolla, CA 92037 USA. [Chen, Yu] NICHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Krueger, Marcus] Max Planck Inst Heart & Lung Res, Bad Nauheim, Germany. RP Jiang, ZY (reprint author), Sanford Burnham Med Res Inst, Diabet & Obes Res Ctr, Metab Signaling & Dis Program, Orlando, FL 32827 USA. EM zjiang@sanfordburnham.org RI Gong, Zhenwei/G-2435-2012; Chen, Yu/G-8724-2013; Mann, Matthias/A-3454-2013; OI Mann, Matthias/0000-0003-1292-4799; Mansuy-Aubert, Virginie/0000-0002-9976-446X FU SBMRI; American Diabetes Association; NIH [DK060564]; James and Esther King Postdoctoral Research Fellowship FX We wish to thank Tao Xu for IRAP-pHluorin and GLUT4-EGFP constructs, Jennifer Lippincott-Schwartz for the fast-switching TIRFM platform, Harry Dolan (Cell Signaling Technology) for Lot-2 stock of PAS (# 9611) Ab, and Supriyo Ray for preparing lipid vesicles. We appreciate Tim Osborne, Dan Kelly, and Tod Gulick for critical reading of the manuscript and suggestions, and Shonna Hyde for administrative support. These studies were supported by SBMRI funding to Z.Y.J. Initial SILAC proteomic studies were supported by a Junior Faculty Award from the American Diabetes Association to Z.Y.J. and by NIH program project grant DK060564 to M.P.C. X.X. is supported by a James and Esther King Postdoctoral Research Fellowship. Z.Y.J. and M.K. did SILAC proteomics with M.M., F.G., and M.P.G.; Z.G., M.K., L.M.B., K.M., and Z.Y.J. did protein phosphorylation analysis. X.X. did TIRFM and confocal imaging analysis. Q.L.Z. did glucose transport assays. Z.Y.J. did widefield GLUT4 translocation assays and analyzed endogenous GLUT4 distribution with TIRFM. V.M.A. did membrane fractionation. V.M.A., S.A.T., and D.S. did Ca2+- and lipid-binding assays. Y.C. was involved in high-resolution imaging. Z.Y.J., M.K., X.X., Z.G., V.M.A., Q.L.Z., and S.A.T. designed experiments and analyzed data. Z.Y.J. wrote the manuscript. NR 39 TC 28 Z9 32 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD SEP 7 PY 2011 VL 14 IS 3 BP 378 EP 389 DI 10.1016/j.cmet.2011.06.015 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 830MD UT WOS:000295660200012 PM 21907143 ER PT J AU Kim, SY Romero, R Tarca, AL Bhatti, G Lee, J Chaiworapongsa, T Hassan, SS Kim, CJ AF Kim, Sun Young Romero, Roberto Tarca, Adi L. Bhatti, Gaurav Lee, JoonHo Chaiworapongsa, Tinnakorn Hassan, Sonia S. Kim, Chong Jai TI miR-143 Regulation of Prostaglandin-Endoperoxidase Synthase 2 in the Amnion: Implications for Human Parturition at Term SO PLOS ONE LA English DT Article ID HUMAN FETAL MEMBRANES; GENE-EXPRESSION; MESENCHYMAL CELLS; MESSENGER-RNA; MICRORNAS; CYCLOOXYGENASE-2; MYOFIBROBLAST; MECHANISMS; REPRESSION; PLASTICITY AB Background: The human amnion plays a pivotal role in parturition. Two of its compartments, the placental amnion and the reflected amnion, have distinct transcriptome and are functionally coordinated for parturition. This study was conducted to determine the microRNA (miRNA) expression pattern and its significance in the placental amnion and the reflected amnion in association with labor at term. Methodology/Principal Findings: MicroRNA microarray, real-time quantitative RT-PCR (qRT-PCR), and miRNA in situ hybridization analyses of the placental amnion and the reflected amnion (n = 20) obtained at term were conducted. Luciferase assay, transfection, and qRT-PCR analyses of primary amnion epithelial cells (AECs) and amnion mesenchymal cells (AMCs) were performed. MicroRNA microarray analysis demonstrated differential expression of 32 miRNAs between the placental amnion and the reflected amnion after labor. Thirty-one (97%) miRNAs, which included miR-143 and miR-145, a cardiovascular-specific miRNA cluster, were down-regulated in the reflected amnion. Analyses of miR-143 and miR-145 by qRT-PCR confirmed microarray results, and further demonstrated their decreased expression in the reflected amnion with labor. Interestingly, expression of miR-143 and miR-145 was higher in AMCs than in AECs (p<0.05). Luciferase assay and transfection confirmed miR-143 binding to 3' UTR of prostaglandin-endoperoxidase synthase 2 (PTGS2) mRNA and miR-143 regulation of PTGS2 in AMCs. Conclusions: We report region-specific amniotic microRNAome and miR-143 regulation of PTGS2 in the context of human labor at term for the first time. The findings indicate that miRNA-mediated post-transcriptional regulation of gene expression machinery in the amnion plays an important role in the compartments (placental amnion vs reflected amnion) and in a cell type-specific manner (AECs vs AMCs) for parturition. C1 [Kim, Sun Young; Romero, Roberto; Tarca, Adi L.; Bhatti, Gaurav; Lee, JoonHo; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Kim, Chong Jai] NICHHD, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Kim, Sun Young; Romero, Roberto; Tarca, Adi L.; Bhatti, Gaurav; Lee, JoonHo; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.; Kim, Chong Jai] NICHHD, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Tarca, Adi L.] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Kim, Chong Jai] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. RP Kim, SY (reprint author), NICHHD, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. EM cjkim@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX This work was supported in part by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 9 Z9 9 U1 0 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 SEP 7 PY 2011 VL 6 IS 9 AR e24131 DI 10.1371/journal.pone.0024131 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CH UT WOS:000294802500028 ER PT J AU Feero, WG Green, ED AF Feero, W. Gregory Green, Eric D. TI Genomics Education for Health Care Professionals in the 21st Century SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID COMPETENCES; REVOLUTION; GENETICS C1 [Feero, W. Gregory; Green, Eric D.] NHGRI, NIH, Bethesda, MD 20892 USA. [Feero, W. Gregory] Maine & Dartmouth Family Med Residency, Augusta, GA USA. RP Feero, WG (reprint author), NHGRI, NIH, 31 Ctr Dr,Bldg 31,Room 4B09, Bethesda, MD 20892 USA. EM feerow@mail.nih.gov NR 10 TC 51 Z9 52 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 7 PY 2011 VL 306 IS 9 BP 989 EP 990 DI 10.1001/jama.2011.1245 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 815QT UT WOS:000294542600017 PM 21900139 ER PT J AU Shi, YB Hasebe, T Fu, LZ Fujimoto, K Ishizuya-Oka, A AF Shi, Yun-Bo Hasebe, Takashi Fu, Liezhen Fujimoto, Kenta Ishizuya-Oka, Atsuko TI The development of the adult intestinal stem cells: Insights from studies on thyroid hormone-dependent amphibian metamorphosis SO CELL AND BIOSCIENCE LA English DT Review ID XENOPUS-LAEVIS; POSTEMBRYONIC DEVELOPMENT; EPITHELIAL DEVELOPMENT; RECEPTOR SUPERFAMILY; GENE REPRESSION; TR-ALPHA; TRANSCRIPTION; RECRUITMENT; EXPRESSION; COMPLEXES AB Adult organ-specific stem cells are essential for organ homeostasis and repair in adult vertebrates. The intestine is one of the best-studied organs in this regard. The intestinal epithelium undergoes constant self-renewal throughout adult life across vertebrates through the proliferation and subsequent differentiation of the adult stem cells. This self-renewal system is established late during development, around birth, in mammals when endogenous thyroid hormone (T3) levels are high. Amphibian metamorphosis resembles mammalian postembryonic development around birth and is totally dependent upon the presence of high levels of T3. During this process, the tadpole intestine, predominantly a monolayer of larval epithelial cells, undergoes drastic transformation. The larval epithelial cells undergo apoptosis and concurrently, adult epithelial stem/progenitor cells develop de novo, rapidly proliferate, and then differentiate to establish a trough-crest axis of the epithelial fold, resembling the crypt-villus axis in the adult mammalian intestine. We and others have studied the T3-dependent remodeling of the intestine in Xenopus laevis. Here we will highlight some of the recent findings on the origin of the adult intestinal stem cells. We will discuss observations suggesting that liganded T3 receptor (TR) regulates cell autonomous formation of adult intestinal progenitor cells and that T3 action in the connective tissue is important for the establishment of the stem cell niche. We will further review evidence suggesting similar T3-dependent formation of adult intestinal stem cells in other vertebrates. C1 [Shi, Yun-Bo; Fu, Liezhen; Fujimoto, Kenta] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, PCRM,NIH, Bethesda, MD 20892 USA. [Hasebe, Takashi; Ishizuya-Oka, Atsuko] Nippon Med Sch, Dept Biol, Kawasaki, Kanagawa 2110063, Japan. RP Shi, YB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, PCRM,NIH, Bethesda, MD 20892 USA. EM shi@helix.nih.gov; a-oka@nms.ac.jp FU NICHD; NIH; JSPS [20570060] FX This research was supported in part by the Intramural Research Program of NICHD, NIH and the JSPS Grants-in-Aid for Scientific Research (C) (Grant number 20570060 to A. I.-O.). NR 61 TC 31 Z9 32 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD SEP 6 PY 2011 VL 1 AR 30 DI 10.1186/2045-3701-1-30 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982PM UT WOS:000307057900001 PM 21896185 ER PT J AU Akula, N Baranova, A Seto, D Solka, J Nalls, MA Singleton, A Ferrucci, L Tanaka, T Bandinelli, S Cho, YS Kim, YJ Lee, JY Han, BG McMahon, FJ AF Akula, Nirmala Baranova, Ancha Seto, Donald Solka, Jeffrey Nalls, Michael A. Singleton, Andrew Ferrucci, Luigi Tanaka, Toshiko Bandinelli, Stefania Cho, Yoon Shin Kim, Young Jin Lee, Jong-Young Han, Bok-Ghee McMahon, Francis J. CA Bipolar Disorder Genome Study BiG Wellcome Trust Case-Control Consor TI A Network-Based Approach to Prioritize Results from Genome-Wide Association Studies SO PLOS ONE LA English DT Article ID HARDY-WEINBERG EQUILIBRIUM; COMMON HUMAN-DISEASES; PATHWAY ANALYSIS; COMPLEX DISEASES; SYSTEMS BIOLOGY; HYPERCATABOLIC PATIENTS; MOLECULAR NETWORKS; PROTEIN NETWORKS; GENE-EXPRESSION; LARGE-SCALE AB Genome-wide association studies (GWAS) are a valuable approach to understanding the genetic basis of complex traits. One of the challenges of GWAS is the translation of genetic association results into biological hypotheses suitable for further investigation in the laboratory. To address this challenge, we introduce Network Interface Miner for Multigenic Interactions (NIMMI), a network-based method that combines GWAS data with human protein-protein interaction data (PPI). NIMMI builds biological networks weighted by connectivity, which is estimated by use of a modification of the Google PageRank algorithm. These weights are then combined with genetic association p-values derived from GWAS, producing what we call 'trait prioritized sub-networks.' As a proof of principle, NIMMI was tested on three GWAS datasets previously analyzed for height, a classical polygenic trait. Despite differences in sample size and ancestry, NIMMI captured 95% of the known height associated genes within the top 20% of ranked sub-networks, far better than what could be achieved by a single-locus approach. The top 2% of NIMMI height-prioritized sub-networks were significantly enriched for genes involved in transcription, signal transduction, transport, and gene expression, as well as nucleic acid, phosphate, protein, and zinc metabolism. All of these sub-networks were ranked near the top across all three height GWAS datasets we tested. We also tested NIMMI on a categorical phenotype, Crohn's disease. NIMMI prioritized sub-networks involved in B- and T-cell receptor, chemokine, interleukin, and other pathways consistent with the known autoimmune nature of Crohn's disease. NIMMI is a simple, user-friendly, open-source software tool that efficiently combines genetic association data with biological networks, translating GWAS findings into biological hypotheses. C1 [Akula, Nirmala; McMahon, Francis J.] NIMH, Mood & Anxiety Sect, Human Genet Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Baranova, Ancha; Seto, Donald; Solka, Jeffrey] George Mason Univ, Coll Sci, Sch Syst Biol, Fairfax, VA 22030 USA. [Baranova, Ancha] RAMS, Med Genet Res Ctr, Moscow, Russia. [Nalls, Michael A.; Singleton, Andrew] NIA, Mol Genet Sect, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Ferrucci, Luigi; Tanaka, Toshiko] NIA, Longitudinal Studies Sect, Clin Res Branch, Intramural Res Program,NIH, Bethesda, MD 20892 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Cho, Yoon Shin; Kim, Young Jin; Lee, Jong-Young; Han, Bok-Ghee] Natl Inst Hlth, Ctr Genome Sci, Seoul, South Korea. RP Akula, N (reprint author), NIMH, Mood & Anxiety Sect, Human Genet Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM akulan@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Baranova, Ancha/B-4608-2012; Smith, Erin/E-5933-2011; OI Baranova, Ancha/0000-0001-6810-5982; McMahon, Francis/0000-0002-9469-305X FU National Institute of Mental Health (NIMH); Italian Ministry of Health [ICS 110.1RS97.71]; U.S. National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 9164 13, 263 MD 821336]; National Institute on Aging, National Institutes of Health, USA FX This work was supported by the National Institute of Mental Health (NIMH) Intramural Research Program. The InCHIANTI study was supported as a "targeted project" (ICS 110.1RS97.71) by the Italian Ministry of Health, by the U.S. National Institute on Aging (Contracts N01-AG-916413, N01-AG-821336, 263 MD 9164 13, and 263 MD 821336) and in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health, USA. Funding support for the Whole Genome Association Study of Bipolar Disorder was provided by NIMH, and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 84 TC 31 Z9 32 U1 0 U2 11 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 SEP 6 PY 2011 VL 6 IS 9 AR e24220 DI 10.1371/journal.pone.0024220 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817QP UT WOS:000294689200027 PM 21915301 ER PT J AU Bokenkamp, R Raz, V Venema, A DeRuiter, MC van Munsteren, C Olive, M Nabel, EG Gittenberger-de Groot, AC AF Bokenkamp, Regina Raz, Vered Venema, Andrea DeRuiter, Marco C. van Munsteren, Conny Olive, Michelle Nabel, Elizabeth G. Gittenberger-de Groot, Adriana C. TI Differential Temporal and Spatial Progerin Expression during Closure of the Ductus Arteriosus in Neonates SO PLOS ONE LA English DT Article ID HUTCHINSON-GILFORD-PROGERIA; MOUSE MODEL; LAMIN; APOPTOSIS; MUSCLE; DISEASE; PROGRESSION; BIOMARKER; DEFECTS AB Closure of the ductus arteriosus (DA) at birth is essential for the transition from fetal to postnatal life. Before birth the DA bypasses the uninflated lungs by shunting blood from the pulmonary trunk into the systemic circulation. The molecular mechanism underlying DA closure and degeneration has not been fully elucidated, but is associated with apoptosis and cytolytic necrosis in the inner media and intima. We detected features of histology during DA degeneration that are comparable to Hutchinson Gilford Progeria syndrome and ageing. Immunohistochemistry on human fetal and neonatal DA, and aorta showed that lamin A/C was expressed in all layers of the vessel wall. As a novel finding we report that progerin, a splicing variant of lamin A/C was expressed almost selectively in the normal closing neonatal DA, from which we hypothesized that progerin is involved in DA closure. Progerin was detected in 16.2% +/- 7.2 cells of the DA. Progerin-expressing cells were predominantly located in intima and inner media where cytolytic necrosis accompanied by apoptosis will develop. Concomitantly we found loss of a-smooth muscle actin as well as reduced lamin A/C expression compared to the fetal and non-closing DA. In cells of the adjacent aorta, that remains patent, progerin expression was only sporadically detected in 2.5%+/- 1.5 of the cells. Data were substantiated by the detection of mRNA of progerin in the neonatal DA but not in the aorta, by PCR and sequencing analysis. The fetal DA and the non-closing persistent DA did not present with progerin expressing cells. Our analysis revealed that the spatiotemporal expression of lamin A/C and progerin in the neonatal DA was mutually exclusive. We suggest that activation of LMNA alternative splicing is involved in vascular remodeling in the circulatory system during normal neonatal DA closure. C1 [Bokenkamp, Regina] Leiden Univ Med Ctr, Dept Pediat Cardiol, Leiden, Netherlands. [Raz, Vered; Venema, Andrea] Leiden Univ Med Ctr, Dept Human Genet, Leiden, Netherlands. [Bokenkamp, Regina; DeRuiter, Marco C.; van Munsteren, Conny; Gittenberger-de Groot, Adriana C.] Leiden Univ Med Ctr, Dept Anat & Embryol, Leiden, Netherlands. [Olive, Michelle] NHLBI, Bethesda, MD 20892 USA. [Nabel, Elizabeth G.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Bokenkamp, R (reprint author), Leiden Univ Med Ctr, Dept Pediat Cardiol, Leiden, Netherlands. EM r.bokenkamp@lumc.nl FU Landspitali University Hospital; University of Iceland; Science and Technology Policy Council; European Science Foundation FX This work was supported by grants from Landspitali University Hospital Research Fund, University of Iceland Research Fund (www.hi.is/research_degrees), Science and Technology Policy Council-Thematic program in postgenomic biomedicine (www.rannis.is), Science and Technology Policy Council Research fund (TG, MKM), European Science Foundation (EuroCORES program, EuroSTELLS) (TG). "Gongum saman", a supporting group for breast cancer research in Iceland (www.gongumsaman.is) (VS). Nordforsk, the Nordic Research Board (www.nordforsk.org), Nordic Stem Cell Mobility Program (HS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 13 Z9 14 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 6 PY 2011 VL 6 IS 9 AR e23975 DI 10.1371/journal.pone.0023975 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817QP UT WOS:000294689200012 PM 21915271 ER PT J AU Lewis, D Le, P Zurla, C Finzi, L Adhya, S AF Lewis, Dale Phuoc Le Zurla, Chiara Finzi, Laura Adhya, Sankar TI Multilevel autoregulation of lambda repressor protein CI by DNA looping in vitro SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE activation; cooperativity; repression ID COOPERATIVE OPERATOR BINDING; SINGLE-SITE MUTATIONS; BACTERIOPHAGE-LAMBDA; GENE-REGULATION; CRYSTAL-STRUCTURE; PHAGE REPRESSOR; TERMINAL DOMAIN; TRANSCRIPTION; CRO; MODEL AB The prophage state of bacteriophage lambda is extremely stable and is maintained by a highly regulated level of lambda repressor protein, CI, which represses lytic functions. CI regulates its own synthesis in a lysogen by activating and repressing its promoter, P-RM. CI participates in long-range interactions involving two regions of widely separated operator sites by generating a loop in the intervening DNA. We investigated the roles of each individual site under conditions that permitted DNA loop formation by using in vitro transcription assays for the first time on supercoiled DNA that mimics in vivo situation. We confirmed that DNA loops generated by oligomerization of CI bound to its operators influence the autoactivation and autorepression of P-RM regulation. We additionally report that different configurations of DNA loops are central to this regulation-one configuration further enhances autoactivation and another is essential for autorepression of P-RM. C1 [Lewis, Dale; Phuoc Le; Adhya, Sankar] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zurla, Chiara] Georgia Inst Technol, Dept Biomed Engn, Atlanta, GA 30332 USA. [Finzi, Laura] Emory Univ, Dept Phys, Atlanta, GA 30322 USA. RP Adhya, S (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM adhyas@mail.nih.gov FU National Institutes of Health; National Cancer Institute; Center for Cancer Research; [RGM084070A] FX We thank Donald Court and Robert Weisberg for helpful discussions. We especially thank Gary Gussin, Jeffrey Roberts, Ann Hochschild, and John Little for critical comments on the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, the Center for Cancer Research, and by an Extramural Research Grant, RGM084070A. NR 59 TC 19 Z9 19 U1 2 U2 12 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 SEP 6 PY 2011 VL 108 IS 36 BP 14807 EP 14812 DI 10.1073/pnas.1111221108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 815QZ UT WOS:000294543400025 PM 21873207 ER PT J AU Arao, Y Hamilton, KJ Ray, MK Scott, G Mishina, Y Korach, KS AF Arao, Yukitomo Hamilton, Katherine J. Ray, Manas K. Scott, Gregory Mishina, Yuji Korach, Kenneth S. TI Estrogen receptor alpha AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BREAST-CANCER CELLS; TRANSCRIPTIONAL ACTIVATION; RESPONSE ELEMENTS; PROVIDES EVIDENCE; NULL MICE; ER-ALPHA; IN-VIVO; BINDING; IDENTIFICATION; ANTIESTROGEN AB The estrogen receptor (ER) is a ligand-dependent transcription factor containing two transcriptional activation domains. AF-1 is in the N terminus of the receptor protein and AF-2 activity is dependent on helix 12 of the C-terminal ligand-binding domain. Two point mutations of leucines 543 and 544 to alanines (L543A, L544A) in helix 12 minimized estrogen-dependent transcriptional activation and reversed the activity of the estrogen antagonists ICI182780 (ICI) and tamoxifen (TAM) into agonists in a similar manner that TAM activated WT ER alpha through AF-1 activation. To evaluate the physiological role of AF-1 and AF-2 for the tissue-selective function of TAM, we generated an AF-2-mutated ER alpha knock-in (AF2ERKI) mouse model. AF2ERKI homozygote female mice have hypoplastic uterine tissue and rudimentary mammary glands similar to ER alpha-KO mice. Female mice were infertile as a result of anovulation from hemorrhagic cystic ovaries and elevated serum LH and E2 levels, although the mutant ER alpha protein is expressed in the AF2ERKI model. The AF2ERKI phenotype suggests that AF-1 is not activated independently, even with high serum E2 levels. ICI and TAM induced uterotropic and ER-mediated gene responses in ovariectomized AF2ERKI female mice in the same manner as in TAM- and E2-treated WT mice. In contrast, ICI and TAM did not act as agonists to regulate negative feedback of serum LH or stimulate pituitary prolactin gene expression in a different manner than TAM- or E2-treated WT mice. The functionality of the mutant ER alpha in the pituitary appears to be different from that in the uterus, indicating that ER alpha uses AF-1 differently in the uterus and the pituitary for TAM action. C1 [Arao, Yukitomo; Hamilton, Katherine J.; Korach, Kenneth S.] NIEHS, Receptor Biol Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Mishina, Yuji] Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. RP Korach, KS (reprint author), NIEHS, Receptor Biol Sect, Lab Reprod & Dev Toxicol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Division of Intramural Research of the National Institute of Environmental Health [Z01ES70065] FX We thank Dr. Geoffrey Greene for the gift of the ACN cassette plasmid, Sandra Burkett (Mouse Cancer Genetics Program/National Cancer Institute) for conducting the FISH analysis, and David Monroy and members of the National Institute of Environmental Health Sciences Comparative Medicine Branch staff for animal care. We also thank Drs. Karina Rodriguez, Joy Winuthayanon, and April Binder for the hormone analysis; Sylvia Hewitt for critical reading of the manuscript; and other members of the Receptor Biology Group for helpful discussions. We also value the early contributions of Trisha Castranio and Dr. Deborah Swope to this project. This study was funded by Z01ES70065 from the Division of Intramural Research of the National Institute of Environmental Health (to K. S. K.). NR 34 TC 35 Z9 36 U1 1 U2 3 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 SEP 6 PY 2011 VL 108 IS 36 BP 14986 EP 14991 DI 10.1073/pnas.1109180108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 815QZ UT WOS:000294543400055 PM 21873215 ER PT J AU Reis, JP Loria, CM Sorlie, PD Park, Y Hollenbeck, A Schatzkin, A AF Reis, Jared P. Loria, Catherine M. Sorlie, Paul D. Park, Yikyung Hollenbeck, Albert Schatzkin, Arthur TI Lifestyle Factors and Risk for New-Onset Diabetes A Population-Based Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID HEALTH-AMERICAN-ASSOCIATION; MODERATE ALCOHOL INTAKE; RETIRED-PERSONS DIET; INSULIN SENSITIVITY; CIGARETTE-SMOKING; NATIONAL-INSTITUTES; PHYSICAL-ACTIVITY; OLDER-ADULTS; BODY-WEIGHT; MELLITUS AB Background: Epidemiologic data on the combined influence of several lifestyle factors on diabetes risk are rare, particularly among older adults. Objective: To examine how combinations of lifestyle risk factors relate to the 11-year risk for incident diabetes. Design: Population-based prospective cohort study. Setting: National Institutes of Health (NIH)-AARP Diet and Health Study. Participants: 114 996 men and 92 483 women, aged 50 to 71 years in 1995 to 1996, without evidence of heart disease, cancer, or diabetes. Measurements: A comprehensive survey of demographic characteristics and lifestyle factors, including dietary intake, body weight and height, physical activity, smoking, and alcohol consumption at baseline (1995 to 1996). Low-risk groups were formed by dichotomizing each lifestyle factor. Incident self-reported, physician-diagnosed diabetes was identified with a follow-up survey in 2004 to 2006. Results: 11 031 men (9.6%) and 6969 women (7.5%) developed new-onset diabetes. For each additional lifestyle factor in the low-risk group, the odds for diabetes were 31% lower (odds ratio [OR], 0.69 [95% CI, 0.68 to 0.71]) among men and 39% lower (OR, 0.61 [CI, 0.60 to 0.63]) among women. Men and women whose diet score, physical activity level, smoking status, and alcohol use were all in the low-risk group had ORs for diabetes of 0.61 (CI, 0.56 to 0.66) and 0.43 (CI, 0.34 to 0.55), respectively. When absence of overweight or obesity was added, the respective ORs were 0.28 (CI, 0.23 to 0.34) and 0.16 (CI, 0.10 to 0.24) for men and women. Results did not differ by family history of diabetes or level of adiposity. Limitation: The study was observational, with potential for residual confounding. Conclusion: Lifestyle factors, when considered in combination, are associated with a substantial reduction in risk for diabetes. C1 [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. NCI, Rockville, MD 20852 USA. AARP, Washington, DC 20049 USA. RP Reis, JP (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM reisjp@mail.nih.gov OI Park, Yikyung/0000-0002-6281-489X FU NIH FX The NIH-AARP Diet and Health Study was supported by the Intramural Research Program of the NIH. NR 36 TC 41 Z9 42 U1 0 U2 6 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 6 PY 2011 VL 155 IS 5 BP 292 EP U45 DI 10.7326/0003-4819-155-5-201109060-00006 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 815PX UT WOS:000294538900002 PM 21893622 ER PT J AU Schwartz Longacre, L Kloner, RA Arai, AE Baines, CP Bolli, R Braunwald, E Downey, J Gibbons, RJ Gottlieb, RA Heusch, G Jennings, RB Lefer, DJ Mentzer, RM Murphy, E Ovize, M Ping, PP Przyklenk, K Sack, MN Vander Heide, RS Vinten-Johansen, J Yellon, DM AF Schwartz Longacre, Lisa Kloner, Robert A. Arai, Andrew E. Baines, Christopher P. Bolli, Roberto Braunwald, Eugene Downey, James Gibbons, Raymond J. Gottlieb, Roberta A. Heusch, Gerd Jennings, Robert B. Lefer, David J. Mentzer, Robert M. Murphy, Elizabeth Ovize, Michel Ping, Peipei Przyklenk, Karin Sack, Michael N. Vander Heide, Richard S. Vinten-Johansen, Jakob Yellon, Derek M. TI New Horizons in Cardioprotection Recommendations From the 2010 National Heart, Lung, and Blood Institute Workshop SO CIRCULATION LA English DT Article DE cardioprotection; heart; ischemia; myocardial infarction; reperfusion injury ID ACUTE MYOCARDIAL-INFARCTION; PERCUTANEOUS CORONARY INTERVENTION; MITOCHONDRIAL PERMEABILITY TRANSITION; ISCHEMIA-REPERFUSION INJURY; CARDIOVASCULAR MAGNETIC-RESONANCE; EMISSION COMPUTED-TOMOGRAPHY; ST-SEGMENT RESOLUTION; NO-REFLOW PHENOMENON; PRECONDITIONING PROTECTS; RANDOMIZED-TRIAL C1 [Arai, Andrew E.; Murphy, Elizabeth; Sack, Michael N.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Kloner, Robert A.] Good Samaritan Hosp, Los Angeles, CA USA. [Kloner, Robert A.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Baines, Christopher P.] Univ Missouri, Columbia, MO 65211 USA. [Bolli, Roberto] Univ Louisville, Louisville, KY 40292 USA. [Braunwald, Eugene] Harvard Univ, Boston, MA 02115 USA. [Downey, James] Univ S Alabama, Mobile, AL 36688 USA. [Gibbons, Raymond J.] Mayo Clin, Rochester, MN USA. [Gottlieb, Roberta A.; Mentzer, Robert M.] San Diego State Univ, San Diego, CA 92182 USA. [Heusch, Gerd] Univ Essen Gesamthsch, Sch Med, Essen, Germany. [Jennings, Robert B.] Duke Univ, Durham, NC USA. [Lefer, David J.; Vinten-Johansen, Jakob] Emory Univ, Atlanta, GA 30322 USA. [Mentzer, Robert M.; Przyklenk, Karin] Wayne State Univ, Detroit, MI USA. [Ovize, Michel] Univ & Hosp Civils Lyon, Lyon, France. [Ping, Peipei] Univ Calif Los Angeles, Los Angeles, CA USA. [Vander Heide, Richard S.] Louisiana State Univ, New Orleans, LA USA. [Yellon, Derek M.] UCL, London, England. [Schwartz Longacre, Lisa] NHLBI, Heart Failure & Arrhythmia Branch, Div Cardiovasc Sci, NIH,Rockledge Ctr 2, 6701 Rockledge Dr,MSC 7956,Room 8166, Bethesda, MD 20892 USA. RP Schwartz Longacre, L (reprint author), NHLBI, Heart Failure & Arrhythmia Branch, Div Cardiovasc Sci, NIH,Rockledge Ctr 2, 6701 Rockledge Dr,MSC 7956,Room 8166, Bethesda, MD 20892 USA. EM schwartzlongal@nhlbi.nih.gov RI Lefer, David/A-6372-2012; Kloner, Robert/B-2971-2012; Bolli, Roberto/A-6870-2010; OI Ping, Peipei/0000-0003-3583-3881 FU Division of Cardiovascular Sciences, NHLBI, National Institutes of Health; Gilead; Stealth; US government Cooperative Research and Development Agreement with Siemens; National Institutes of Health [U24 HL094373, R01 HL020648, R01 HL060590, R01 HL092136, R01 AG033283, P01 HL085577, R01 HL084405, R21 HL098786]; American Heart Association; Ikaria; German Research Foundation; NeuroVive; British Heart Foundation; National Institute for Health Research; Fibrogen; Merck Sharp Dohme FX This study was supported by the Division of Cardiovascular Sciences, NHLBI, National Institutes of Health.r Dr Schwartz Longacre is an employee of National Institutes of Health; Dr Kloner receives research support (>$10K) and honoraria (>$10K) from Gilead (formerly CV Therapeutics), receives research support from Stealth (>$10K), and consulted with Gilead and Stealth; Dr Arai is an employee of National Institutes of Health and receives research support through a US government Cooperative Research and Development Agreement with Siemens (>$10K); Dr Baines receives research support from National Institutes of Health (>$10K) and the American Heart Association (>$10K); Dr Bolli receives National Institutes of Health research support for CAESAR (U24 HL094373), which is a consortium to study cardioprotective therapies (>$10K); Dr Braunwald reports no disclosures; Dr Downey receives research support from National Institutes of Health (>$10K; R01 HL020648); Dr Gibbons receives research support from Ikaria (>$10K); Dr Gottlieb receives research support from National Institutes of Health (R01 HL060590, R01 HL092136, R01 AG033283, and P01 HL085577) (>$10K), receives honoraria for various academic visiting professorships (<$10K), and is a co-founder of Radical Therapeutix, Inc (>$10K invested); Dr Heusch receives research support from the German Research Foundation (>$10K) and honoraria for educational lectures (<$10K) and speakers bureau payments (>$10K) for Servier; Dr Jennings reports no disclosures; Dr Lefer receives research support from National Institutes of Health on nitrate-mediated cardioprotection and H2S-mediated cardioprotection (>$10K); Dr Mentzer receives research support from National Institutes of Health for studies on autophagy, adenosine, and pyruvate protection during heart surgery (<$10K) and is a scientific advisor to the Board of Radical Therapeutix; Dr Murphy is an employee of National Institutes of Health, and a family member receives research support from National Institutes of Health (>$10K) and serves on the ACADESINE advisory board (<$10K); Dr Ovize is conducting the CIRCUS study supported by a program hospitalier de recherche cinique with study treatment (iCsA) provided by NeuroVive (<$10K); Dr Ping has no disclosures; Dr Przyklenk received honoraria for invited lectures on preconditioning and remote preconditioning (>$10K); Dr Sack is an employee of National Institutes of Health; Dr Vander Heide receives research support from National Institutes of Health (>$10K; R01 HL084405 and R21 HL098786); Dr Vinten-Johansen holds 2 patents on postconditioning (<$10K) and is a consultant for Reperfusion Therapeutics, Inc (<$10K); Dr Yellon receives research support from the British Heart Foundation Program (>$10K), British Heart Foundation Project on mitochondria (>$10K), British Heart Foundation Project on Akt Signaling (>$10K), British Heart Foundation Project on Preconditioning (>$10K), and National Institute for Health Research Clinical Trial (>$10K), drugs and research support from Fibrogen (>$10K), drugs and research support from Merck Sharp & Dohme (>$10K), payments for speakers bureau appointments to Pfizer, Bristol-Myers Squibb, and Glaxo (<$10K), honoraria from Roche (<$10K), and consultations for Roche (<$10K). NR 69 TC 145 Z9 147 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 6 PY 2011 VL 124 IS 10 BP 1172 EP 1179 DI 10.1161/CIRCULATIONAHA.111.032698 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 815VF UT WOS:000294557400021 PM 21900096 ER PT J AU Hou, SJ Kovac, P AF Hou, Shujie Kovac, Pavol TI Synthesis of the conjugation ready, downstream disaccharide fragment of the O-PS of Vibrio cholerae O:139 SO CARBOHYDRATE RESEARCH LA English DT Article DE Glycosylation; Vibrio cholerae O:139; Conjugation; Neoglycoconjugate ID O139 SYNONYM BENGAL; SEROTYPES OGAWA; POLYSACCHARIDE; INABA; LIPOPOLYSACCHARIDE; ANALOGS; SUGARS; O-1 AB The linker-equipped disaccharide, 8-amino-3,6-dioxaoctyl 2,6-dideoxy-2-acetamido-3-O-beta-D-galactopyranosyluronate-beta-D-glucopyranoside (10), was synthesized in eight steps from acetobromogalactose and ethyl 4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-1-thio-beta-D-glucopyranoside. The hydroxyl group present at C-4(II) in the last intermediate, 8-azido-3,6-dioxaoctyl 4-O-benzyl-6-bromo-2,6-dideoxy-2-trichloroacetamido-3-O-(benzyl 2,3-di-O-benzyl-beta-D-galactopyranosyluronate)-beta-D-glucopyranoside (9), is positioned to allow further build-up of the molecule and, eventually, construction of the complete hexasaccharide. Global deprotection (9 -> 10) was done in one step by catalytic hydrogenolysis over palladium-on-charcoal. (C) 2011 Published by Elsevier Ltd. C1 [Hou, Shujie; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov FU NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 18 TC 7 Z9 7 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD SEP 6 PY 2011 VL 346 IS 12 SI SI BP 1394 EP 1397 DI 10.1016/j.carres.2011.02.011 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 793VN UT WOS:000292852100005 PM 21641585 ER PT J AU Pozsgay, V Kubler-Kielb, J Coxon, B Marques, A Robbins, JB Schneerson, R AF Pozsgay, Vince Kubler-Kielb, Joanna Coxon, Bruce Marques, Adriana Robbins, John B. Schneerson, Rachel TI Synthesis and antigenicity of BBGL-2 glycolipids of Borrelia burgdorferi, the causative agent of Lyme disease SO CARBOHYDRATE RESEARCH LA English DT Article DE Antigen; Borrelia burgdorferi; Vaccine; Diacylglycerol; Dot-blot; Glycolipid ID CHOLESTERYL GALACTOSIDE; NKT CELLS; VACCINE; ACID; DERIVATIVES; IDENTIFICATION; GLYCOSYLATION; SPIROCHETE; PROTECTION; ARTHRITIS AB Borrelia burgdorferi is the etiological agent for Lyme disease (LD), the most common vector borne disease in the United States. There is no human vaccine against LD currently available. Our approach to a vaccine is based on its surface-exposed glycolipids. One group of these glycolipids termed BBGL-2 consists of 1,2-di-O-acyl-3-O-(alpha-D-galactopyranosyl)-sn-glycerol congeners having palmitic, oleic, stearic, linoleic, and myristic acids. In order to delineate the immunodominant region(s) of the BBGL-2 components, we embarked on a synthetic project to provide available structurally defined, homogeneous analogs of BBGL-2 that might help identify the best vaccine candidate. The antigenicity of the synthetic glycolipids was examined by dot-blot analysis using mice sera obtained by immunization with killed B. burgdorferi cells, with native BBGL-2 in complete Freund's adjuvant, as well as sera obtained from patients with Lyme disease. We found that the presence of two acyl groups in the glycerol moiety was essential for antigenicity. At least one of these groups must be an oleoyl moiety. Neither the anomeric configuration of the galactose nor the configuration of the glycerol at C-2 was a decisive factor. Based on these findings we designed an 'unnatural' BBGL-2 analog having the structure 3-O-(beta-D-galactopyranosyl)-1,2-di-O-oleoyl-DL-glycerol which is easier and less expensive to synthesize than the other BBGL-2 congeners prepared in this study. This substance proved to be antigenic and is considered a candidate vaccine for Lyme disease. Published by Elsevier Ltd. C1 [Pozsgay, Vince; Kubler-Kielb, Joanna; Coxon, Bruce; Robbins, John B.; Schneerson, Rachel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev & Mol Immun, Bethesda, MD 20892 USA. [Marques, Adriana] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Pozsgay, V (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev & Mol Immun, Bethesda, MD 20892 USA. EM pozsgayv@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD FX This work was supported by the intramural programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. NR 40 TC 10 Z9 10 U1 1 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD SEP 6 PY 2011 VL 346 IS 12 SI SI BP 1551 EP 1563 DI 10.1016/j.carres.2011.04.045 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 793VN UT WOS:000292852100023 PM 21601180 ER PT J AU Bilusic, M Heery, C Madan, RA AF Bilusic, Marijo Heery, Christopher Madan, Ravi A. TI Immunotherapy in prostate cancer: Emerging strategies against a formidable foe SO VACCINE LA English DT Review DE Prostate cancer; Immunotherapy; Cancer vaccines; Immune checkpoint inhibitors ID REGULATORY T-CELLS; PHASE-I TRIAL; DIVERSIFIED SUBCUTANEOUS/INTRATUMORAL VACCINATION; ANTIGEN-PRESENTING CELLS; FRAME PROTEIN TARP; GROWTH-FACTOR-BETA; IMMUNE-RESPONSE; ACID-PHOSPHATASE; CELLULAR IMMUNOTHERAPY; COMBINATION THERAPY AB Recent clinical trials have shown therapeutic vaccines to be promising treatment modalities against prostate cancer. Unlike preventive vaccines that teach the immune system to fight off specific microorganisms, therapeutic vaccines stimulate the immune system to recognize and attack certain cancer-associated proteins. Additional strategies are being investigated that combine vaccines and standard therapeutics, including radiation, chemotherapy, targeted therapies, and hormonal therapy, to optimize the vaccines' effects. Recent vaccine late-phase clinical trials have reported evidence of clinical benefit while maintaining excellent quality of life. One such vaccine, sipuleucel-T, was recently FDA-approved for the treatment of metastatic prostate cancer. Another vaccine, PSA-TRICOM, is also showing promise in completed and ongoing randomized multicenter clinical trials in both early- and late-stage prostate cancer. Clinical results available to date indicate that immune-based therapies could play a significant role in the treatment of prostate and other malignancies. Published by Elsevier Ltd. C1 [Bilusic, Marijo; Heery, Christopher; Madan, Ravi A.] NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. [Bilusic, Marijo; Heery, Christopher; Madan, Ravi A.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Madan, RA (reprint author), Bldg 10,Rm 8B09,10 Ctr Dr,MSC 1750, Bethesda, MD 20892 USA. EM madanr@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX The authors thank Dr. Jeffrey Schlom and Dr. James L. Gulley for their review of this manuscript and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research for their support of this study. We also thank Bonnie L. Casey for editorial assistance in the preparation of this manuscript. NR 151 TC 12 Z9 13 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD SEP 2 PY 2011 VL 29 IS 38 BP 6485 EP 6497 DI 10.1016/j.vaccine.2011.06.088 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 823TG UT WOS:000295148800012 PM 21741424 ER PT J AU Maas, S Sie, CPG Stoev, I Dupuis, DE Latona, J Porman, AM Evans, B Rekawek, P Kluempers, V Mutter, M Gommans, WM Lopresti, D AF Maas, S. Sie, C. P. Godfried Stoev, I. Dupuis, D. E. Latona, J. Porman, A. M. Evans, B. Rekawek, P. Kluempers, V. Mutter, M. Gommans, W. M. Lopresti, D. TI Genome-wide evaluation and discovery of vertebrate A-to-I RNA editing sites SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE RNA editing; ADAR; Inosine; Adenosine deamination ID DATABASE; IDENTIFICATION; ADENOSINE; EVOLUTION; TARGETS AB RNA editing by adenosine deamination, catalyzed by adenosine deaminases acting on RNA (ADAR), is a post-transcriptional modification that contributes to transcriptome and proteome diversity and is widespread in mammals. Here we administer a bioinformatics search strategy to the human and mouse genomes to explore the landscape of A-to-I RNA editing. In both organisms we find evidence for high excess of A/G-type discrepancies (inosine appears as a guanosine in cloned cDNA) at non-polymorphic, non-synonymous codon sites over other types of discrepancies, suggesting the existence of several thousand recoding editing sites in the human and mouse genomes. We experimentally validate recoding-type A-to-I RNA editing in a number of human genes with high scoring positions including the coatomer protein complex subunit alpha (COPA) as well as cyclin dependent kinase CDK13. Published by Elsevier Inc. C1 [Maas, S.; Sie, C. P. Godfried; Dupuis, D. E.; Latona, J.; Porman, A. M.; Evans, B.; Rekawek, P.; Kluempers, V.; Mutter, M.; Gommans, W. M.] Lehigh Univ, Dept Biol Sci, Bethlehem, PA 18015 USA. [Stoev, I.; Lopresti, D.] Lehigh Univ, Dept Comp Sci & Engn, Bethlehem, PA 18015 USA. Natl Inst Gen Med, NIH, Bethesda, MD 20892 USA. RP Maas, S (reprint author), Lehigh Univ, Dept Biol Sci, Bethlehem, PA 18015 USA. EM swm3@lehigh.edu OI Evans, Benjamin/0000-0003-2069-4938 NR 18 TC 14 Z9 16 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 2 PY 2011 VL 412 IS 3 BP 407 EP 412 DI 10.1016/j.bbrc.2011.07.075 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 819OC UT WOS:000294835200002 PM 21835166 ER PT J AU Kim, JS Park, YY Park, SY Cho, H Kang, D Cho, H AF Kim, Jo-Sun Park, Yong-Yea Park, Sun-Yi Cho, Hyeseon Kang, Dongmin Cho, Hyeseong TI The Auto-ubiquitylation of E3 Ubiquitin-protein Ligase Chfr at G(2) Phase Is Required for Accumulation of Polo-like Kinase 1 and Mitotic Entry in Mammalian Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VERTEBRATE SOMATIC-CELLS; CHECKPOINT GENE; EPIGENETIC INACTIVATION; DAMAGE CHECKPOINT; STRESS CHECKPOINT; LUNG-CANCER; DNA-DAMAGE; CENP-F; MITOSIS; HYPERMETHYLATION AB The E3 ubiquitin-protein ligase Chfr is a mitotic stress checkpoint protein that delays mitotic entry in response to microtubule damage; however, the molecular mechanism by which Chfr accomplishes this remains elusive. Here, we show that Chfr levels are elevated in response to microtubule-damaging stress. Moreover, G(2)/M transition is associated with cell cycle-dependent turnover of Chfr accompanied by high autoubiquitylation activity, suggesting that regulation of Chfr levels and auto-ubiquitylation activity are functionally significant. To test this, we generated Chfr mutants Chfr-K2A and Chfr-K5A in which putative lysine target sites of auto-ubiquitylation were replaced with alanine. Chfr-K2A did not undergo cell cycle-dependent degradation, and its levels remained high during G(2)/M phase. The elevated levels of Chfr-K2A caused a significant reduction in phosphohistone H3 levels and cyclinB1/Cdk1 kinase activities, leading to mitotic entry delay. Notably, polo-like kinase 1 levels at G(2) phase, but not at S phase, were similar to 2-3-fold lower in cells expressing Chfr-K2A than in wild-type Chfr-expressing cells. Consistent with this, ubiquitylation of Plk1 at G(2) phase was accelerated in Chfr-K2A-expressing cells. In contrast, Aurora A levels remained constant, indicating that Plk1 is a major target of Chfr in controlling the timing of mitotic entry. Indeed, overexpression of Plk1 in Chfr-K2A-expressing cells restored cyclin B1/Cdk1 kinase activity and promoted mitotic entry. Collectively, these data indicate that Chfr auto-ubiquitylation is required to allow Plk1 to accumulate to levels necessary for activation of cyclin B1/Cdk1 kinase and mitotic entry. Our results provide the first evidence that Chfr auto-ubiquitylation and degradation are important for the G(2)/M transition. C1 [Kim, Jo-Sun; Park, Yong-Yea; Park, Sun-Yi; Cho, Hyeseong] Ajou Univ, Sch Med, Dept Biochem, Suwon 443721, South Korea. [Kim, Jo-Sun; Park, Yong-Yea; Park, Sun-Yi; Cho, Hyeseong] Ajou Univ, Grad Sch Mol Sci & Technol, Suwon 443721, South Korea. [Cho, Hyeseon] NIH, Cell Mol Immunol Sect B, Immunoregulat Lab, Bethesda, MD 20892 USA. [Kang, Dongmin] Ewha Womans Univ, Dept Life Sci, Div Life & Pharmaceut Sci, Seoul 120750, South Korea. [Kang, Dongmin] Ewha Womans Univ, Ctr Cell Signaling & Drug Discovery Res, Seoul 120750, South Korea. RP Cho, H (reprint author), Ajou Univ, Sch Med, Dept Biochem, 5 Wonchon Dong, Suwon 443721, South Korea. EM hscho@ajou.ac.kr; hscho@ajou.ac.kr FU Ministry of Health and Welfare [0820060]; Ajon University FX This work was supported by National R&D Program for Cancer Control (0820060), Ministry of Health and Welfare. Y. Park is supported by the grant of "The Ajon University Excellence Research Program in 2011." NR 31 TC 5 Z9 5 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 SEP 2 PY 2011 VL 286 IS 35 BP 30615 EP 30623 DI 10.1074/jbc.M111.231803 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 812HT UT WOS:000294283600041 PM 21768102 ER PT J AU Oh, HM Yu, CR Golestaneh, N Amadi-Obi, A Lee, YS Eseonu, A Mahdi, RM Egwuagu, CE AF Oh, Hyun-Mee Yu, Cheng-Rong Golestaneh, Nady Amadi-Obi, Ahjoku Lee, Yun Sang Eseonu, Amarachi Mahdi, Rashid M. Egwuagu, Charles E. TI STAT3 Protein Promotes T-cell Survival and Inhibits Interleukin-2 Production through Up-regulation of Class O Forkhead Transcription Factors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; DNA-BINDING; ACTIVATION; IL-2; PROLIFERATION; SUPPRESSORS; MECHANISMS; EXPRESSION; GENERATION; CONTRIBUTE AB Much is known about the role of STAT3 in regulating differentiation of interleukin-17-producing Th17 cells, but its function in other lymphocyte subsets is not well understood. In this report, we reveal wide-ranging functions of STAT3 in T-cells and provide evidence that STAT3 is convergence point for mechanisms that regulate lymphocyte quiescence and those controlling T-cell activation and survival. We show here that STAT3 inhibits T-lymphocyte proliferation by up-regulating the expression of Class-O Forkhead transcription factors, which play essential roles in maintaining T-cells in quiescent state. We further show that STAT3 binds directly to FoxO1 or FoxO3a promoter and that STAT3-deficiency resulted in down-regulation of the expression of FoxO1, FoxO3a and FoxO-target genes (I kappa B and p27Kip1). Compared with wild-type T-cells, STAT3-deficient T-cells produced more IL-2, due in part, to marked decrease in I kappa B-mediated sequestration of NF-kappa B in the cytoplasm and resultant enhancement of NF-kappa B activation. However, the high level of IL-2 production by STAT3-deficient T-cells was partially restored to normal levels by overexpressing FoxO1. It is notable that their exaggerated increase in IL-2 production rendered STAT3-deficient lymphocytes more susceptible to activation-induced cell death, suggesting that STAT3 might protect T-cells from apoptosis by limiting their production of IL-2 through up-regulation of FoxO1/FoxO3a expression. Moreover, we found that STAT3 enhanced survival of activated T-cells by up-regulating OX-40 and Bcl-2 while down-regulating FasL and Bad expression, suggesting that similar to role of FoxOs in regulating the lifespan of worms, STAT3 and FoxO pathways converge to regulate lifespan of T-lymphocytes. C1 [Oh, Hyun-Mee; Yu, Cheng-Rong; Amadi-Obi, Ahjoku; Lee, Yun Sang; Mahdi, Rashid M.; Egwuagu, Charles E.] NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Golestaneh, Nady] Georgetown Univ, Sch Med, Dept Biochem & Mol & Cellular Biol, Washington, DC 20057 USA. [Eseonu, Amarachi] Harvard Univ, Harvard Coll, Dept Biomed Engn, Cambridge, MA 02138 USA. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, Immunol Lab, NIH, 10-10N116,10 Ctr Dr, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov FU NEI, National Institutes of Health FX This work was supported, in whole or in part, by NEI, National Institutes of Health Intramural Research Programs. NR 31 TC 32 Z9 32 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 SEP 2 PY 2011 VL 286 IS 35 BP 30888 EP 30897 DI 10.1074/jbc.M111.253500 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 812HT UT WOS:000294283600068 PM 21730069 ER PT J AU Kireeva, ML Domecq, C Coulombe, B Burton, ZF Kashlev, M AF Kireeva, Maria L. Domecq, Celine Coulombe, Benoit Burton, Zachary F. Kashlev, Mikhail TI Interaction of RNA Polymerase II Fork Loop 2 with Downstream Non-template DNA Regulates Transcription Elongation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NTP-DRIVEN TRANSLOCATION; STRUCTURAL BASIS; ACTIVE-SITE; NUCLEOSIDE TRIPHOSPHATES; ALLOSTERIC BINDING; COMPLEX; RESOLUTION; MECHANISM; CATALYSIS; DYNAMICS AB Fork loop 2 is a small semiconservative segment of the larger fork domain in the second largest Rpb2 subunit of RNA polymerase II (Pol II). This flexible loop, juxtaposed at the leading edge of transcription bubble, has been proposed to participate in DNA strand separation, translocation along DNA, and NTP loading to Pol II during elongation. Here we show that the Rpb2 mutant carrying a deletion of the flexible part of the loop is not lethal in yeast. The mutation exhibits no defects in DNA melting and translocation in vitro but confers a moderate decrease of the catalytic activity of the enzyme caused by the impaired sequestration of the NTP substrate in the active center prior to catalysis. In the structural model of the Pol II elongation complex, fork loop 2 directly interacts with an unpaired DNA residue in the non-template DNA strand one nucleotide ahead from the active center (the i + 2 position). We showed that elimination of this putative interaction by replacement of the i + 2 residue with an abasic site inhibits Pol II activity to the same degree as the deletion of fork loop 2. This replacement has no detectable effect on the activity of the mutant enzyme. We provide direct evidence that interaction of fork loop 2 with the non-template DNA strand facilitates NTP sequestration through interaction with the adjacent segment of the fork domain involved in the active center of Pol II. C1 [Kireeva, Maria L.; Kashlev, Mikhail] NCI Frederick, NIH, Ctr Canc Res, Frederick, MD 21702 USA. [Domecq, Celine; Coulombe, Benoit] Univ Montreal, Gene Transcript & Prote Lab, Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. [Domecq, Celine; Coulombe, Benoit] Univ Montreal, Dept Biochem, Montreal, PQ H2W 1R7, Canada. [Burton, Zachary F.] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. RP Kashlev, M (reprint author), NCI Frederick, NIH, Ctr Canc Res, Frederick, MD 21702 USA. EM kashlevm@mail.nih.gov FU National Institutes of Health [R01 GM 092949] FX This work was supported, in whole or in part, by National Institutes of Health Grant R01 GM 092949 (to Z.F.B.). NR 44 TC 14 Z9 14 U1 0 U2 8 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 SEP 2 PY 2011 VL 286 IS 35 BP 30898 EP 30910 DI 10.1074/jbc.M111.260844 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 812HT UT WOS:000294283600069 PM 21730074 ER PT J AU Darc, M Hait, SH Soares, EA Cicala, C Seuanez, HN Machado, ES Arthos, JA Soares, MA AF Darc, Mirela Hait, Sabrina H. Soares, Esmeralda A. Cicala, Claudia Seuanez, Hector N. Machado, Elizabeth S. Arthos, James A. Soares, Marcelo A. TI Polymorphisms in the alpha 4 Integrin of Neotropical Primates: Insights for Binding of Natural Ligands and HIV-1 gp120 to the Human alpha 4 beta 7 SO PLOS ONE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; NEW-WORLD PRIMATES; MULTIPLE-SCLEROSIS; CYCLOPHILIN-A; T-CELLS; INFECTION; EVOLUTION; ADHESION; MONKEY; RECEPTOR AB The alpha 4 integrin subunit associates with beta 7 and beta 1 and plays important roles in immune function and cell trafficking. The gut-homing receptor alpha 4 beta 7 has been recently described as a new receptor for HIV. Here, we describe polymorphisms of ITGA4 gene in New World primates (NWP), and tested their impact on the binding to monoclonal antibodies, natural ligands (MAdCAM and VCAM), and several gp120 HIV-1 envelope proteins. Genomic DNA of NWP specimens comprising all genera of the group had their exons 5 and 6 (encoding the region of binding to the ligands studied) analyzed. The polymorphisms found were introduced into an ITGA4 cDNA clone encoding the human alpha 4 subunit. Mutant alpha 4 proteins were co-expressed with beta 7 and were tested for binding of mAbs, MAdCAM, VCAM and gp120 of HIV-1, which was compared to the wild-type (human) alpha 4. Mutant alpha 4 proteins harboring the K201E/I/N substitution had reduced binding of all ligands tested, including HIV-1 gp120 envelopes. The mAbs found with reduced biding included one from which a clinically-approved drug for the treatment of neurological disorders has been derived. alpha 4 polymorphisms in other primate species may influence outcomes in the development and treatment of infectious and autoimmune diseases in humans and in non-human primates. C1 [Darc, Mirela; Hait, Sabrina H.; Seuanez, Hector N.; Machado, Elizabeth S.; Soares, Marcelo A.] Univ Fed Rio de Janeiro, Dept Genet, Rio De Janeiro, Brazil. [Darc, Mirela; Hait, Sabrina H.; Soares, Esmeralda A.; Seuanez, Hector N.; Soares, Marcelo A.] Inst Nacl Canc, Programa Genet, Rio De Janeiro, Brazil. [Cicala, Claudia; Arthos, James A.] NIAID, NIH, Bethesda, MD 20892 USA. [Machado, Elizabeth S.] Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Rio De Janeiro, Brazil. RP Darc, M (reprint author), Univ Fed Rio de Janeiro, Dept Genet, Rio De Janeiro, Brazil. EM masoares@inca.gov.br RI Inca, Inct/K-2204-2013 FU National Institutes of Health; Brazilian Ministry of Education (CAPES); Brazilian Research Council (CNPq) [151595/2008-9]; Rio de Janeiro State Science Foundation (FAPERJ) [E-26/102.858/2008] FX MD and SHH were recipients of a National Institutes of Health training grant to sponsor their visiting program at that Institution. Both authors were also sponsored by the Brazilian Ministry of Education (CAPES). This work was developed as part of the requirements of MD and SHH for obtaining their Masters of Sciences degrees at the Graduate Program of Genetics of the Federal University of Rio de Janeiro, Brazil. JAA and CC were supported by the Intramural Research Program of the National Institutes of Health, which had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was additionally supported by the Brazilian Research Council (CNPq) grant no. 151595/2008-9 and by the Rio de Janeiro State Science Foundation (FAPERJ) grant no. E-26/102.858/2008. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 4 Z9 8 U1 1 U2 7 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 SEP 2 PY 2011 VL 6 IS 9 AR e24461 DI 10.1371/journal.pone.0024461 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817PK UT WOS:000294686100043 PM 21912696 ER PT J AU Lee, MR Gallen, CL Zhang, XC Hodgkinson, CA Goldman, D Stein, EA Barr, CS AF Lee, Mary R. Gallen, Courtney L. Zhang, Xiaochu Hodgkinson, Colin A. Goldman, David Stein, Elliot A. Barr, Christina S. TI Functional Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) Influences Reinforcement Learning in Humans SO PLOS ONE LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISM; A118G POLYMORPHISM; DOPAMINE NEURONS; STRESS-RESPONSE; REWARD; ASSOCIATION; BEHAVIOR; BINDING; SYSTEM; PAIN AB Previous reports on the functional effects (i.e., gain or loss of function), and phenotypic outcomes (e. g., changes in addiction vulnerability and stress response) of a commonly occurring functional single nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1 A118G) have been inconsistent. Here we examine the effect of this polymorphism on implicit reward learning. We used a probabilistic signal detection task to determine whether this polymorphism impacts response bias to monetary reward in 63 healthy adult subjects: 51 AA homozygotes and 12 G allele carriers. OPRM1 AA homozygotes exhibited typical responding to the rewarded response-that is, their bias to the rewarded stimulus increased over time. However, OPRM1 G allele carriers exhibited a decline in response to the rewarded stimulus compared to the AA homozygotes. These results extend previous reports on the heritability of performance on this task by implicating a specific polymorphism. Through comparison with other studies using this task, we suggest a possible mechanism by which the OPRM1 polymorphism may confer reduced response to natural reward through a dopamine-mediated decrease during positive reinforcement learning. C1 [Lee, Mary R.; Gallen, Courtney L.; Zhang, Xiaochu; Stein, Elliot A.] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. [Hodgkinson, Colin A.; Goldman, David; Barr, Christina S.] NIAAA, Intramural Res Program, Rockville, MD 20852 USA. RP Lee, MR (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. EM leemary@mail.nih.gov RI Zhang, Xiaochu/O-9592-2014; Goldman, David/F-9772-2010 OI Zhang, Xiaochu/0000-0002-7541-0130; Goldman, David/0000-0002-1724-5405 FU National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 10 Z9 10 U1 0 U2 7 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 SEP 2 PY 2011 VL 6 IS 9 AR e24203 DI 10.1371/journal.pone.0024203 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817PK UT WOS:000294686100022 PM 21912675 ER PT J AU Li, R Wen, R Banzon, T Maminishkis, A Miller, SS AF Li, Rong Wen, Rong Banzon, Tina Maminishkis, Arvydas Miller, Sheldon S. TI CNTF Mediates Neurotrophic Factor Secretion and Fluid Absorption in Human Retinal Pigment Epithelium SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; INTRACELLULAR SIGNALING PATHWAYS; MACULAR DEGENERATION; RAT RETINA; FACTOR-RECEPTOR; OUTER SEGMENTS; TGF-BETA; PHOTOTRANSDUCTION MACHINERY; ROD PHOTORECEPTORS; GENE-TRANSFER AB Ciliary neurotrophic factor (CNTF) protects photoreceptors and regulates their phototransduction machinery, but little is known about CNTF's effects on retinal pigment epithelial (RPE) physiology. Therefore, we determined the expression and localization of CNTF receptors and the physiological consequence of their activation in primary cultures of human fetal RPE (hfRPE). Cultured hfRPE express CNTF, CT1, and OsM and their receptors, including CNTFR alpha, LIFR beta, gp130, and OsMR beta, all localized mainly at the apical membrane. Exogenous CNTF, CT1, or OsM induces STAT3 phosphorylation, and OsM also induces the phosphorylation of ERK1/2 (p44/42 MAP kinase). CNTF increases RPE survivability, but not rates of phagocytosis. CNTF increases secretion of NT3 to the apical bath and decreases that of VEGF, IL8, and TGF beta 2. It also significantly increases fluid absorption (J(V)) across intact monolayers of hfRPE by activating CFTR chloride channels at the basolateral membrane. CNTF induces profound changes in RPE cell biology, biochemistry, and physiology, including the increase in cell survival, polarized secretion of cytokines/neurotrophic factors, and the increase in steady-state fluid absorption mediated by JAK/STAT3 signaling. In vivo, these changes, taken together, could serve to regulate the microenvironment around the distal retinal/RPE/Bruch's membrane complex and provide protection against neurodegenerative disease. C1 [Li, Rong; Banzon, Tina; Maminishkis, Arvydas; Miller, Sheldon S.] NEI, NIH, Bethesda, MD 20892 USA. [Wen, Rong] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. RP Li, R (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM millers@nei.nih.gov FU National Institutes of Health [R01-EY018586] FX This work was supported by the Intramural Research Program of the National Institutes of Health (SSM, RL, TB and AM) and National Institutes of Health grant R01-EY018586 (RW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 TC 17 Z9 17 U1 1 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 SEP 2 PY 2011 VL 6 IS 9 AR e23148 DI 10.1371/journal.pone.0023148 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817PK UT WOS:000294686100002 PM 21912637 ER PT J AU Murphy, E AF Murphy, Elizabeth TI Estrogen Signaling and Cardiovascular Disease SO CIRCULATION RESEARCH LA English DT Article DE estrogen; hormone replacement therapy; ischemia-reperfusion; nitric oxide ID ISCHEMIA-REPERFUSION INJURY; NITRIC-OXIDE SYNTHASE; POSTMENOPAUSAL HORMONE-THERAPY; BREAST-CANCER CELLS; RECEPTOR-ALPHA; GENDER-DIFFERENCES; ER-BETA; S-NITROSYLATION; ESTROGEN/PROGESTIN REPLACEMENT; ISCHEMIA/REPERFUSION INJURY AB Estrogen has pleiotropic effects on the cardiovascular system. The mechanisms by which estrogen confers these pleiotropic effects are undergoing active investigation. Until a decade ago, all estrogen signaling was thought to occur by estrogen binding to nuclear estrogen receptors (estrogen receptor-alpha and estrogen receptor-beta), which bind to DNA and function as ligand-activated transcription factors. Estrogen binding to the receptor alters gene expression, thereby altering cell function. Estrogen also binds to nuclear estrogen receptors that are tethered to the plasma membrane, resulting in acute activation of signaling kinases such as PI3K. An orphan G-protein-coupled receptor, G-protein-coupled receptor 30, can also bind estrogen and activate acute signaling pathways. Thus, estrogen can alter cell function by binding to different estrogen receptors. This article reviews the different estrogen receptors and their signaling mechanisms, discusses mechanisms that regulate estrogen receptor levels and locations, and considers the cardiovascular effects of estrogen signaling. (Circ Res. 2011;109:687-696.) C1 NHLBI, Cardiac Physiol Sect, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), NHLBI, Cardiac Physiol Sect, Syst Biol Ctr, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health FX Funding from the National Heart, Lung, and Blood Institute, National Institutes of Health Intramural Program is acknowledged. NR 128 TC 120 Z9 122 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 2 PY 2011 VL 109 IS 6 BP 687 EP 696 DI 10.1161/CIRCRESAHA.110.236687 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 814SJ UT WOS:000294477200014 PM 21885836 ER PT J AU Kim, WC Berquist, BR Chohan, M Uy, C Wilson, DM Lee, CH AF Kim, Wan-Cheol Berquist, Brian R. Chohan, Manbir Uy, Christopher Wilson, David M., III Lee, Chow H. TI Characterization of the Endoribonuclease Active Site of Human Apurinic/Apyrimidinic Endonuclease 1 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE endoribonuclease; APE1; RNA ID HUMAN APURINIC ENDONUCLEASE; DNA-REPAIR ENZYME; MESSENGER-RNA DECAY; MAJOR HUMAN; DIRECTED MUTAGENESIS; EXONUCLEASE ACTIVITY; ABASIC ENDONUCLEASE; C-MYC; APE1; PROTEIN AB Apurinic/apyrimidinic endonuclease 1 (APE1) is the major mammalian enzyme in DNA base excision repair that cleaves the DNA phosphodiester backbone immediately 5' to abasic sites. Recently, we identified APE1 as an endoribonuclease that cleaves a specific coding region of c-myc mRNA in vitro, regulating c-myc mRNA level and half-life in cells. Here, we further characterized the endoribonuclease activity of APE1, focusing on the active-site center of the enzyme previously defined for DNA nuclease activities. We found that most site-directed APE1 mutant proteins (N68A, D70A, Y171F, D210N, F266A, D308A, and H309S), which target amino acid residues constituting the abasic DNA endonuclease active-site pocket, showed significant decreases in endoribonuclease activity. Intriguingly, the D283N APE1 mutant protein retained endoribonuclease and abasic single-stranded RNA cleavage activities, with concurrent loss of apurinic/apyrimidinic (AP) site cleavage activities on double-stranded DNA and single-stranded DNA (ssDNA). The mutant proteins bound c-myc RNA equally well as wild-type (WT) APE1, with the exception of H309N, suggesting that most of these residues contributed primarily to RNA catalysis and not to RNA binding. Interestingly, both the endoribonuclease and the ssRNA AP site cleavage activities of WT APE1 were present in the absence of Mg(2+), while ssDNA AP site cleavage required Mg(2+) (optimally at 0.5-2.0 mM). We also found that a 2'-OH on the sugar moiety was absolutely required for RNA cleavage by WT APE1, consistent with APE1 leaving a 3'-PO(4)(2-) group following cleavage of RNA. Altogether, our data support the notion that a common active site is shared for the endoribonuclease and other nuclease activities of APE1; however, we provide evidence that the mechanisms for cleaving RNA, abasic single-stranded RNA, and abasic DNA by APE1 are not identical, an observation that has implications for unraveling the endoribonuclease function of APE1 in vivo. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kim, Wan-Cheol; Chohan, Manbir; Uy, Christopher; Lee, Chow H.] Univ No British Columbia, Chem Program, Prince George, BC V2N 4Z9, Canada. [Berquist, Brian R.; Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Lee, CH (reprint author), Univ No British Columbia, Chem Program, 3333 Univ Way, Prince George, BC V2N 4Z9, Canada. EM leec@unbc.ca FU Natural Sciences and Engineering Research Council (NSERC) [227158]; Pacific Century Scholarship; Michael Smith Foundation of Health Research; NSERC Canada; NSERC; National Institute on Aging, National Institutes of Health FX This work was supported by Discovery Grant 227158 from the Natural Sciences and Engineering Research Council (NSERC) to C.H.L. W.-C.K. was the recipient of a Pacific Century Scholarship, a Michael Smith Foundation of Health Research Junior Graduate Scholarship Award, and an NSERC Canada Graduate Scholarship. C.U. was the recipient of an NSERC Undergraduate Student Research Award. This work was also supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (D.M.W.). NR 44 TC 13 Z9 15 U1 1 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 SEP 2 PY 2011 VL 411 IS 5 BP 960 EP 971 DI 10.1016/j.jmb.2011.06.050 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 815HM UT WOS:000294516700005 PM 21762700 ER PT J AU Chen, XK Gabitto, M Peng, YQ Ryba, NJP Zuker, CS AF Chen, Xiaoke Gabitto, Mariano Peng, Yueqing Ryba, Nicholas J. P. Zuker, Charles S. TI A Gustotopic Map of Taste Qualities in the Mammalian Brain SO SCIENCE LA English DT Article ID BITTER TASTE; GUSTATORY CORTEX; CORTICAL-NEURONS; UMAMI TASTE; RECEPTORS; CELLS; RESPONSES; STIMULI; SWEET; MOUSE AB The taste system is one of our fundamental senses, responsible for detecting and responding to sweet, bitter, umami, salty, and sour stimuli. In the tongue, the five basic tastes are mediated by separate classes of taste receptor cells each finely tuned to a single taste quality. We explored the logic of taste coding in the brain by examining how sweet, bitter, umami, and salty qualities are represented in the primary taste cortex of mice. We used in vivo two-photon calcium imaging to demonstrate topographic segregation in the functional architecture of the gustatory cortex. Each taste quality is represented in its own separate cortical field, revealing the existence of a gustotopic map in the brain. These results expose the basic logic for the central representation of taste. C1 [Chen, Xiaoke; Gabitto, Mariano; Peng, Yueqing; Zuker, Charles S.] Columbia Univ, Coll Phys & Surg, Howard Hughes Med Inst, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Chen, Xiaoke; Gabitto, Mariano; Peng, Yueqing; Zuker, Charles S.] Columbia Univ, Coll Phys & Surg, Dept Neurosci, New York, NY 10032 USA. [Ryba, Nicholas J. P.] Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. [Zuker, Charles S.] Univ Calif San Diego, Dept Neurobiol, La Jolla, CA 92093 USA. [Zuker, Charles S.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP Zuker, CS (reprint author), Columbia Univ, Coll Phys & Surg, Howard Hughes Med Inst, Dept Biochem & Mol Biophys, New York, NY 10032 USA. EM cz2195@columbia.edu RI chen, xiaoke/E-5385-2011 FU Human Frontier Science Program fellowship; National Institute of Dental and Craniofacial Research FX We thank A. Devor and Y. Dan for their hospitality and technical help with our early intrinsic imaging attempts, R. Barreto for valuable help with imaging and data analysis, S. Hunter-Smith for help with viral tracing experiments, and R. Axel, K. Scott, D. Steddler, R. Bruno, and members of the Zuker lab for helpful comments. Supported by a Human Frontier Science Program fellowship (X. C.) and by the Intramural Research Program of the National Institute of Dental and Craniofacial Research. C.S.Z. is an investigator of the Howard Hughes Medical Institute. NR 43 TC 96 Z9 100 U1 7 U2 53 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 SEP 2 PY 2011 VL 333 IS 6047 BP 1262 EP 1266 DI 10.1126/science.1204076 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 813YM UT WOS:000294406400046 PM 21885776 ER PT J AU Haemmerich, D Dreher, MR Panescu, D Peitgen, HO AF Haemmerich, Dieter Dreher, Matthew R. Panescu, Dorin Peitgen, Heinz-Otto TI Image-Guided Therapies SO IEEE PULSE LA English DT Article C1 [Haemmerich, Dieter] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Haemmerich, Dieter] Clemson Univ, Dept Bioengn, Clemson, SC 29631 USA. [Dreher, Matthew R.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Bethesda, MD USA. [Panescu, Dorin] Newcardio Inc, Santa Clara, CA USA. RP Haemmerich, D (reprint author), Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. EM dreherm@cc.nih.gov; dpanescu@newcardio.com; heinz-otto.peitgen@mevis.fraunhofer.de OI Haemmerich, Dieter/0000-0003-1127-7024 NR 0 TC 0 Z9 0 U1 0 U2 2 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2154-2287 J9 IEEE PULSE JI IEEE Pulse PD SEP-OCT PY 2011 VL 2 IS 5 BP 25 EP 27 DI 10.1109/MPUL.2011.942953 PG 3 WC Engineering, Biomedical SC Engineering GA 992GW UT WOS:000307764600009 PM 25372966 ER PT J AU Klee, MM AF Klee, Maurice M. TI Hummingbirds, Orioles, and Butterflies SO IEEE PULSE LA English DT Editorial Material C1 [Klee, Maurice M.] Michigan State Univ, Coll Engn, E Lansing, MI 48824 USA. [Klee, Maurice M.] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2154-2287 J9 IEEE PULSE JI IEEE Pulse PD SEP-OCT PY 2011 VL 2 IS 5 BP 66 EP 66 DI 10.1109/MPUL.2011.942607 PG 1 WC Engineering, Biomedical SC Engineering GA 992GW UT WOS:000307764600014 ER PT J AU Knodler, LA Celli, J AF Knodler, Leigh A. Celli, Jean TI Eating the strangers within: host control of intracellular bacteria via xenophagy SO CELLULAR MICROBIOLOGY LA English DT Review ID SALMONELLA-CONTAINING VACUOLE; ENDOPLASMIC-RETICULUM; MYCOBACTERIUM-TUBERCULOSIS; ANTIBACTERIAL AUTOPHAGY; FRANCISELLA-TULARENSIS; LISTERIOLYSIN-O; INNATE IMMUNITY; UBIQUITIN; CELLS; MACROPHAGES AB Many bacterial pathogens rely on an intracellular cycle to ensure their proliferation within infected hosts, through their ability to avoid or circumvent host bactericidal pathways. Recent evidence supports an increasingly important role for the autophagy pathway in innate immune defences against intracellular pathogens, as a mechanism of capture of either cytosol-adapted or vacuolar bacteria that redirect them to the lysosomal compartment for killing. Antibacterial autophagy, also referred to as xenophagy, involves selective recognition of intracellular bacteria and their targeting to the autophagic machinery for degradation. Here we review recent advances in our molecular understanding of these processes, and in how bacteria have adapted to avoid xenophagy or even take advantage of this innate immune process. C1 [Knodler, Leigh A.; Celli, Jean] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Celli, J (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM jcelli@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We are grateful to Anita Mora for graphics assistance. We apologize to those whose work we did not cite due to space limitations. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 71 TC 58 Z9 58 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD SEP PY 2011 VL 13 IS 9 BP 1319 EP 1327 DI 10.1111/j.1462-5822.2011.01632.x PG 9 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 915FX UT WOS:000302010600003 PM 21740500 ER PT J AU Lodish, MB Stratakis, CA AF Lodish, Maya B. Stratakis, Constantine A. TI The differential diagnosis of familial lentiginosis syndromes SO FAMILIAL CANCER LA English DT Article DE Hamartoma; Lentigines; Mamallian target of rapamycin; Tumor suppressor ID PEUTZ-JEGHERS-SYNDROME; LAUGIER-HUNZIKER-SYNDROME; RILEY-RUVALCABA-SYNDROME; BANNAYAN-ZONANA-SYNDROME; CARNEY-COMPLEX; REGULATORY SUBUNIT; TUMOR-SUPPRESSOR; COWDEN-DISEASE; ENDOCRINE OVERACTIVITY; MALIGNANT-MELANOMA AB Cutaneous markers of systemic disease are vital for clinicians to recognize. This chapter outlines familial lentiginosis syndromes that include Peutz-Jeghers syndrome, Carney Complex, the PTEN hamartomatous syndromes, and LEOPARD/Noonan syndrome. The inheritance of these syndromes is autosomal dominant; they also share characteristic skin findings that offer a clue to their recognition and treatment. We will discuss the clinical presentation of these disorders, with a focus on the dermatological manifestations, and will provide an update on the molecular mechanisms involved. Recognition of cutaneous markers associated with these rare familial cancer syndromes provides the opportunity to pursue early surveillance for malignancies, as well as genetic counseling. C1 [Lodish, Maya B.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol Genet, Bethesda, MD 20892 USA. [Lodish, Maya B.; Stratakis, Constantine A.] NIH, Pediat Endocrinol Interinst Training Program, Bethesda, MD 20892 USA. RP Lodish, MB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol Genet, Bldg 10,CRC Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM lodishma@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 99 TC 14 Z9 14 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 J9 FAM CANCER JI Fam. Cancer PD SEP PY 2011 VL 10 IS 3 SI SI BP 481 EP 490 DI 10.1007/s10689-011-9446-x PG 10 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 908RI UT WOS:000301507400010 PM 21538076 ER PT J AU Yang, XHR Jessop, L Myers, T Amundadottir, L Pfeiffer, RM Wheeler, W Pike, KM Yuenger, J Burdett, L Yeager, M Chanock, SJ Tucker, MA Goldstein, AM AF Yang, Xiaohong R. Jessop, Lea Myers, Timothy Amundadottir, Laufey Pfeiffer, Ruth M. Wheeler, William Pike, Kristen M. Yuenger, Jeff Burdett, Laurie Yeager, Meredith Chanock, Stephen J. Tucker, Margaret A. Goldstein, Alisa M. TI Lack of germline PALB2 mutations in melanoma-prone families with CDKN2A mutations and pancreatic cancer SO FAMILIAL CANCER LA English DT Article DE CDKN2A; PALB2; Familial melanoma; Pancreatic cancer; Germline mutation ID ASSOCIATION; RISK AB The presence of pancreatic cancer (PC) in melanoma-prone families has been consistently associated with an increased frequency of CDKN2A mutations, the major high-risk susceptibility gene identified for melanoma. However, the precise relationship between CDKN2A, melanoma and PC remains unknown. We evaluated a recently identified PC susceptibility gene PALB2 using both sequencing and tagging to determine whether PALB2 might explain part of the relationship between CDKN2A, melanoma, and PC. No disease-related mutations were identified from sequencing PALB2 in multiple pancreatic cancer patients or other mutation carrier relatives of PC patients from the eight melanoma-prone families with CDKN2A mutations and PC. In addition, no significant associations were observed between 11 PALB2 tagging SNPs and melanoma risk in 23 melanoma-prone families with CDKN2A mutations or the subset of 11 families with PC or PC-related CDKN2A mutations. The results suggested that PALB2 does not explain the relationship between CDKN2A, melanoma, and pancreatic cancer in these melanoma-prone families. C1 [Yang, Xiaohong R.; Jessop, Lea; Myers, Timothy; Amundadottir, Laufey; Pfeiffer, Ruth M.; Yuenger, Jeff; Burdett, Laurie; Yeager, Meredith; Chanock, Stephen J.; Tucker, Margaret A.; Goldstein, Alisa M.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Myers, Timothy; Yuenger, Jeff; Burdett, Laurie; Yeager, Meredith] SAIC Frederick Inc, Core Genotyping Facil, NCI Frederick, Frederick, MD USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD USA. [Pike, Kristen M.] SAIC Frederick Inc, Lab Mol Technol, NCI Frederick, Frederick, MD USA. RP Goldstein, AM (reprint author), Bldg EPS,Rm 7004,6120 Execut Blvd, Bethesda, MD 20892 USA. EM goldstea@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Tucker, Margaret/B-4297-2015; Amundadottir, Laufey/L-7656-2016 OI Amundadottir, Laufey/0000-0003-1859-8971 FU NIH; NCI; DCEG FX We are indebted to the participating families, whose generosity and cooperation have made this study possible. We also acknowledge the contributions to this work that were made by Virginia Pichler, Deborah Zametkin, and Mary Fraser. This research was supported by the Intramural Research Program of the NIH, NCI, DCEG. NR 15 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 J9 FAM CANCER JI Fam. Cancer PD SEP PY 2011 VL 10 IS 3 SI SI BP 545 EP 548 DI 10.1007/s10689-011-9447-9 PG 4 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 908RI UT WOS:000301507400018 PM 21614589 ER PT J AU Ortiz, AP Lopez, M Flores, LT Soto-Salgado, M Rutten, LJF Serrano-Rodriguez, RA Hesse, BW Tortolero-Luna, G AF Ortiz, Ana Patricia Lopez, Magdalena Flores, Libertad T. Soto-Salgado, Marievelisse Rutten, Lila J. Finney Serrano-Rodriguez, Ruby A. Hesse, Bradford W. Tortolero-Luna, Guillermo TI Awareness of Direct-to-Consumer Genetic Tests and Use of Genetic Tests Among Puerto Rican Adults, 2009 SO PREVENTING CHRONIC DISEASE LA English DT Article ID CANCER-RISK; ETHNIC DISPARITIES; GENOMIC MEDICINE; BREAST-CANCER; UNITED-STATES; KNOWLEDGE; HEALTH; SUSCEPTIBILITY; ACCULTURATION; HISPANICS AB Introduction Genetic testing remains low among racial/ethnic minority populations in the United States. We aimed to determine the prevalence and correlates of awareness of direct-to-consumer (DTC) genetic tests and the prevalence of genetic test use in a population-based sample of adults in Puerto Rico. Methods We analyzed data from adults aged 18 years or older who completed information on genetic test awareness (n = 611; 96% of study population) from the Health Information National Trends Survey conducted in Puerto Rico in 2009. Odds ratios with 95% confidence intervals were estimated by using logistic regression models to identify factors associated with awareness of DTC genetic tests. Results The majority of respondents (56%) were aware of direct-to-consumer genetic tests, and approximately 4% had ever undergone any genetic test. Respondents who had never been married were less likely to be aware of DTC tests, as were current smokers. Respondents who ever sought cancer information were more likely to be aware of these tests. Conclusion We provide the first published data on the awareness of DTC genetic tests and on use of genetic testing in Puerto Rico. Forty-four percent of our sample of Puerto Rican adults were unaware of direct-to-consumer genetic tests. Given the lack of clear benefits of DTC genetic tests to the general population, educational interventions should be developed to increase awareness and specific knowledge regarding the appropriate use of DTC genetic tests among people who are already aware of their existence. C1 [Ortiz, Ana Patricia] Univ Puerto Rico, Dept Biostat & Epidemiol, Grad Sch Publ Hlth, San Juan, PR 00936 USA. [Ortiz, Ana Patricia; Tortolero-Luna, Guillermo] Univ Puerto Rico, Ctr Comprehens Canc, San Juan, PR 00936 USA. [Lopez, Magdalena] Univ N Carolina, Chapel Hill, NC USA. [Flores, Libertad T.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Rutten, Lila J. Finney] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Serrano-Rodriguez, Ruby A.] Puerto Rico Dept Hlth, San Juan, PR USA. [Hesse, Bradford W.] NCI, Bethesda, MD 20892 USA. RP Ortiz, AP (reprint author), Univ Puerto Rico, Dept Biostat & Epidemiol, Grad Sch Publ Hlth, Med Sci Campus,POB 365067, San Juan, PR 00936 USA. EM ana.ortiz7@upr.edu FU National Institutes of Health, National Cancer Institute [HHSN261200800001E, 5R25CA094186-08]; University of Puerto Rico-MD Anderson Cancer Center [U54CA96297, U54CA96300]; Research Center of Minority Institutions, University of Puerto Rico [G12RR03051]; Centers for Disease Control and Prevention, Hispanic-Serving Health Professions School [U50/325128-02] FX This project was supported by contract no. HHSN261200800001E from the National Institutes of Health, National Cancer Institute; no. 5R25CA094186-08 from the National Institutes of Health, National Cancer Institute: Training in Computational Genomic Epidemiology of Cancer; nos. U54CA96297 and U54CA96300 from the University of Puerto Rico-MD Anderson Cancer Center, Partnership for Excellence in Cancer Research; no. G12RR03051 from the Research Center of Minority Institutions, University of Puerto Rico; and no. U50/325128-02 from the Centers for Disease Control and Prevention, Hispanic-Serving Health Professions School. NR 28 TC 11 Z9 11 U1 2 U2 8 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD SEP PY 2011 VL 8 IS 5 AR A110 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 896JS UT WOS:000300562300020 PM 21843413 ER PT J AU Schenck, AP Klabunde, CN Warren, JL Jackson, E Peacock, S Lapin, P AF Schenck, Anna P. Klabunde, Carrie N. Warren, Joan L. Jackson, Eric Peacock, Sharon Lapin, Pauline TI Physician Visits and Colorectal Cancer Testing Among Medicare Enrollees in North Carolina and South Carolina, 2005 SO PREVENTING CHRONIC DISEASE LA English DT Article ID IOWA FAMILY PHYSICIANS; GEOGRAPHIC-VARIATION; PREVENTIVE SERVICES; CARE; DELIVERY; RECOMMENDATION; BENEFICIARIES; MAMMOGRAPHY; POPULATION; PATTERNS AB Introduction Many Medicare enrollees do not receive colorectal cancer tests at recommended intervals despite having Medicare screening coverage. Little is known about the physician visits of Medicare enrollees who are untested. Our study objective was to evaluate physician visits of enrollees who lack appropriate testing to identify opportunities to increase colorectal cancer testing. Methods We used North Carolina and South Carolina Medicare data to compare type and frequency of physician visits for Medicare enrollees with and without a colorectal cancer test in 2005. Type of physician visit was defined by the physician specialty as primary care, mixed specialty (more than 1 specialty, 1 of which was primary care), and nonprimary care. We used multivariate modeling to assess the influence of type and frequency of physician visits on colorectal cancer testing. Results Approximately half (46.5%) of enrollees lacked appropriate colorectal cancer testing. Among the untested group, 19.8% had no physician visits in 2005. Enrollees with primary care visits were more likely to be tested than those without a primary care visit. Many enrollees who had primary care visits remained untested. Enrollees with visits to all physician types had a greater likelihood of having colorectal cancer testing. Conclusions We identified 3 categories of Medicare enrollees without appropriate colorectal cancer testing: those with no visits, those who see primary care physicians only, and those with multiple visits to physicians with primary and nonprimary care specialties. Different strategies are needed for each category to increase colorectal cancer testing in the Medicare population. C1 [Schenck, Anna P.; Jackson, Eric; Peacock, Sharon] Carolinas Ctr Med Excellence, Cary, NC USA. [Klabunde, Carrie N.; Warren, Joan L.] NCI, Bethesda, MD 20892 USA. [Lapin, Pauline] Ctr Medicare Serv, Baltimore, MD USA. [Lapin, Pauline] Ctr Medicaid Serv, Baltimore, MD USA. RP Schenck, AP (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Campus Box 7469, Chapel Hill, NC 27599 USA. EM anna.schenck@unc.edu FU Centers for Medicare and Medicaid Services, Department of Health and Human Services [500-05-NC03]; National Cancer Institute [Y1-PC-8108-01] FX The analyses on which this publication is based were performed under contract no. 500-05-NC03, sponsored by the Centers for Medicare and Medicaid Services, Department of Health and Human Services, and the National Cancer Institute under interagency agreement no. Y1-PC-8108-01. This article is a result of the Health Care Quality Improvement Program initiated by the Centers for Medicare and Medicaid Services, which has encouraged identification of quality improvement projects derived from analysis of patterns of care, and therefore required no special funding on the part of this contractor. NR 34 TC 0 Z9 0 U1 0 U2 0 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD SEP PY 2011 VL 8 IS 5 AR A112 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 896JS UT WOS:000300562300022 PM 21843415 ER PT J AU Rohani, P Drake, JM AF Rohani, Pejman Drake, John M. TI The decline and resurgence of pertussis in the US SO EPIDEMICS LA English DT Article DE Pertussis; Epidemiology; Time series; Resurgence; Transmission ID BORDETELLA-PERTUSSIS; UNITED-STATES; VACCINATION; EPIDEMIOLOGY; INFECTION; RECOMMENDATIONS; ADAPTATION; PREVENTION; COUNTRIES; VACCINES AB Although the resurgence of pertussis in nations with long-standing vaccination programs has raised serious concerns about the effectiveness of current immunization policy, the epidemiology of resurgence remains poorly understood. We analyzed pertussis notifications in US states obtained from the National Notifiable Disease Surveillance System from 1951 to 2010 to explore the timing, spatial pattern and consistency of resurgence across the country. Here we show that resurgence occurred at different times in different states, spread out over a transition period of roughly three decades. Further, despite this spatial variation, broad patterns in pertussis epidemiology can be described by two dominant phases: (1) a period of decline ending in the mid-1970s, followed by (2) nationwide resurgence. Together, these patterns explain 89.7% of the variation in US case notifications between 1951 and 2005. This resurgence was interrupted, however, by a synchronized downturn in 2005 that continues to the present in many large states. The causes of these two transitions in pertussis epidemiology remain hotly debated, though our findings suggest that evolution of the Bordetella pertussis bacterium, loss of immunity and persistent transmission among adults, and demographic drivers are more probable explanations than changes in reporting or the introduction of acellular vaccines. (C) 2011 Elsevier B. V. All rights reserved. C1 [Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Drake, John M.] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. RP Rohani, P (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM rohani@umich.edu RI Drake, John/D-6622-2012; OI Drake, John/0000-0003-4646-1235 FU Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation FX PR is supported by the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, National Institutes of Health and by the Vaccine Modeling Initiative of the Bill & Melinda Gates Foundation. NR 37 TC 41 Z9 43 U1 1 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1755-4365 J9 EPIDEMICS-NETH JI Epidemics PD SEP-DEC PY 2011 VL 3 IS 3-4 BP 183 EP 188 DI 10.1016/j.epidem.2011.10.001 PG 6 WC Infectious Diseases SC Infectious Diseases GA 898AE UT WOS:000300706400006 PM 22094341 ER PT J AU Pfeffermann, D Landsman, V AF Pfeffermann, Danny Landsman, Victoria TI ARE PRIVATE SCHOOLS BETTER THAN PUBLIC SCHOOLS? APPRAISAL FOR IRELAND BY METHODS FOR OBSERVATIONAL STUDIES SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Average treatment effect; goodness of fit; identifiability; instrumental variables; private-dependent schools; propensity scores; sample distribution ID PROPENSITY SCORE; REGRESSION; INFERENCE; MODELS AB In observational studies the assignment of units to treatments is not under control. Consequently, the estimation and comparison of treatment effects based on the empirical distribution of the responses can be biased since the units exposed to the various treatments could differ in important unknown pretreatment characteristics, which are related to the response. An important example studied in this article is the question of whether private schools offer better quality of education than public schools. In order to address this question, we use data collected in the year 2000 by OECD for the Programme for International Student Assessment (PISA). Focusing for illustration on scores in mathematics of 15-year-old pupils in Ireland, we find that the raw average score of pupils in private schools is higher than of pupils in public schools. However, application of a newly proposed method for observational studies suggests that the less able pupils tend to enroll in public schools, such that their lower scores are not necessarily an indication of bad quality of the public schools. Indeed, when comparing the average score in the two types of schools after adjusting for the enrollment effects, we find quite surprisingly that public schools perform better on average. This outcome is supported by the methods of instrumental variables and latent variables, commonly used by econometricians for analyzing and evaluating social programs. C1 [Pfeffermann, Danny] Hebrew Univ Jerusalem, IL-91905 Jerusalem, Israel. [Pfeffermann, Danny] Univ Southampton, Southampton SO17 1BJ, Hants, England. [Landsman, Victoria] NCI, NIH, Rockville, MD 20852 USA. RP Pfeffermann, D (reprint author), Hebrew Univ Jerusalem, IL-91905 Jerusalem, Israel. EM msdanny@soton.ac.uk; landsmanv@mail.nih.gov FU Israel Science Foundation [1277/05] FX Supported by the Israel Science Foundation Grant 1277/05. NR 35 TC 2 Z9 2 U1 2 U2 7 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD SEP PY 2011 VL 5 IS 3 BP 1726 EP 1751 DI 10.1214/11-AOAS456 PG 26 WC Statistics & Probability SC Mathematics GA 893UR UT WOS:000300382500002 PM 22242110 ER PT J AU Volkow, ND Baler, RD Normand, JL AF Volkow, Nora D. Baler, Ruben D. Normand, Jacques L. TI The Unrealized Potential of Addiction Science in Curbing the HIV Epidemic SO CURRENT HIV RESEARCH LA English DT Article DE HAART; highly active antiretroviral therapy; HIV prevention; substance use disorders; substance use disorders; treatment ID INJECTING DRUG-USERS; ACTIVE ANTIRETROVIRAL THERAPY; OPIOID DEPENDENCE; DOPAMINE; IMPULSIVITY; PERSPECTIVE; RESISTANCE; METHADONE; RATS; CARE AB The stubbornly high incidence of new HIV infections belies the overwhelming evidence showing that sustained highly active antiretroviral therapy (HAART) has the power to dramatically reduce the spread of HIV infection and forever change the face of this devastating epidemic. One of the main contributors to this public health paradox is the ongoing HIV epidemic among substance users who contribute significantly to HIV infection rates through injection drug use and high- risk sexual behaviours. Current evidence clearly shows that, in order to fill this gap, we need to integrate substance abuse treatment with HIV treatment programmes and provide substance abusers with universal access to HIV treatment through a focussed effort to seek, test, treat, and retain hard- to- reach high risk individuals. These aims will require structural changes in the health care system to overcome many of the obstacles that have inhibited the merging of substance abuse treatment with HIV programmes for far too long. C1 [Volkow, Nora D.; Baler, Ruben D.; Normand, Jacques L.] Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, NIH, 6001 Execut Blvd,Room 5274,MSC 9581, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 30 TC 7 Z9 7 U1 0 U2 4 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-162X J9 CURR HIV RES JI Curr. HIV Res. PD SEP PY 2011 VL 9 IS 6 BP 393 EP 395 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 883ZA UT WOS:000299673000005 PM 21999774 ER PT J AU Das, DK Mukhopadhyay, P AF Das, Dipak K. Mukhopadhyay, Partha TI MicroRNA signatures of stem cells SO EXPERIMENTAL & CLINICAL CARDIOLOGY LA English DT Review DE MicroRNA; MicroRNA-based therapeutics; MicroRNA biogenesis; Redox cycling; Regenerative medicine; Stem cells ID MODIFIED GOLD NANOPARTICLES; INHIBITION; RNAS; DIFFERENTIATION; PLURIPOTENCY; BIOGENESIS; GENES AB The unique properties of embryonic stem (ES) cells to self-renew indefinitely or to differentiate to any cell type (pluripotency) warrants their clinical application in regenerative medicine. MicroRNAs are crucial for post-transcriptional gene regulation and, thus, remain an essential element of the regulation of ES cells. The present review discusses the essential elements of microRNAs that regulate the life and death of ES cells. C1 [Das, Dipak K.; Mukhopadhyay, Partha] Univ Connecticut, Sch Med, Cardiovasc Res Ctr, Farmington, CT 06030 USA. [Das, Dipak K.; Mukhopadhyay, Partha] NIH, Bethesda, MD 20892 USA. RP Das, DK (reprint author), Univ Connecticut, Sch Med, Cardiovasc Res Ctr, Farmington, CT 06030 USA. EM ddas@neuron.uchc.edu FU NIH [HL 34360, HL 33889, HL 22559] FX This study was supported in part by NIH HL 34360, HL 33889 and HL 22559. NR 30 TC 0 Z9 0 U1 0 U2 2 PU PULSUS GROUP INC PI OAKVILLE PA 2902 S SHERIDAN WAY, OAKVILLE, ONTARIO L6J 7L6, CANADA SN 1205-6626 J9 EXP CLIN CARDIOL JI Exp. Clin. Cardiol. PD FAL PY 2011 VL 16 IS 3 BP E13 EP E16 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 896GA UT WOS:000300552500001 PM 22065941 ER PT J AU Korten, N Comijs, H Penninx, B Lamers, F AF Korten, Nicole Comijs, H. Penninx, B. Lamers, F. TI Early and late onset depression: Differential symptomatology, characteristics and risk factors? SO INTERNATIONAL PSYCHOGERIATRICS LA English DT Meeting Abstract C1 [Korten, Nicole; Comijs, H.; Penninx, B.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Lamers, F.] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1041-6102 J9 INT PSYCHOGERIATR JI Int. Psychogeriatr. PD SEP PY 2011 VL 23 SU 1 BP S312 EP S313 PG 2 WC Psychology, Clinical; Geriatrics & Gerontology; Gerontology; Psychiatry; Psychology SC Psychology; Geriatrics & Gerontology; Psychiatry GA 889UX UT WOS:000300101100420 ER PT J AU Andaya, AA Arredondo, EM Alcaraz, JE Lindsay, SP Elder, JP AF Andaya, Abegail A. Arredondo, Elva M. Alcaraz, John E. Lindsay, Suzanne P. Elder, John P. TI The Association between Family Meals, TV Viewing during Meals, and Fruit, Vegetables, Soda, and Chips Intake among Latino Children SO JOURNAL OF NUTRITION EDUCATION AND BEHAVIOR LA English DT Article DE Latino; fruit; vegetables; child; family meals; TV ID FOOD FREQUENCY QUESTIONNAIRE; MEXICAN-AMERICAN CHILDREN; SOFT DRINK CONSUMPTION; HIGH-SCHOOL-STUDENTS; PRESCHOOL-CHILDREN; DIETARY-INTAKE; US CHILDREN; FAT INTAKE; EATING PATTERNS; UNITED-STATES AB Objective: Examine the relationship of family meals to children's consumption of fruit and vegetables as well as soda and chips. Additionally, to assess the relationship between viewing TV during family meals and children's diet. Design: Cross-sectional study that used a questionnaire completed by parents. Setting: Thirteen schools in San Diego, California. Participants: Seven hundred ninety-four children and their parents. Analysis: Ordinal regression assessed associations between children's intake of fruit, vegetables, soda, and chips with family meal frequency and TV viewing during family meals. Results: Children who consumed breakfast, lunch, or dinner with their family at least 4 days per week ate fruit and vegetables 5 or more times a week 84%, 85%, and 80%, respectively. Of those children who ate breakfast, lunch, or dinner with their family at least 4 days per week, 40%, 44%, and 43% consumed soda and chips 5 or more times a week, respectively. Children who ate breakfast with their families at least 4 times a week were more likely to consume fruit and vegetables, and children whose TV was never or rarely on during family meals were less likely to consume soda and chips (P = .04 and P < .001, respectively). Conclusions: Interventions geared at increasing the frequency of eating breakfast as a family and decreasing the amount of TV watched during family meals are needed, especially among acculturating Latino families. C1 [Andaya, Abegail A.] NCI, NIH, Rockville, MD 20852 USA. [Arredondo, Elva M.; Elder, John P.] San Diego State Univ, Grad Sch Publ Hlth, Ctr Behav & Community Hlth Studies, San Diego, CA 92182 USA. [Lindsay, Suzanne P.] San Diego State Univ, Grad Sch Publ Hlth, Inst Publ Hlth, San Diego, CA 92182 USA. RP Andaya, AA (reprint author), NCI, NIH, 6120 Execut Blvd,EPS 5009, Rockville, MD 20852 USA. EM abegail.andaya@gmail.com FU National Heart Lung and Blood Institute [RO1 HL073776]; American Cancer Society [PFT-04-156-01] FX This effort was funded by the National Heart Lung and Blood Institute (RO1 HL073776) and the American Cancer Society (PFT-04-156-01). This study was conducted at San Diego State University's Graduate School of Public Health. NR 53 TC 36 Z9 37 U1 6 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1499-4046 J9 J NUTR EDUC BEHAV JI J. Nutr. Educ. Behav. PD SEP-OCT PY 2011 VL 43 IS 5 BP 308 EP 315 DI 10.1016/j.jneb.2009.11.005 PG 8 WC Education, Scientific Disciplines; Nutrition & Dietetics SC Education & Educational Research; Nutrition & Dietetics GA 890WY UT WOS:000300178000003 PM 20965787 ER PT J AU Miller, P Moore, RH Kral, TVE AF Miller, Paige Moore, Renee H. Kral, Tanja V. E. TI Children's Daily Fruit and Vegetable Intake: Associations with Maternal Intake and Child Weight Status SO JOURNAL OF NUTRITION EDUCATION AND BEHAVIOR LA English DT Article DE fruits; vegetables; mothers; children; obesity ID ENERGY DENSITY; EATING BEHAVIORS; DIET QUALITY; LOW-INCOME; OBESITY; FOODS; FAT; INTERVENTION; PREFERENCES; FAMILIES AB Objective: To evaluate associations between children's and their mothers' fruit and vegetable (FV) intake and children's FV intake and weight status. Methods: Mothers (n = 39) residing in Philadelphia, PA completed a subsection of the Diet History Questionnaire assessing their FV intake. Mothers also completed this questionnaire to estimate FV intake among their 5-or 6-year-old children (n = 39). Children's height and weight were measured. Pearson correlation, Student t tests, and binary logistic regression analyses were performed. Results: A significant positive mother-child association was found for FV intake (P < .001). Overweight/obese children consumed fewer FVs than normal-weight children (P = .02). Conclusions and Implications: Efforts to promote FV consumption in mothers may help children achieve the recommended intake of FVs. Higher intakes of FVs in turn may help with child weight management. C1 [Kral, Tanja V. E.] Univ Penn, Perelman Sch Med, Ctr Weight & Eating Disorders, Dept Psychiat, Philadelphia, PA 19104 USA. [Miller, Paige] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. RP Kral, TVE (reprint author), Univ Penn, Perelman Sch Med, Ctr Weight & Eating Disorders, Dept Psychiat, 3535 Market St,3rd Floor, Philadelphia, PA 19104 USA. EM tkral@mail.med.upenn.edu FU The Obesity Society FX This study was conducted at the University of Pennsylvania. This research was supported by a grant from The Obesity Society, which the senior investigator (TVEK) received as part of a New Investigator Research Award. NR 29 TC 14 Z9 16 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1499-4046 J9 J NUTR EDUC BEHAV JI J. Nutr. Educ. Behav. PD SEP-OCT PY 2011 VL 43 IS 5 BP 396 EP 400 DI 10.1016/j.jneb.2010.10.003 PG 5 WC Education, Scientific Disciplines; Nutrition & Dietetics SC Education & Educational Research; Nutrition & Dietetics GA 890WY UT WOS:000300178000015 PM 21764642 ER PT J AU Nayak, TK Brechbiel, MW AF Nayak, Tapan K. Brechbiel, Martin W. TI Y-86 Based PET Radiopharmaceuticals: Radiochemistry and Biological Applications SO MEDICINAL CHEMISTRY LA English DT Article DE PET imaging; radiochemistry; Y-90; Y-86; bioconjugate chemistry; peptides; antibodies ID RECEPTOR RADIONUCLIDE THERAPY; POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO BIODISTRIBUTION; B3 MONOCLONAL-ANTIBODY; NON-HODGKINS-LYMPHOMA; ZR-89 IMMUNO-PET; NEUROENDOCRINE TUMORS; CARCINOMA XENOGRAFTS; PROSTATE-CANCER; CHX-DTPA AB Development of targeted radionuclide therapy with Y-90 labeled antibodies and peptides has gained momentum in the past decade due to the successes of Y-90-ibritumomab tiuxetan and Y-90-DOTA-Phe(1)-Tyr(3)-octreotide in treatment of cancer. Y-90 is a pure beta(-)-emitter and cannot be imaged for patient-specific dosimetry which is essential for pre-therapeutic treatment planning and accurate absorbed dose estimation in individual patients to mitigate radiation related risks. This review article describes the utility of Y-86, a positron emitter (33%) with a 14.7-h half-life that can be imaged by positron emission tomography and used as an isotopically matched surrogate radionuclide for Y-90 radiation doses estimations. This review discusses various aspects involved in the development of Y-86 labeled radiopharmaceuticals with the specific emphasis on the radiochemistry and biological applications with antibodies and peptides. C1 [Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Nayak, Tapan K.] F Hoffmann La Roche & Co Ltd, Imaging Sci Translat Res Sci,Pharma Res & Early D, CH-4072 Basel, Switzerland. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, 10 Ctr Dr,MSC 1002,Room B3B69, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov OI Nayak, Tapan/0000-0002-3706-6092 FU NIH, NCI, Center for Cancer Research; United States Department of Health and Human Services FX This report was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research, and the United States Department of Health and Human Services. Gratitude is expressed to Prof. Hari Seldon for useful discussion. NR 58 TC 12 Z9 12 U1 3 U2 18 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1573-4064 J9 MED CHEM JI Med. Chem. PD SEP PY 2011 VL 7 IS 5 BP 380 EP 388 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 882PG UT WOS:000299575500004 PM 21711222 ER PT J AU Choi, KY Chang, K Pickel, JM Badger, JD Roche, KW AF Choi, K. Y. Chang, K. Pickel, J. M. Badger, J. D., II Roche, K. W. TI Expression of mGluR5 Induces Melanoma in Transgenic Mice SO CURRENT NEUROPHARMACOLOGY LA English DT Meeting Abstract C1 [Choi, K. Y.; Chang, K.; Badger, J. D., II; Roche, K. W.] NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. [Pickel, J. M.] NIMH, Transgen Core Facil, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1570-159X J9 CURR NEUROPHARMACOL JI Curr. Neuropharmacol. PD SEP PY 2011 VL 9 SU 1 MA 29 BP 10 EP 11 PG 2 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 883IJ UT WOS:000299627200030 ER PT J AU Gardner, EL Li, X Peng, XQ Li, J Spiller, K Xi, ZX AF Gardner, E. L. Li, X. Peng, X-Q. Li, J. Spiller, K. Xi, Z. -X. TI Metabotropic Glutamate Mechanisms and Cocaine's Addictive Actions SO CURRENT NEUROPHARMACOLOGY LA English DT Meeting Abstract C1 [Gardner, E. L.; Li, X.; Peng, X-Q.; Li, J.; Spiller, K.; Xi, Z. -X.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 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 1570-159X J9 CURR NEUROPHARMACOL JI Curr. Neuropharmacol. PD SEP PY 2011 VL 9 SU 1 MA 60 BP 22 EP 22 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 883IJ UT WOS:000299627200061 ER PT J AU Zhao, L Ma, WX Fariss, RN Wong, WT AF Zhao, Lian Ma, Wenxin Fariss, Robert N. Wong, Wai T. TI Minocycline Attenuates Photoreceptor Degeneration in a Mouse Model of Subretinal Hemorrhage Microglial Inhibition as a Potential Therapeutic Strategy SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TISSUE-PLASMINOGEN ACTIVATOR; EXPERIMENTAL INTRACEREBRAL HEMORRHAGE; CHOROIDAL NEOVASCULAR LESIONS; NF-KAPPA-B; MACULAR DEGENERATION; SUBMACULAR HEMORRHAGE; BRAIN-INJURY; MACROPHAGE ACTIVATION; RETINAL MICROGLIA; WHOLE-BLOOD AB Hemorrhage under the neural retina (subretinal hemorrhage) can occur in the context of age-related macular degeneration and induce subsequent photoreceptor cell death and permanent vision loss. Current treatments with the objective of removing or displacing the hemorrhage are invasive and of mixed efficacy. We created a mouse model of subretinal hemorrhage to characterize the inflammatory responses and photoreceptor degeneration that occur in the acute aftermath of hemorrhage. It was observed that microglial infiltration into the outer retina commences as early as 6 hours after hemorrhage. Inflammatory cells progressively accumulate in the outer nuclear layer concurrently with photoreceptor degeneration and apoptosis. Administration of minocycline, an inhibitor of microglial activation, decreased microglial expression of chemotactic cytokines in vitro and reduced microglial infiltration and photoreceptor cell loss after subretinal hemorrhage in vivo. Inflammatory responses and photoreceptor atrophy occurred after subretinal hemorrhage, however, the degree of response and atrophy were similar between C3-deficient and C3-sufficient mice, indicating a limited role for complement-mediated processes. Our data indicate a role for inflammatory responses in driving photoreceptor cell loss in subretinal hemorrhage, and it is proposed that microglial inhibition may be beneficial in the treatment of subretinal hemorrhage. (Am J Pathol 2011, 179:1265-1277; DOI: 10.1016/j.ajpath.2011.05.042) C1 [Zhao, Lian; Ma, Wenxin; Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, Off Sci Director, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), NEI, Unit Neuron Glia Interact Retinal Dis, Off Sci Director, NIH, 6 Ctr Dr,Rm 217, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov OI Wong, Wai/0000-0003-0681-4016 FU Prevention of Blindness Metropolitan Washington; National Eye Institute FX Supported by a grant from Prevention of Blindness Metropolitan Washington and by the National Eye Institute Intramural Research Program. NR 58 TC 18 Z9 18 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2011 VL 179 IS 3 BP 1265 EP 1277 DI 10.1016/j.ajpath.2011.05.042 PG 13 WC Pathology SC Pathology GA 865JN UT WOS:000298307300021 PM 21763674 ER PT J AU Hsu, WM Che, ML Liao, YF Chang, HH Chen, CH Huang, YM Jeng, YM Huang, J Quon, MJ Lee, H Huang, HC Huang, MC AF Hsu, Wen-Ming Che, Mei-leng Liao, Yung-Feng Chang, Hsiu-Hao Chen, Chia-Hua Huang, Yu-Ming Jeng, Yung-Ming Huang, John Quon, Michael J. Lee, Hsinyu Huang, Hsiu-Chin Huang, Min-Chuan TI B4GALNT3 Expression Predicts a Favorable Prognosis and Suppresses Cell Migration and Invasion via beta(1) Integrin Signaling in Neuroblastoma SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID ASPARAGINE-LINKED OLIGOSACCHARIDES; PITUITARY GLYCOPROTEIN HORMONES; IN-SITU HYBRIDIZATION; SIALYLATED OLIGOSACCHARIDES; BOVINE PROOPIOMELANOCORTIN; STRUCTURAL ELUCIDATION; N-GLYCOSYLATION; CANCER; LUTROPIN; GLYCANS AB beta 1,4-N-acetylgalactosaminyltransferase III (B4GALNT3) promotes the formation of GalNAc beta 1,4GlcNAc (LacdiNAc or LDN). Drosophila beta 1,4-N-acetylgalactosaminyltransferase A (B4GALNTA) contributes to the synthesis of LDN, which helps regulate neuronal development. In this study, we investigated the expression and role of B4GALNT3 in human neuroblastoma (NB). We used IHC analysis to examine 87 NB tumors, and we identified correlations between B4GALNT3 expression and clinicopathologic factors, including patient survival. Effects of recombinant B4GALNT3 on cell behavior and signaling were studied in SK-N-SH and SH-SY5Y NB cells. Increased expression of B4GALNT3 in NB tumors correlated with a favorable histologic profile (P < 0.001, chi(2) test) and early clinical staging (P = 0.041, chi(2) test) and was a favorable prognostic factor for survival as evaluated by univariate and multivariate analyses. Reexpression of B4GALNT3 in SK-N-SH and SH-SY5Y cells suppressed cell proliferation, colony formation, migration, and invasion. Moreover, B4GALNT3 increased the LacdiNAc modification of beta(1), integrin, leading to decreased phosphorylation of focal adhesion kinase (FAK), Src, paxillin, Akt, and ERK1/2. B4GALNT3-mediated suppression of cell migration and invasion were substantially reversed by concomitant expression of constitutively active Akt or MEK. We conclude that B4GALNT3 predicts a favorable prognosis for NB and suppresses the malignant phenotype via decreasing beta(1), integrin signaling. (Am J Pathol 2011, 179:1394-1404; DOI: 10.1016/j.ajpath.2011.05.025) C1 [Che, Mei-leng; Chen, Chia-Hua; Huang, Yu-Ming; Huang, Min-Chuan] Natl Taiwan Univ, Coll Med, Grad Inst Anat & Cell Biol, Taipei 100, Taiwan. [Hsu, Wen-Ming; Huang, John] Natl Taiwan Univ Hosp, Dept Surg, Taipei 100, Taiwan. [Chang, Hsiu-Hao] Natl Taiwan Univ Hosp, Dept Pediat, Taipei 100, Taiwan. [Jeng, Yung-Ming] Natl Taiwan Univ Hosp, Dept Pathol, Taipei 100, Taiwan. [Hsu, Wen-Ming; Che, Mei-leng; Lee, Hsinyu; Huang, Min-Chuan] Natl Taiwan Univ, Res Ctr Dev Biol & Regenerat Med, Taipei 100, Taiwan. [Lee, Hsinyu] Natl Taiwan Univ, Dept Life Sci, Taipei 100, Taiwan. [Liao, Yung-Feng] Acad Sinica, Inst Cellular & Organism Biol, Taipei 115, Taiwan. [Quon, Michael J.] NIH, Diabet Unit, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Huang, Hsiu-Chin] Anim Technol Inst Taiwan, Miaoli, Taiwan. RP Huang, MC (reprint author), Natl Taiwan Univ, Coll Med, Grad Inst Anat & Cell Biol, 1,Sec 1 Jen Ai Rd, Taipei 100, Taiwan. EM mchuang@ntu.edu.tw RI Liao, Yung-Feng/A-9761-2011; OI HSU, WEN-MING/0000-0002-5145-9538; Quon, Michael/0000-0002-9601-9915; CHANG, HSIU-HAO/0000-0003-1832-8509 FU National Taiwan University [95R0101]; National Health Research Institute [NHRI-EX97-94108C, NHRIEX96-9620NI]; National Science Council (R.O.C.) [NSC98-2320-B-002-032-MY3, NSC99-2628-B-002-056-MY3]; National Center for Complementary and Alternative Medicine, National Institutes of Health FX Supported by the Frontier and Innovative Research Program of National Taiwan University (grant 95R0101 to M.-C.H.), by the National Health Research Institute (grants NHRI-EX97-94108C to M.-C.H. and NHRIEX96-9620NI to W.-M.H.), by the National Science Council (R.O.C. grants NSC98-2320-B-002-032-MY3 to M.-C.H. and NSC99-2628-B-002-056-MY3 to W.-M.H.), and, in part, by the Intramural Research Program of the National Center for Complementary and Alternative Medicine, National Institutes of Health (M.J.Q.). NR 38 TC 17 Z9 17 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2011 VL 179 IS 3 BP 1394 EP 1404 DI 10.1016/j.ajpath.2011.05.025 PG 11 WC Pathology SC Pathology GA 865JN UT WOS:000298307300033 PM 21741930 ER PT J AU Yang, Y Liu, Y Yao, XH Ping, YF Jiang, T Liu, Q Xu, SL Huang, J Mou, HW Gong, WH Chen, KQ Bian, XW Wang, JM AF Yang, Yan Liu, Ying Yao, Xiaohong Ping, Yifang Jiang, Tao Liu, Qin Xu, Senlin Huang, Jian Mou, Haiwei Gong, Wanghua Chen, Keqiang Bian, Xiuwu Wang, Ji Ming TI Annexin 1 Released by Necrotic Human Glioblastoma Cells Stimulates Tumor Cell Growth through the Formyl Peptide Receptor 1 SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID FPR; METASTASIS; NEUTROPHIL; CANCER; TRANSACTIVATION; IDENTIFICATION; RECRUITMENT; INVOLVEMENT; PROGRESSION; LL-37 AB Highly malignant human gliomas overexpress the G-protein-coupled chemoattractant receptor forinyl peptide receptor (FPR1), which promotes tumor progression when activated. Our previous studies demonstrated that necrotic glioblastoma cells release chemotactic agonist(s) that activate FPR1 on viable tumor cells. In the present study, we identified an FPR1 agonist released by necrotic human glioblastoma cells. Necrotic tumor cell supernatant (NecSup) contained Annexin 1 (Anx A1), a chemotatic polypeptide agonist for FPR1 Immunoabsorption of Anx A1 with a specific antibody markedly reduced the chemotactic activity of NecSup for tumor cells and diminished its capacity to promote tumor cell growth, invasion, and colony formation on soft agar. In addition, Anx A1 was present in tumor xenografts formed by human glioblastoma cells in nude mice. Anx A1 knockdown significantly reduced the tumorigenicity of glioblastoma cells in nude mice, but FPR1/Anx A1 double knockdown diminished tumor growth even further. The clinical relevance of Anx A1 in gliomas was supported by the observation that Anx A1 was more highly expressed in poorly differentiated human primary gliomas compared with lower grade tumors. Our study implicates Anx A1 as a major component in necrotic tumor cell-derived stimulants of the growth of glioblastoma via the activation of FPR1. (Am J Pathol 2011, 179:1504-1512; DOI: 10.1016/j.ajpath.2011.05.059) C1 [Yang, Yan; Liu, Ying; Chen, Keqiang; Wang, Ji Ming] NCI, LMI, CIP, CCR, Frederick, MD 21702 USA. [Yang, Yan] Ocean Univ China, Coll Marine Life Sci, Qingdao, Peoples R China. [Yao, Xiaohong; Ping, Yifang; Liu, Qin; Xu, Senlin; Bian, Xiuwu] Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing, Peoples R China. [Yao, Xiaohong; Ping, Yifang; Liu, Qin; Xu, Senlin; Bian, Xiuwu] Third Mil Med Univ, Southwest Hosp, SW Canc Ctr, Chongqing, Peoples R China. [Jiang, Tao] Capital Med Univ, Tiantan Hosp, Dept Nerosurg, Beijing, Peoples R China. [Huang, Jian] Third Mil Med Univ, Coll High Altitude Mil Med, Dept Pathophysiol, Chongqing, Peoples R China. [Mou, Haiwei] Shanghai Inst Biol Sci, Inst Nutr Sci, Shanghai, Peoples R China. [Gong, Wanghua; Wang, Ji Ming] Sci Applicat Int Corp SAIC Frederick, Basic Res Program, Frederick, MD USA. RP Wang, JM (reprint author), NCI, LMI, CIP, CCR, Bldg 560,Room 31-76, Frederick, MD 21702 USA. EM wangji@mail.nih.gov RI Jiang, Tao/N-8142-2014; Bian, Xiu-wu/D-4736-2017 OI Bian, Xiu-wu/0000-0003-4383-0197 FU National Cancer Institute; National Institutes of Health [HHSN261200800001E]; NCI, NIH; National Natural Science Foundation of China [30973446] FX Supported in part by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E, and in part by the Intramural Research Program of the NCI, NIH. J.H. was funded in part by the National Natural Science Foundation of China (#30973446). NR 25 TC 22 Z9 22 U1 1 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2011 VL 179 IS 3 BP 1504 EP 1512 DI 10.1016/j.ajpath.2011.05.059 PG 9 WC Pathology SC Pathology GA 865JN UT WOS:000298307300043 PM 21782780 ER PT J AU Zappacosta, R Aiello, FB D'Antuono, T Procopio, AD Durum, SK Conti, P Rosini, S AF Zappacosta, Roberta Aiello, Francesca B. D'Antuono, Tommaso Procopio, Antonio D. Durum, Scott K. Conti, Pio Rosini, Sandra TI Detection of Nuclear and Membrane Antigens by Liquid-Based Cytology Following Long-Term Storage of D1 Cells, Karpas Cells, and Peripheral Blood Mononuclear Cells SO ANNALS OF CLINICAL AND LABORATORY SCIENCE LA English DT Article DE liquid-based cytology; fixation; immunocytochemistry; double-staining ID LYMPHOMA; EXPRESSION; SPECIMENS; CD30; IL-7 AB Immunofluorescence is the most frequently utilized technique to analyze protein expression. Fixed immunofluorescent cell suspensions, however, can only be stored for a week. We investigated whether liquid-based cytology could be used to detect antigens in cultured cells after a long storage period. Murine and human cells were fixed in PreservCyt solution, stored for various periods, and then used to perform an automated immunocytochemical analysis. Phosphorylation of the nuclear transcription factor Stat-5 induced by IL-7 was detected up to 4 months after IL-7 stimulation. Simultaneous nuclear positivity for the proliferation index MIB-1 and membrane positivity for the CD30 antigen were evident three months after fixation. Liquid-based cytology thus ensures long-lasting nuclear and membrane antigen immunoreactivity and permits the storage of cells from laborious experiments at room temperature for future analyses. C1 [Zappacosta, Roberta] G dAnnunzio Univ Chieti Pescara, Dept Oncol & Expt Med, Sect Cytopathol, I-66100 Chieti, Italy. [Procopio, Antonio D.] Marche Univ, Dept Expt Pathol, Ancona, Italy. [Durum, Scott K.] NCI, Sect Cytokines & Immun, Frederick, MD 21701 USA. [Conti, Pio] G dAnnunzio Univ Chieti Pescara, Div Immunol, I-66100 Chieti, Italy. RP Zappacosta, R (reprint author), G dAnnunzio Univ Chieti Pescara, Dept Oncol & Expt Med, Sect Cytopathol, Via Vestini, I-66100 Chieti, Italy. EM zappacosta2@hotmail.com NR 14 TC 0 Z9 0 U1 1 U2 4 PU ASSOC CLINICAL SCIENTISTS PI MIDDLEBURY PA PO BOX 1287, MIDDLEBURY, VT 05753 USA SN 0091-7370 J9 ANN CLIN LAB SCI JI Ann. Clin. Lab. Sci. PD FAL PY 2011 VL 41 IS 4 BP 353 EP 359 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 872PP UT WOS:000298822100008 PM 22166505 ER PT J AU Knight, MG Goedecke, JH Ricks, M Evans, J Levitt, NS Tulloch-Reid, MK Sumner, AE AF Knight, Michael G. Goedecke, Julia H. Ricks, Madia Evans, Juliet Levitt, Naomi S. Tulloch-Reid, Marshall K. Sumner, Anne E. TI THE TG/HDL-C RATIO DOES NOT PREDICT INSULIN RESISTANCE IN OVERWEIGHT WOMEN OF AFRICAN DESCENT: A STUDY OF SOUTH AFRICAN, AFRICAN AMERICAN AND WEST AFRICAN WOMEN SO ETHNICITY & DISEASE LA English DT Article DE Triglyceride; TG/HDL-C Ratio; Insulin Resistance; Africans; African Americans ID HIGH-DENSITY-LIPOPROTEIN; HDL-CHOLESTEROL RATIO; ETHNIC-DIFFERENCES; TRIGLYCERIDE; ASSOCIATION; POPULATION; MARKERS; HEALTH; RISK AB Women of African descent have a high prevalence of diseases caused by insulin resistance. To positively impact cardiometabolic health in Black women, effective screening tests for insulin resistance must be identified. Recently, the TG/HDL-C ratio has been recommended as a tool to predict insulin resistance in overweight people. While the ratio predicts insulin resistance in White women, it is ineffective in African American women. As there are no data for African women, we tested the ability of the TG/HDL-C ratio to predict insulin resistance in Black women from South Africa, West Africa and the United States. For comparison, the ratio was also tested in White women from South Africa. Participants were 801 women (157 Black South African, 382 African American, 119 West African, 143 White South African, age 36 +/- 9y [mean +/- SD]). Standardized scores were created from log-transformed homeostasis model assessment-insulin resistance values from each population. Participants in the upper third of their population distribution were classified as insulin-resistant. To predict insulin resistance by the TG/HDL-C ratio, area under the receiver operating characteristic (AUC-ROC) curve was used and criteria were: 0.50 for no discrimination and >= 0.70 for acceptable. Seventy-one percent of the Black women were overweight vs 51% of White women (P<.01). In overweight White women, AUC-ROC curve for prediction of insulin resistance by TG/HDL-C was 0.76 +/- 0.06, but below the 0.70 threshold in each group of overweight Black women (Black South African: 0.64 +/- 0.06, African American: 0.66 +/- 0.03, and West African: 0.63 +/- 0.07). Therefore, TG/HDL-C does not predict insulin resistance in overweight African American women and this investigation extends that finding to overweight Black South African and West African women. Resources to identify effective markers of insulin resistance are needed to improve cardiometabolic health in women of African descent. (Ethn Dis. 2011;21(4):490-494) C1 [Knight, Michael G.; Ricks, Madia; Sumner, Anne E.] NIDDK, DEOB, NIH, Bethesda, MD 20892 USA. [Goedecke, Julia H.; Evans, Juliet] Univ Cape Town, Dept Human Biol, ZA-7700 Rondebosch, South Africa. [Levitt, Naomi S.] Univ Cape Town, Div Endocrinol & Diabet, Dept Med, ZA-7700 Rondebosch, South Africa. [Tulloch-Reid, Marshall K.] Univ W Indies, Epidemiol Res Unit, TMRI, Kingston 7, Jamaica. RP Sumner, AE (reprint author), NIDDK, DEOB, NIH, Bld 10 CRC,Rm 6-5940,MSC 1612,9000 Rockville Pike, Bethesda, MD 20892 USA. EM AnneS@intra.niddk.nih.gov RI Tulloch-Reid, Marshall/E-4383-2012; Goedecke, Julia/J-8628-2013; Goedecke, Julia/E-1820-2016 OI Goedecke, Julia/0000-0001-6795-4771; Goedecke, Julia/0000-0001-6795-4771 FU NIDDK, NIH; NIH; Pfizer Inc; South African Medical Research Council; National Research Foundation of South Africa; University of Cape Town; NCRR [2M01RR010284]; National Human Genome Center at Howard University; NCMHD; NHGRI; NIDDK; [S06GM008016-320107] FX The authors thank Ms. Sophia S.K. Yu and Ms. Darleen C. Castillo for their careful review of the manuscript. AES and MR were supported by the Intramural Program of NIDDK, NIH. MGK was supported through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc (via a grant to the Foundation for NIH from Pfizer Inc). The South African study was funded by the South African Medical Research Council, the National Research Foundation of South Africa and the University of Cape Town. The HUFS was supported by grant S06GM008016-320107. African American enrollment from HUFS was carried out at the General Clinical Research Center supported by NCRR grant 2M01RR010284 and the National Human Genome Center at Howard University. The AADM study was supported by grants obtained from NCMHD, NHGRI and NIDDK. We thank the HUFS and AADM investigators. Sponsors or funders did not participate in the design and conduct of the study, collection, management, analysis, and interpretation of the data, or preparation, review, or approval of the manuscript. NR 18 TC 5 Z9 5 U1 0 U2 1 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD FAL PY 2011 VL 21 IS 4 BP 490 EP 494 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 867FH UT WOS:000298439800016 PM 22428356 ER PT J AU Tsuji, PA Naranjo-Suarez, S Carlson, BA Tobe, R Yoo, MH Davis, CD AF Tsuji, Petra A. Naranjo-Suarez, Salvador Carlson, Bradley A. Tobe, Ryuta Yoo, Min-Hyuk Davis, Cindy D. TI Deficiency in the 15 kDa Selenoprotein Inhibits Human Colon Cancer Cell Growth SO NUTRIENTS LA English DT Article DE HCT116 cells; HT29 cells; shRNA; selenium; cancer prevention ID SEP15; SELENIUM; PROTEIN; CARCINOMA; FAMILY; GENE AB Selenium is an essential micronutrient for humans and animals, and is thought to provide protection against some forms of cancer. These protective effects appear to be mediated, at least in part, through selenium-containing proteins (selenoproteins). Recent studies in a mouse colon cancer cell line have shown that the 15 kDa selenoprotein (Sep15) may also play a role in promoting colon cancer. The current study investigated whether the effects of reversing the cancer phenotype observed when Sep15 was removed in mouse colon cancer cells, were recapitulated in HCT116 and HT29 human colorectal carcinoma cells. Targeted down-regulation of Sep15 using RNAi technology in these human colon cancer cell lines resulted in similarly decreased growth under anchorage-dependent and anchorage-independent conditions. However, the magnitude of reduction in cell growth was much less than in the mouse colon cancer cell line investigated previously. Furthermore, changes in cell cycle distribution were observed, indicating a delayed release of Sep15 deficient cells from the G(0)/G(1) phase after synchronization. The potential mechanism by which human colon cancer C1 [Tsuji, Petra A.] NCI, Canc Prevent Fellowship Program, Rockville, MD 20892 USA. [Tsuji, Petra A.; Naranjo-Suarez, Salvador; Carlson, Bradley A.; Tobe, Ryuta; Yoo, Min-Hyuk] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Bethesda, MD 20892 USA. [Tsuji, Petra A.; Davis, Cindy D.] NCI, Nutr Sci Res Grp, Rockville, MD 20892 USA. [Tsuji, Petra A.] Towson Univ, Dept Biol Sci, Towson, MD 21252 USA. RP Tsuji, PA (reprint author), NCI, Canc Prevent Fellowship Program, Rockville, MD 20892 USA. EM ptsuji@towson.edu; naranjos@mail.nih.gov; carlsonb@mail.nih.gov; tober@mail.nih.gov; yoom@mail.nih.gov; davisci@mail.nih.gov FU Center for Cancer Research; Cancer Prevention Fellowship Program; Division of Cancer Prevention; National Cancer Institute; National Institutes of Health FX We would like to acknowledge the assistance with FACS analysis by Barbara Taylor from the Center for Cancer Research, National Cancer Institute. This study was funded by the Intramural Research Program of the Center for Cancer Research, the Cancer Prevention Fellowship Program and the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. NR 23 TC 11 Z9 14 U1 0 U2 6 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD SEP PY 2011 VL 3 IS 9 BP 805 EP 817 DI 10.3390/nu3090805 PG 13 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 864NW UT WOS:000298247900003 PM 22254125 ER PT J AU Nelson, PG AF Nelson, Phillip G. TI MARSHALL WARREN NIRENBERG 10 APRIL 1927 . 15 JANUARY 2010 SO PROCEEDINGS OF THE AMERICAN PHILOSOPHICAL SOCIETY LA English DT Biographical-Item C1 NICHHD, Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Nelson, PG (reprint author), NICHHD, Neurobiol Sect, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER PHILOSOPHICAL SOC PI PHILADELPHIA PA 104 SOUTH FIFTH ST, PHILADELPHIA, PA 19106-3387 USA SN 0003-049X J9 P AM PHILOS SOC JI Proc. Amer. Philos. Soc. PD SEP PY 2011 VL 155 IS 3 BP 367 EP 375 PG 9 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA 868OB UT WOS:000298531500012 ER PT J AU Resnik, DB AF Resnik, David B. TI Scientific Research and the Public Trust SO SCIENCE AND ENGINEERING ETHICS LA English DT Article DE Public trust; Science; Ethics; Policy; Public expectations ID BIOMEDICAL-RESEARCH; CLINICAL-RESEARCH; HEALTH RESEARCH; OF-INTEREST; COMMUNITY; PERCEPTION; ATTITUDES; OPINION AB This essay analyzes the concept of public trust in science and offers some guidance for ethicists, scientists, and policymakers who use this idea defend ethical rules or policies pertaining to the conduct of research. While the notion that public trusts science makes sense in the abstract, it may not be sufficiently focused to support the various rules and policies that authors have tried to derive from it, because the public is not a uniform body with a common set of interests. Well-focused arguments that use public trust to support rules or policies for the conduct of research should specify (a) which public is being referred to (e. g. the general public or a specific public, such as a particular community or group); (b) what this public expects from scientists; (c) how the rule or policy will ensure that these expectations are met; and (d) why is it important to meet these expectations. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, POB 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU National Institute of Environmental Health Science (NIEHS), National Institutes of Health (NIH) FX This research was supported by the Intramural Program of the National Institute of Environmental Health Science (NIEHS), National Institutes of Health (NIH). It does not represent the views of the NIEHS, NIH, or U.S. Government. NR 51 TC 15 Z9 15 U1 4 U2 19 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1353-3452 J9 SCI ENG ETHICS JI Sci. Eng. Ethics PD SEP PY 2011 VL 17 IS 3 BP 399 EP 409 DI 10.1007/s11948-010-9210-x PG 11 WC Ethics; Engineering, Multidisciplinary; History & Philosophy Of Science; Multidisciplinary Sciences; Philosophy SC Social Sciences - Other Topics; Engineering; History & Philosophy of Science; Science & Technology - Other Topics; Philosophy GA 865SY UT WOS:000298331800001 PM 20803259 ER PT J AU Schneider, JA Grodzinski, P Liang, XJ AF Schneider, Julie A. Grodzinski, Piotr Liang, Xing-Jie TI Cancer nanotechnology research in the United States and China: cooperation to promote innovation SO WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY LA English DT Review ID SCIENCE-AND-TECHNOLOGY; DEVELOPING-WORLD AB The application of nanotechnology to cancer research is a promising area for US-China cooperation. Cancer is a major public health burden in both countries, and progress in cancer nanotechnology research is increasing in several fields, including imaging, biomarker detection, and targeted drug delivery. The United States and China are international leaders in nanotechnology research, and have both launched national programs to support nanotechnology efforts in the recent past. The accelerating trend of co-authorship among US and Chinese nanotechnology researchers demonstrates that individual scientists already recognize the potential for cooperation, providing a strong platform for creating additional partnerships in pre-competitive research areas. Mechanisms that could help to enhance US-China cancer nanotechnology partnerships include: developing new programs for bi-directional training and exchange; convening workshops focused on specific scientific topics of high priority to both countries; and joint support of collaborative research projects by US and Chinese funders. In addition to the accelerating scientific progress, expanded cooperation will stimulate important dialog on regulatory, policy, and technical issues needed to lay the groundwork for US and Chinese scientists to move greater numbers of cancer nanotechnology applications into the clinic. (C) 2011 JohnWiley& Sons, Inc. WIREs Nanomed Nanobiotechnol 2011 3 441-448 DOI: 10.1002/wnan.149 C1 [Schneider, Julie A.] Embassy US, NCI, NIH, Beijing, Peoples R China. [Grodzinski, Piotr] NCI, NCI Alliance Nanotechnol Canc, Bethesda, MD 20892 USA. [Liang, Xing-Jie] Chinese Acad Sci, Natl Ctr Nanosci & Technol China, Beijing, Peoples R China. RP Schneider, JA (reprint author), Embassy US, NCI, NIH, Beijing, Peoples R China. EM schneidj@mail.nih.gov FU Chinese and Danish research funders FX For example, the Danish-Chinese Center for Molecular Nanoelectronics is jointly supported by Chinese and Danish research funders. See http://nano.ku.dk/english/research/dkcncenter/content/. NR 19 TC 1 Z9 1 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1939-5116 J9 WIRES NANOMED NANOBI JI Wiley Interdiscip. Rev.-Nanomed. Nanobiotechnol. PD SEP-OCT PY 2011 VL 3 IS 5 BP 441 EP 448 DI 10.1002/wnan.149 PG 8 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA 864RX UT WOS:000298258800002 PM 21656699 ER PT J AU Frankel, TL Zhang, L Burns, WR Zheng, Z Morgan, RA AF Frankel, Timothy L. Zhang, Ling Burns, William R. Zheng, Zhili Morgan, Richard A. TI The position of the AUG start codon in MFG-based gamma-retroviral vectors has a dramatic effect on translation-dependent protein expression SO JOURNAL OF GENE MEDICINE LA English DT Article DE Kozak sequence; mutational analysis; retroviral vector; TCR gene transfer; untranslated region ID GENE-THERAPY; MESSENGER-RNA; ENGINEERED LYMPHOCYTES; CANCER REGRESSION; INITIATOR CODON; IN-VIVO; CELLS; EFFICIENCY; SEQUENCES; MELANOMA AB Background In the past three decades, much advancement has been made in gamma-retroviral vector mediated gene transfer. One widely used vector design is based on the MFG vector, which uses the Moloney murine leukemia virus (MoMLV) transcriptional unit with extended packaging signals and insertion of the native MoMLV envelope splice acceptor region immediate 5' to the gene of interest inserted at an NcoI restriction site, which contains a translation start codon. Little is known about the impact of variations in start codon location within MFG-based vectors on protein expression. Methods To evaluate variation in start condo placement, a gene encoding a T-cell receptor (TCR) was cloned into an MFG-based vector and site-directed mutagenesis was used to move the gene away from the splice acceptor, as well as alter the frame with respect to the upstream start codon. Kozak consensus sequences were also added to the gene in an attempt to improve translation. Results Protein expression as measured by TCR surface expression and biological activity was substantially reduced when the gene was placed downstream and out-of-frame with the NcoI start codon. Expression was reestablished by mutation of the upstream start site, although at a reduced level. These findings were repeated with two other genes, a dominant negative TGF beta RII and the reporter protein dEGFP. Conclusions These finding emphasize the scanning rule for translation initiation and stress the importance of cloning genes of interest into or near the native NcoI start site of MFG-based retroviral vectors. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Frankel, Timothy L.; Zhang, Ling; Burns, William R.; Zheng, Zhili; Morgan, Richard A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), 10 Ctr Dr,Bldg 10-CRC,Rm 3-5940, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Arnold Mixon and Shawn Farid in the FACS laboratory and all members in the TIL laboratory at the Surgery Branch for providing technical support and maintenance of PBL and tumor cells from patients. This work is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The authors declare that they have no competing financial interests. NR 39 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD SEP PY 2011 VL 13 IS 9 BP 478 EP 486 DI 10.1002/jgm.1599 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 860MT UT WOS:000297953100004 PM 21796743 ER PT J AU McCune, B Schoch, C Root, HT Kageyama, SA Miadlikowska, J AF McCune, Bruce Schoch, Conrad Root, Heather T. Kageyama, Stacie A. Miadlikowska, Jolanta TI Geographic, climatic, and chemical differentiation in the Hypogymnia imshaugii species complex (Lecanoromycetes, Parmeliaceae) in North America SO BRYOLOGIST LA English DT Article DE Chemotypes; DNA sequences; Hypogymnia amplexa; lichenized ascomycetes; lichen substances; nonparametric multiplicative regression; Parmeliaceae ID LICHEN; PRIMERS; ECOLOGY; TERRAIN; FUNGAL; MODELS; DNA AB Hypogymnia imshaugii is one of the most common, conspicuous and morphologically variable epiphytic lichens of the Pacific coastal states and provinces. The species varies greatly in morphology and chemistry, suggesting multiple closely related species or one or more phenotypically plastic species. We sought to determine whether additional ecologically meaningful species might be present within the H. imshaugii complex. Improving our species concepts could potentially improve ecological inferences based on community sampling. Three relatively well-defined genetic groups and one residual group in the H. imshaugii complex were detected with haplotype networks based on the ITS locus; however, phylogenetic reconstructions on combined ITS, mtSSU, GPD1 and TEF1 loci did not reflect this pattern. At present, we have insufficient evidence to support defining any of these groups as new taxa. The four major chemotypes in H. imshaugii differed in frequency among the genetic groups. None of the genetic groups was, however, qualitatively uniform in chemotype. Only one chemotype occurred in a single genetic group, but several chemotypes occurred in that group. While broadly sympatric, each chemotype had a distinct geographic distribution, and each chemotype showed its own relationship to climate, as shown by regression of occurrences of chemotypes against climatic variables. The genetic variation detected within H. imshaugii did not correspond to geographic variation in morphology, chemistry, or climate. Within the broader H. imshaugii complex, we recommend treating H. amplexa as a synonym of H. imshaugii unless it can be more distinctly separated from the clinal variation in morphology, chemistry, or DNA sequences. In contrast to H. amplexa, however, H. inactiva and H. gracilis are both easily separated morphologically from H. imshaugii and do not intergrade with it. C1 [McCune, Bruce; Schoch, Conrad; Root, Heather T.; Kageyama, Stacie A.] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. [Schoch, Conrad] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Kageyama, Stacie A.] USDA ARS, Miles City, MT 59301 USA. [Miadlikowska, Jolanta] Duke Univ, Dept Biol, Durham, NC 27708 USA. RP McCune, B (reprint author), Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. EM Bruce.McCune@science.oregonstate.edu RI Schoch, Conrad/J-4825-2012 FU USDA Forest Service, Portland, Oregon; NSF [DEB-0228668] FX We thank curators of ASU, BM, COLO, DUKE, H, MIN, MONT, MONTU, NY, OSC, S, SBBG, UBC, UC, UCR, UPS, US, WIS, and WTU who kindly cooperated with loans and visits, Desiree Johnson and Sara McCune for laboratory assistance, Joey Spatafora for use of his laboratory facilities, and Chicita Culberson for her advice on lichen substances. Thanks to the many people provided specimens, including Curtis Bjork, Trevor Goward, Jill Grenon, Sarah Jovan, Dave Kofranek, Kerry Knudsen, Eric Peterson, Jennifer Riddell, Jim Riley, and Daphne Stone. We thank Sergio Perez-Ortega and an anonymous reviewer for their suggestions. This work was funded in part by a cooperative agreement with the USDA Forest Service, Portland, Oregon and by NSF Assembling the Tree of Life (ATOL) award DEB-0228668 to JM. NR 39 TC 3 Z9 4 U1 1 U2 10 PU AMER BRYOLOGICAL LICHENOLOGICAL SOC INC PI OMAHA PA C/O DR ROBERT S EGAN, SEC-TRES, ABLS, UNIV NEBRASKA OMAHA, DEPT BIOLOGY, OMAHA, NE 68182-0040 USA SN 0007-2745 J9 BRYOLOGIST JI Bryologist PD FAL PY 2011 VL 114 IS 3 BP 526 EP 544 DI 10.1639/0007-2745-114.3.526 PG 19 WC Plant Sciences SC Plant Sciences GA 855MO UT WOS:000297568700008 ER PT J AU Murugan, RN Park, JE Kim, EH Shin, SY Cheong, C Lee, KS Bang, JK AF Murugan, Ravichandran N. Park, Jung-Eun Kim, Eun-Hee Shin, Song Yub Cheong, Chaejoon Lee, Kyung S. Bang, Jeong Kyu TI Plk1-Targeted Small Molecule Inhibitors: Molecular Basis for Their Potency and Specificity SO MOLECULES AND CELLS LA English DT Review DE cancer therapy; inhibitors; Plk1; polo-box domain (PBD); polo-like kinase ID POLO-LIKE-KINASE; ADVANCED SOLID TUMORS; BOX DOMAIN; CANCER-CELLS; ANTITUMOR-ACTIVITY; ACTIVE METABOLITE; CATALYTIC DOMAIN; DOSE-ESCALATION; WILD-TYPE; IN-VIVO AB Members of polo-like kinases (collectively, Plks) have been identified in various eukaryotic organisms and play pivotal roles in cell proliferation. They are characterized by the presence of a distinct region of homology in the C-terminal noncatalytic domain, called polo-box domain (PBD). Among them, Plk1 and its functional homologs in other organisms have been best characterized because of its strong association with tumorigenesis. Plk1 is overexpressed in a wide spectrum of cancers in humans, and is thought to be an attractive anti-cancer drug target. Plk1 offers, within one molecule, two functionally different drug targets with distinct properties-the N-terminal catalytic domain and the C-terminal PBD essential for targeting the catalytic activity of Plk1 to specific subcellular locations. In this review, we focused on discussing the recent development of small-molecule and phosphopeptide inhibitors for their potency and specificity against Plk1. Our effort in understanding the binding mode of various inhibitors to Plk1 PBD are also presented. C1 [Murugan, Ravichandran N.; Kim, Eun-Hee; Cheong, Chaejoon; Bang, Jeong Kyu] Korea Basic Sci Inst, Div Magnet Resonance, Ochang 363883, South Korea. [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Shin, Song Yub] Chosun Univ, Sch Med, Dept Cellular & Mol Med, Kwangju 501759, South Korea. RP Bang, JK (reprint author), Korea Basic Sci Inst, Div Magnet Resonance, Ochang 363883, South Korea. EM bangjk@kbsi.re.kr FU Korea Basic Science Institute [F30601] FX The authors gratefully acknowledge financial support from the Korea Basic Science Institute's International Joint Research Program grant F30601 (J.K.B). NR 73 TC 33 Z9 33 U1 1 U2 17 PU KOREAN SOC MOLECULAR & CELLULAR BIOLOGY PI SEOUL PA 635-4, YUCKSAM-DONG, GANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1016-8478 EI 0219-1032 J9 MOL CELLS JI Mol. Cells PD SEP PY 2011 VL 32 IS 3 BP 209 EP 220 DI 10.1007/s10059-011-0126-3 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 856GQ UT WOS:000297627300001 PM 21809214 ER PT J AU Bevilacqua, L Doly, S Kaprio, J Maroteaux, L Coccaro, E Rose, RJ Virkkunen, M Goldman, D AF Bevilacqua, L. Doly, S. Kaprio, J. Maroteaux, L. Coccaro, E. Rose, R. J. Virkkunen, M. Goldman, D. TI 5-HT2B receptor and impulsivity SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th Congress of the European-College-of-Neuropsychopharmacology CY SEP 03-07, 2011 CL Paris, FRANCE SP European Coll Neuropsychopharmacol C1 [Bevilacqua, L.; Goldman, D.] NIAAA, NIH, Neurogenet Lab, Rockville, MD 20852 USA. [Doly, S.; Maroteaux, L.] INSERM, Inst Fer Mulin, UMR S 839, Paris, France. [Doly, S.] Univ Paris 06, Paris, France. [Kaprio, J.] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Coccaro, E.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Rose, R. J.] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA. [Virkkunen, M.] Inst Clin Med, Dept Psychiat, Helsinki, Finland. NR 1 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2011 VL 21 SU 3 BP S218 EP S218 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 852US UT WOS:000297383600091 ER PT J AU Holmes, A Martin, K Lederle, L Gaburro, S Debrouse, L Bravo, JA O'Connor, RM Cryan, JF Singewald, N Camp, M AF Holmes, A. Martin, K. Lederle, L. Gaburro, S. Debrouse, L. Bravo, J. A. O'Connor, R. M. Cryan, J. F. Singewald, N. Camp, M. TI Genetic variation driving fear and anxiety SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th Congress Meeting of the European-College-of-Neuropsychopharmacology CY SEP 03-07, 2011 CL Paris, FRANCE SP European Coll Neuropsychopharmacol ID EXTINCTION C1 [Holmes, A.; Martin, K.; Lederle, L.; Debrouse, L.; Camp, M.] NIAAA, Sect Behav Sci & Genet, A-6020 Bethesda, MD USA. [Gaburro, S.; Singewald, N.] Univ Innsbruck, Dept Pharmacol & Toxicol, Innsbruck, Austria. [Bravo, J. A.; O'Connor, R. M.; Cryan, J. F.] Natl Univ Ireland Univ Coll Cork, Dept Psychol & Brain Sci, Cork, Ireland. RI Cryan, John/A-6950-2013 OI Cryan, John/0000-0001-5887-2723 NR 3 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2011 VL 21 SU 3 BP S224 EP S224 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 852US UT WOS:000297383600106 ER PT J AU Leibenluft, E AF Leibenluft, E. TI Imaging the emotional brain in youth: implications for paediatric bipolar disorder and severe irritability SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th Congress Meeting of European-College-of-Neuropsychopharmacology CY SEP 03-07, 2011 CL Paris, FRANCE SP European Coll Neuropsychopharmacol C1 [Leibenluft, E.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2011 VL 21 SU 3 BP S205 EP S205 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 852US UT WOS:000297383600057 ER PT J AU Singewald, N Hauschild, M Sartori, SB Muigg, P Landgraf, R Hefner, K Camp, M Neumann, ID Holmes, A Whittle, N AF Singewald, N. Hauschild, M. Sartori, S. B. Muigg, P. Landgraf, R. Hefner, K. Camp, M. Neumann, I. D. Holmes, A. Whittle, N. TI Rodent models of impaired fear extinction: therapeutic approaches SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th Congress of the European-College-of-Neuropsychopharmacology CY SEP 03-07, 2011 CL Paris, FRANCE SP European Coll Neuropsychopharmacol C1 [Singewald, N.; Hauschild, M.; Sartori, S. B.; Muigg, P.; Whittle, N.] Inst Pharm, Innsbruck, Austria. [Whittle, N.] Ctr Mol Biosci Innsbruck, Dept Pharmacol & Toxicol, Innsbruck, Austria. [Singewald, N.; Hauschild, M.; Sartori, S. B.; Muigg, P.] CMBI, Innsbruck, Austria. [Landgraf, R.] Max Planck Inst Psychiat, Dept Behav Neuroendocrinol, D-80804 Munich, Germany. [Hefner, K.; Camp, M.] NIAAA, Lab Integrat Neurosci, Sect Behav Sci & Genet, Rockville, MD 20852 USA. [Neumann, I. D.] Univ Regensburg, Dept Behav & Mol Neuroendocrinol, Regensburg, Germany. [Holmes, A.] NIAAA, Lab Integrat Neurosci, Dept Behav & Mol Neuroendocrinol, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2011 VL 21 SU 3 BP S224 EP S224 PG 1 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 852US UT WOS:000297383600107 ER PT J AU Li, FY Lenardo, MJ Chaigne-Delalande, B AF Li, Feng-Yen Lenardo, Michael J. Chaigne-Delalande, Benjamin TI Loss of MAGT1 abrogates the Mg2+ flux required for T cell signaling and leads to a novel human primary immunodeficiency SO MAGNESIUM RESEARCH LA English DT Article DE immunology; signaling; magnesium; disease; MAGT1 ID LYMPHOCYTE-PROLIFERATION; MAGNESIUM HOMEOSTASIS; CALCIUM; 2ND-MESSENGER; TRANSDUCTION; TRANSPORTER; GROWTH AB Although Mg2+ has a well-recognized role as an essential cofactor for all ATP-binding enzymes, its role as a signaling ion, like Ca2+, has been controversial. A requirement for Mg2+ for optimal T lymphocyte stimulation was demonstrated more than 30 years ago, but the mechanism of its synergistic effect with Ca2+ in T cell activation remains elusive. Here, we summarize our recent discovery of a signaling role for Mg2+ in the T cell antigen receptor (TCR) signaling pathway from the study of a novel primary immunodeficiency, now named X-linked immunodeficiency with Mg2+ defect, EBV infection and neoplasia (XMEN). XMEN patients were found to have a deficiency in magnesium transporter 1 (MAGT1), an Mg2+-specific transporter, which leads to the absence of a TCR-stimulated Mg2+ flux and an attenuation of T cell activation. We further showed that this Mg2+ flux is required proximally for the temporal orchestration of phospholipase C-gamma 1 (PLC gamma 1) activation. Thus, our study not only provides a second messenger role for Mg2+ to explain its synergism with calcium in T cell signaling, it also identifies a potential extracellular therapeutic target for T cell-specific immunomodulation. C1 [Li, Feng-Yen; Lenardo, Michael J.; Chaigne-Delalande, Benjamin] NIAID, Mol Dev Sect, Lymphocyte Mol Genet Unit, Immunol Lab,NIH, Bethesda, MD 20892 USA. [Li, Feng-Yen] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94143 USA. RP Chaigne-Delalande, B (reprint author), NIAID, Mol Dev Sect, Lymphocyte Mol Genet Unit, Immunol Lab,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM chaignedelalab@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000769-11] NR 21 TC 18 Z9 18 U1 0 U2 7 PU JOHN LIBBEY EUROTEXT LTD PI MONTROUGE PA 127 AVE DE LA REPUBLIQUE, 92120 MONTROUGE, FRANCE SN 0953-1424 J9 MAGNESIUM RES JI Magnes. Res. PD SEP PY 2011 VL 24 IS 3 BP S109 EP S114 DI 10.1684/mrh.2011.0286 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 852NW UT WOS:000297365700003 PM 21983175 ER PT J AU Zhou, ZG Wang, YL Bryant, SH AF Zhou, Zhigang Wang, Yanli Bryant, Stephen H. TI Multi-conformation 3D QSAR study of benzenesulfonyl-pyrazol-ester compounds and their analogs as cathepsin B inhibitors SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Article DE Multi-conformation QSAR; 4D QSAR; Docking; CoMFA; CoMSIA; Cathepsin B; Inhibitors; Regression; Partial least squares; PubChem ID ATOM FORCE-FIELD; CYSTEINE PROTEASES; ALZHEIMERS-DISEASE; ACCURATE DOCKING; PLASMA-MEMBRANE; DRUG DESIGN; CANCER; BINDING; PROTEIN; IDENTIFICATION AB Cathepsin B has been found being responsible for many human diseases. Inhibitors of cathepsin B. a ubiquitous lysosomal cysteine protease, have been developed as a promising treatment for human diseases resulting from malfunction and over-expression of this enzyme. Through a high throughput screening assay, a set of compounds were found able to inhibit the enzymatic activity of cathepsin B. The binding structures of these active compounds were modeled through docking simulation. Three-dimensional (3D) quantitative structure-activity relationship (QSAR) models were constructed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on the docked structures of the compounds. Strong correlations were obtained for both CoMFA and CoMSIA models with cross-validated correlation coefficients (q(2)) of 0.605 and 0.605 and the regression correlation coefficients (r(2)) of 0.999 and 0.997, respectively. The robustness of these models was further validated using leave-one-out (LOO) method and training-test set method. The activities of eight (8) randomly selected compounds were predicted using models built from training set of compounds with prediction errors of less than 1 unit for most compounds in CoMFA and CoMSIA models. Structural features for compounds with improved activity are suggested based on the analysis of the CoMFA and CoMSIA contour maps and the property map of the protein ligand binding site. These results may help to provide better understanding of the structure-activity relationship of cathepsin B inhibitors and to facilitate lead optimization and novel inhibitor design. The multi-conformation method to build 3D QSAR is very effective approach to obtain satisfactory models with high correlation with experimental results and high prediction power for unknown compounds. Published by Elsevier Inc. C1 [Zhou, Zhigang; Wang, Yanli; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Zhou, ZG (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM zhougeor@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov FU NIH, NLM FX This research was supported by the Intramural Research Program of the NIH, NLM. The authors thank NIH Fells Editorial Board (FEB) for assistance on the manuscript reviewing and the developers of Pymol software for sharing the program to prepare the molecular figures used in the paper. NR 42 TC 4 Z9 4 U1 0 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1093-3263 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD SEP PY 2011 VL 30 BP 135 EP 147 DI 10.1016/j.jmgm.2011.06.013 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA 848ZM UT WOS:000297093600016 PM 21798778 ER PT J AU Beisel, CL Storz, G AF Beisel, Chase L. Storz, Gisela TI Discriminating tastes Physiological contributions of the Hfq-binding small RNA Spot 42 to catabolite repression SO RNA BIOLOGY LA English DT Editorial Material DE catabolite repression; Escherichia coli; feedforward loop; glucose; Hfq; regulatory circuit; small RNA; Spot 42 ID ESCHERICHIA-COLI; FEEDFORWARD LOOP; GENE-EXPRESSION; MOUSE INTESTINE; NETWORK; GLUCOSE; PROTEIN; SYSTEM AB Hfq-binding small RNAs (sRNAs) are critical regulators that form limited base-pairing interactions with target mRNAs in bacteria. These sRNAs have been linked to diverse environmental responses, yet little is known how Hfq-binding sRNAs participate in the regulatory networks associated with each response. We recently described how the Hfq-binding sRNA Spot 42 in Escherichia coli contributes to catabolite repression, a regulatory phenomenon that allows bacteria to consume some carbon sources over others. Spot 42 base pairs with numerous mRNAs encoding enzymes in central and secondary metabolism, redox balancing, and the uptake and consumption of non-preferred carbon sources. Many of the corresponding genes are transcriptionally activated by the Spot 42-repressor CRP, forming a regulatory circuit called a multi-output feedforward loop. We found that this loop influences both the steady-state levels and dynamics of gene regulation. In this article, we discuss how the CRP-Spot 42 feedforward loop is integrated into encompassing networks and how this loop may benefit enteric bacteria facing uncertain and changing nutrient conditions. C1 [Beisel, Chase L.; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD USA. RP Beisel, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD USA. EM beiselcl@mail.nih.gov RI Beisel, Chase/D-4823-2015; OI Beisel, Chase/0000-0003-0650-9943; Storz, Gisela/0000-0001-6698-1241 FU Intramural NIH HHS NR 28 TC 14 Z9 15 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1547-6286 J9 RNA BIOL JI RNA Biol. PD SEP-OCT PY 2011 VL 8 IS 5 BP 766 EP 770 DI 10.4161/rna.8.5.16024 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 842CX UT WOS:000296567200010 PM 21788732 ER PT J AU Kino, T Charmandari, E Chrousos, GP AF Kino, T. Charmandari, E. Chrousos, G. P. TI Glucocorticoid receptor: implications for rheumatic diseases SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Article DE glucocorticoid receptor; transcriptional activity; non-genomic action; splicing isoform; circadian rhythm; acetylation ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; TRANSCRIPTIONAL ACTIVITY; NUCLEAR EXPORT; CLINICAL-IMPLICATIONS; MESSENGER-RNA; BETA-ISOFORM; DNA-BINDING; SUBNUCLEAR TRAFFICKING; UNTRANSLATED REGION; ACTIVATION DOMAIN AB The glucocorticoid receptor (GR), a member of the nuclear receptor superfamily, mediates most of the known biologic effects of glucocorticoids. The human GR gene consists of 9 exons and expresses 2 alternative splicing isoforms, the GR alpha and GR beta. GR alpha is the classic receptor that binds to glucocorticoids and mediates most of the known actions of glucocorticoids, while GR beta does not bind to these hormones and exerts a dominant negative effect upon the GR alpha-induced transcriptional activity. Each of the two GR splice isoforms has 8 translational variants with specific transcriptional activity and tissue distribution. GR alpha consists of three subdomains, translocates from the cytoplasm into the nucleus upon binding to glucocorticoids, and regulates the transcriptional activity of numerous glucocorticoid-responsive genes either by binding to its cognate DNA sequences or by interacting with other transcription factors. In addition to these genomic actions, the GR also exerts rapid, non-genomic effects, which are possibly mediated by membrane-localised receptors or by translocation into the mitochondria. All these actions of the GR appear to play an important role in the regulation of the immune system. Specifically, the splicing variant GR beta may he involved in the pathogenesis of rheumatic diseases, while the circadian regulation of the GR activity via acetylation by the Clock transcription factor may have therapeutic implications for the preferential timing of glucocorticoid administration in autoimmune inflammatory disorders. C1 [Kino, T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH,Clin Res Ctr, Bethesda, MD 20892 USA. [Charmandari, E.; Chrousos, G. P.] Univ Athens, Sch Med, Dept Pediat 1, Aghia Sophia Childrens Hosp, GR-11527 Athens, Greece. [Charmandari, E.; Chrousos, G. P.] Acad Athens, Biomed Res Fdn, Div Endocrinol & Metab, Athens, Greece. RP Kino, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH,Clin Res Ctr, Bldg 10,Rm 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM kinot@mail.nih.gov RI Charmandari, Evangelia/B-6701-2011 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; University of Athens; Biomedical Research Foundation of the Academy of Athens, Athens, Greece FX The literary work of this article was funded partly by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, the University of Athens and the Biomedical Research Foundation of the Academy of Athens, Athens, Greece. NR 100 TC 11 Z9 11 U1 0 U2 3 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD SEP-OCT PY 2011 VL 29 IS 5 SU 68 BP S32 EP S41 PG 10 WC Rheumatology SC Rheumatology GA 837SK UT WOS:000296223300006 PM 22018181 ER PT J AU Haas, DW Kuritzkes, DR Ritchie, MD Amur, S Gage, BF Maartens, G Masys, D Fellay, J Phillips, E Ribaudo, HJ Freedberg, KA Petropoulos, C Manolio, TA Gulick, RM Haubrich, R Kim, P Dehlinger, M Abebe, R Telenti, A AF Haas, David W. Kuritzkes, Daniel R. Ritchie, Marylyn D. Amur, Shashi Gage, Brian F. Maartens, Gary Masys, Dan Fellay, Jacques Phillips, Elizabeth Ribaudo, Heather J. Freedberg, Kenneth A. Petropoulos, Christos Manolio, Teri A. Gulick, Roy M. Haubrich, Richard Kim, Peter Dehlinger, Marjorie Abebe, Rahel Telenti, Amalio CA Participants Workshop Pharmacogeno TI Pharmacogenomics of HIV Therapy: Summary of a Workshop Sponsored by the National Institute of Allergy and Infectious Diseases SO HIV CLINICAL TRIALS LA English DT Article DE HIV therapy; pharmacogenetics; pharmacogenomics; workshop ID SINGLE-NUCLEOTIDE POLYMORPHISMS; ANTIRETROVIRAL THERAPY; PLASMA-CONCENTRATIONS; HIV-1-INFECTED INDIVIDUALS; SLCO1B1 POLYMORPHISMS; EFAVIRENZ; HYPERSENSITIVITY; NEVIRAPINE; CYP2B6; ABACAVIR AB Approximately 1 million people in the United States and over 30 million worldwide are living with human immunodeficiency virus type 1 (HIV-1). While mortality from untreated infection approaches 100%, survival improves markedly with use of contemporary antiretroviral therapies (ART). In the United States, 25 drugs are approved for treating HIV-1, and increasing numbers are available in resource-limited countries. Safe and effective ART is a cornerstone in the global struggle against the acquired immunodeficiency syndrome. Variable responses to ART are due at least in part to human genetic variants that affect drug metabolism, drug disposition, and off-site drug targets. Defining effects of human genetic variants on HIV treatment toxicity, efficacy, and pharmacokinetics has far-reaching implications. In 2010, the National Institute of Allergy and Infectious Diseases sponsored a workshop entitled, Pharmacogenomics A Path Towards Personalized HIV Care. This article summarizes workshop objectives, presentations, discussions, and recommendations derived from this meeting. C1 [Haas, David W.; Ritchie, Marylyn D.; Masys, Dan] Vanderbilt Univ, Sch Med, Nashville, TN 37204 USA. [Kuritzkes, Daniel R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kuritzkes, Daniel R.; Freedberg, Kenneth A.] Harvard Univ, Sch Med, Boston, MA USA. [Amur, Shashi] US FDA, Silver Spring, MD USA. [Gage, Brian F.] Washington Univ, St Louis, MO USA. [Maartens, Gary] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Fellay, Jacques; Telenti, Amalio] Univ Lausanne, Lausanne, Switzerland. [Phillips, Elizabeth] Murdoch Univ, Royal Perth Hosp, Sir Charles Gairdner Hosp, Perth, WA, Australia. [Phillips, Elizabeth] Univ Western Australia, Perth, WA 6009, Australia. [Ribaudo, Heather J.] Harvard Univ, Sch Publ Hlth, Stat Data Anal Ctr, Boston, MA 02115 USA. [Freedberg, Kenneth A.] Massachussetts Gen Hosp, Boston, MA USA. [Petropoulos, Christos] Monogram Biosci, San Francisco, CA USA. [Manolio, Teri A.] Natl Genome Res Inst, NIH, Bethesda, MD USA. [Gulick, Roy M.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Haubrich, Richard] Univ Calif San Diego, San Diego, CA 92103 USA. [Kim, Peter; Dehlinger, Marjorie] NIAID, NIH, Bethesda, MD 20892 USA. [Abebe, Rahel] Henry M Jackson Fdn DAIDS, Bethesda, MD USA. RP Haas, DW (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Hlth 1 Hundred Oaks,719 Thompson Lane,, Nashville, TN 37204 USA. EM david.w.haas@vanderbilt.edu RI Ritchie, Marylyn/C-1114-2012; Maartens, Gary/F-3836-2014; Fellay, Jacques/A-6681-2009 OI Maartens, Gary/0000-0003-3080-6606; Fellay, Jacques/0000-0002-8240-939X FU National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C]; Bristol Myers Squibb; Boehringer Ingelheim; Merck; Gilead Sciences; Abbott; Avexa; Boehringer-Ingelheim; Gilead; GlaxoSmithKline (GSK); Oncolys; Roche; Siemens; Tobira; Vertex; ViiV; Viro-Statics; VIRxSYS; ViiV Australia; Merck Pty Ltd; Tibotec; Pfizer; Bristol-Myers Squibb; GSK; Monogram; GlaxoSmithKline; National Institute of Allergy and Infectious Diseases; NIH Office of AIDS Research; AIDS Clinical Trials Group [AI68636, AI38858, AI68634, AI38855]; Swiss National Foundation [324730-124943, HL097036, AI64086, AI36214, AI69432]; CHRP [MC08-SD-700, AI069472, HL065962, AI077505, AI42006, AI085736]; [AI069439]; [RR024975]; [AI54999]; [AI51966]; [RR024996]; [RR69419] FX The views expressed in written conference materials or publications and by speakers and moderators at HHS-sponsored conferences do not necessarily reflect the official policies of the US Department of Health and Human Services nor does mention of trade names, commercial practices, or organizations imply endorsement by the US Government. This project has been funded in whole or in part with federal funds from the National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272200800014C.; David W. Haas: Principal Investigator for research grants to Vanderbilt from Bristol Myers Squibb, Boehringer Ingelheim, Merck, Gilead Sciences. Daniel Kuritzkes: Consultant to and/or received research support from Abbott, Avexa, Boehringer-Ingelheim, Gilead, GlaxoSmithKline (GSK), Merck, Oncolys, Roche, Siemens, Tobira, Vertex, ViiV, Viro-Statics and VIRxSYS. Marylyn D. Ritchie: Consultant for Boehringer Ingelheim. Elizabeth Phillips: Honoraria and consulting fees from ViiV Australia, Merck Pty Ltd, and Tibotec. Christos Petropoulos: Employee of Monogram Biosciences, South San Francisco, CA. Roy M. Gulick: Ad hoc consultant for Bristol-Myers, Gilead, GSK, MedImmune, ViiV, and Virostatics, and as Principal Investigator for research grants to Weill Cornell from Merck and Pfizer. Richard Haubrich: Received honoraria or consultant fees from Abbott, Bristol-Myers Squibb, Gilead Sciences, GSK, Merck, Monogram, Pfizer, Roche, Tibotec, and ViiV and research support (to UCSD) from Abbott, GlaxoSmithKline, Merck, Pfizer, and ViiV. No potential conflicts of interest: Shashi Amur, Brian Gage, Gary Maartens, Dan Masys, Jacques Fellay, Heather J. Ribaudo, Kenneth A. Freedberg, Ten A. Manolio, Peter Kim, Marjorie Dehlinger, Rahel Abebe, and Amalio Telenti.; The workshop entitled, Pharmacogenomics - A Path Towards Personalized HIV Care, was supported by the National Institute of Allergy and Infectious Diseases and the NIH Office of AIDS Research. This work was supported in part by the AIDS Clinical Trials Group (grants AI68636, AI38858, AI68634, and AI38855). Participants were also supported by the following: grants AI069439, RR024975, and AI54999 (DWH); AI51966 (RMG); RR024996 (Cornell CTSC); RR69419 (CTU); Swiss National Foundation 324730-124943 (AT); HL097036 (BFG); AI64086, AI36214, AI69432, and CHRP MC08-SD-700 (RH); AI069472 (DK); HL065962 and AI077505 (MDR); AI42006 and AI085736 (KAF). NR 34 TC 8 Z9 9 U1 0 U2 4 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1528-4336 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD SEP-OCT PY 2011 VL 12 IS 5 BP 277 EP 285 DI 10.1310/hct1205-277 PG 9 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 847UT UT WOS:000296998700006 PM 22180526 ER PT J AU Kretschmer, D Nikola, N Durr, M Otto, M Peschel, A AF Kretschmer, D. Nikola, N. Duerr, M. Otto, M. Peschel, A. TI Staphylococcus epidermidis and Staphylococcus aureus Quorum sensing system agr regulates Formyl Peptide receptor 2 Ligand secretion and thereby the activation of the innate immune system SO INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the German-Society-for-Hygiene-and-Microbiology (DGHM) CY SEP 25-28, 2011 CL Essen, GERMANY SP German Soc Hygiene & Microbiol C1 [Kretschmer, D.; Nikola, N.; Duerr, M.; Peschel, A.] Interfak Inst Mikrobiol & Infekt Med, Sekt Zellulare & Mol Mikrobiol, Tubingen, Germany. [Otto, M.] NIH, Inst Allergy & Infect Dis, Bethesda, MD 20892 USA. [Otto, M.] Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4221 J9 INT J MED MICROBIOL JI Int. J. Med. Microbiol. PD SEP PY 2011 VL 301 SU 47 BP 63 EP 64 PG 2 WC Microbiology; Virology SC Microbiology; Virology GA 847RS UT WOS:000296990800226 ER PT J AU Grosz, M Schafer, D Chatterjee, SS Goerke, C Wolz, C Otto, M Fraunholz, M Sinha, B AF Grosz, M. Schaefer, D. Chatterjee, S. S. Goerke, C. Wolz, C. Otto, M. Fraunholz, M. Sinha, B. TI Small membrane-active peptides (PSM alpha) are required for phagosomal escape by Staphylococcus aureus in non-professional phagocytes SO INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the German-Society-for-Hygiene-and-Microbiology (DGHM) CY SEP 25-28, 2011 CL Essen, GERMANY SP German Soc Hygiene & Microbiol C1 [Grosz, M.; Schaefer, D.; Sinha, B.] Univ Wurzburg, Inst Hyg & Microbiol, Wurzburg, Germany. [Chatterjee, S. S.; Otto, M.] NIAID, Lab Human Bacterial Pathogenesis, NIH, Pathogen Mol Genet Sect, Bethesda, MD USA. [Goerke, C.; Wolz, C.] Inst Med Microbiol & Hyg, Tubingen, Germany. [Fraunholz, M.] Univ Wurzburg, Bioctr, Dept Microbiol, Wurzburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4221 J9 INT J MED MICROBIOL JI Int. J. Med. Microbiol. PD SEP PY 2011 VL 301 SU 47 BP 66 EP 66 PG 1 WC Microbiology; Virology SC Microbiology; Virology GA 847RS UT WOS:000296990800236 ER PT J AU Bloes, D Kretschmer, D Otto, M Peschel, A AF Bloes, D. Kretschmer, D. Otto, M. Peschel, A. TI Sensing of enterococcal pathogens by human formyl peptide receptors SO INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Meeting Abstract CT 63rd Annual Meeting of the German-Society-for-Hygiene-and-Microbiology (DGHM) CY SEP 25-28, 2011 CL Essen, GERMANY SP German Soc Hygiene & Microbiol C1 [Bloes, D.; Kretschmer, D.; Peschel, A.] Zellulare & Mol Mikrobiol, Interfakultares Inst Mikrobiol & Infektionsmed, Tubingen, Germany. [Otto, M.] NIAID, US Natl Inst Hlth, Lab Human Bacterial Pathogenesis, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4221 J9 INT J MED MICROBIOL JI Int. J. Med. Microbiol. PD SEP PY 2011 VL 301 SU 47 BP 90 EP 91 PG 2 WC Microbiology; Virology SC Microbiology; Virology GA 847RS UT WOS:000296990800326 ER PT J AU Namiki, T Coelho, SG Hearing, VJ AF Namiki, Takeshi Coelho, Sergio G. Hearing, Vincent J. TI NUAK2: an emerging acral melanoma oncogene SO ONCOTARGET LA English DT Article DE NUAK2; acral melanoma; migration; metastasis; oncogene ID ACTIVATED PROTEIN-KINASE; COMPARATIVE GENOMIC HYBRIDIZATION; HUMAN-MALIGNANT MELANOMA; CHRONIC MYELOGENOUS LEUKEMIA; ABL TYROSINE KINASE; CHRONIC MYELOID-LEUKEMIA; TUMOR-SUPPRESSOR LKB1; METASTATIC MELANOMA; CUTANEOUS MELANOMAS; BRAF MUTATIONS AB Recent technological advances in cancer genomics make it possible to dissect complicated genomic aberrations of melanomas. In particular, several specific genomic aberrations including 11q13 amplification and KIT aberrations have been identified in acral melanomas. We recently identified NUAK2 at 1q32 as a promising oncogene in acral melanomas and reported its significant roles in tumorigenesis in melanoma cells using both in vitro and in vivo analyses. NUAK2 as a member of the AMPK family has several intriguing aspects both as an oncogene and as a tumor suppressor gene. Here we review genomic aberrations of melanomas focusing on acral melanomas to emphasize the possible roles of NUAK2 in tumorigenesis in general and suggest that NUAK2 has pivotal roles in acral melanomagenesis. C1 [Namiki, Takeshi; Coelho, Sergio G.; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20814 USA. [Namiki, Takeshi] Yokohama Minato Red Cross Hosp, Dept Dermatol, Kanagawa 2310801, Japan. RP Namiki, T (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20814 USA. EM tnamderm@tmd.ac.jp FU NIH, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. NR 95 TC 6 Z9 6 U1 2 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP PY 2011 VL 2 IS 9 BP 695 EP 704 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 846BK UT WOS:000296872000006 PM 21911917 ER PT J AU Zimmerman, JJ Donaldson, A Barker, RM Meert, KL Harrison, R Carcillo, JA Anand, KJS Newth, CJL Berger, J Willson, DF Jack, R Nicholson, C Dean, JM AF Zimmerman, Jerry J. Donaldson, Amy Barker, Ruth M. Meert, Kathleen L. Harrison, Rick Carcillo, Joseph A. Anand, Kanwaljeet J. S. Newth, Christopher J. L. Berger, John Willson, Douglas F. Jack, Rhona Nicholson, Carol Dean, J. Michael CA Eunice Kennedy Shriver Natl Inst C Human Dev Collaborative Pediat Cri TI Real-time free cortisol quantification among critically ill children SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE adrenal insufficiency; centrifugal ultrafiltration; chemiluminescence immunoassay; children; cortisol; critical illness; critical illness related cortisol insufficiency (CIRCI); equilibrium dialysis; free cortisol; hydrocortisone; radioimmunoassay; relative adrenal insufficiency; total cortisol ID SERUM-FREE CORTISOL; INTENSIVE-CARE-UNIT; SEPTIC SHOCK; CORTICOSTEROID INSUFFICIENCY; ADRENAL-FUNCTION; EQUILIBRIUM DIALYSIS; SALIVARY CORTISOL; PLASMA-CORTISOL; SEPSIS; BINDING AB Objectives: Ascertainment of adrenal function assessing free rather that total cortisol may be beneficial for the diagnosis of critical illness-related cortisol insufficiency. We hypothesized that centrifugal ultrafiltration would provide timely free cortisol data that highly correlated with the gold standard, but logistically cumbersome, equilibrium dialysis technique when the free cortisol fractions were identically quantified by chemiluminescence immunoassay. We also hypothesized that free cortisol would correlate with illness severity in a large cohort of critically ill children. Design: Prospective, multi-institutional, observational cohort investigation. Setting: Seven pediatric intensive care units within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Patients: One hundred sixty-five critically ill children across the spectrum of illness severity. Interventions: Blood sampling. Measurements and Main Results: Time to derive plasma free cortisol concentrations after centrifugal ultrafiltration or equilibrium dialysis fractionation with chemiluminescence immunoassay was approximately 2 vs. approximately 24 hrs, respectively. Using centrifugal ultrafiltration, mean plasma free cortisol was 4.1 +/- 6.7 mu g/dL (median, 1.6 mu g/dL; range, 0.2-43.6 g/L), representing an average of 15.2 +/- 9.4% of total cortisol. Nearly 60% of subjects exhibited free cortisol <2 and 30% <0.8 mu g/dL, previously suggested threshold concentrations for defining critical illness-related cortisol insufficiency. Plasma-free cortisol concentrations comparing centrifugal ultrafiltration vs. equilibrium dialysis fractionation demonstrated a strong correlation (R(2) = 0.97). For free cortisol <2 mu g/dL, Bland-Altman analysis revealed minimal negative bias for the centrifugal ultrafiltration technique. Illness severity assessed by Pediatric Risk of Mortality III correlated moderately with free cortisol and percent total cortisol as free cortisol. Conclusions: Determination of centrifugal ultrafiltration fractionated free cortisol was fast and results correlated highly with equilibrium dialysis fractionated free cortisol. Many children exhibited free cortisol <2 and <0.8 mu g/dL but did not demonstrate clinical evidence of critical illness-related cortisol insufficiency. This study ascertains that real-time free cortisol quantification is feasible to potentially help guide clinical decisionmaking for cortisol replacement therapy in the pediatric intensive care unit. (Pediatr Crit Care Med 2011; 12:525-531) C1 [Zimmerman, Jerry J.; Barker, Ruth M.] Univ Washington, Sch Med, Dept Pediat, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Jack, Rhona] Univ Washington, Sch Med, Dept Lab Med, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Willson, Douglas F.] Univ Virginia, Dept Pediat, Childrens Hosp, Charlottesville, VA USA. [Donaldson, Amy; Dean, J. Michael] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Meert, Kathleen L.] Childrens Hosp Michigan, Dept Pediat, Detroit, MI 48201 USA. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Dept Anesthesiol & Crit Care Med, Los Angeles, CA 90027 USA. [Anand, Kanwaljeet J. S.] Le Bonheur Childrens Hosp, Dept Pediat, Memphis, TN USA. Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Berger, John] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Harrison, Rick] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Carcillo, Joseph A.] Childrens Hosp Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15213 USA. [Nicholson, Carol] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Bethesda, MD USA. RP Zimmerman, JJ (reprint author), Univ Washington, Sch Med, Dept Pediat, Seattle Childrens Hosp, Seattle, WA 98195 USA. EM jerry.zimmerman@seattlechildrens.org OI Anand, Kanwaljeet/0000-0001-6498-1483 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, Department of Health and Human Services [U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10HD050012, U01HD049934] FX This work was supported, in part, by cooperative agreements (U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10HD050012, and U01HD049934) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Department of Health and Human Services. NR 32 TC 16 Z9 16 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1529-7535 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD SEP PY 2011 VL 12 IS 5 BP 525 EP 531 DI 10.1097/PCC.0b013e3181fe4474 PG 7 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA 816KP UT WOS:000294598400013 PM 21057361 ER PT J AU Ardeljan, D Tuo, J Chan, CC AF Ardeljan, D. Tuo, J. Chan, C. -C. TI CARBOXYETHYLPYRROLE PLASMA BIOMARKERS IN AGE-RELATED MACULAR DEGENERATION SO DRUGS OF THE FUTURE LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; STRESS-INDUCED APOPTOSIS; OXIDATIVE STRESS; CHOROIDAL NEOVASCULARIZATION; COMPLEMENT ACTIVATION; RETINA PHOTORECEPTORS; DOCOSAHEXAENOIC ACID; VISUAL IMPAIRMENT; RPE LIPOFUSCIN; UNITED-STATES AB Age-related macular degeneration causes irreversible central blindness in people over the age of 50 and is increasing in prevalence among elderly populations. There are currently limited treatment options available for the exudative form of the disease and no formal treatments for the geographic atrophy form, aside from lifestyle change and incorporation of antioxidant supplements in the diet. As such, it is important to be able to assess high-risk AMD patients as early as possible in order to prescribe preventive measures. Carboxyethylpyrrole (CEP) is a promising plasma biomarker suited to this purpose. Both CEP immunoreactivity levels, as well as anti-CEP autoantibody titers, are significantly elevated in AMD patients and thus provide the potential to assess AMD susceptibility with approximately 80% accuracy when evaluated alongside genomic AMD markers. Moreover, strong evidence implicates CEP as functionally related to AMD pathogenesis, a role which must be explored further. This avenue of research will foster improved understanding of the disease itself and perhaps reveal better therapeutic targets and options. Further research into the role of CEP in AMD pathogenesis and the application of CEP as an AMD biomarker is merited. C1 [Ardeljan, D.; Tuo, J.; Chan, C. -C.] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, 10 Ctr Dr,10-10N103, Bethesda, MD 20892 USA. EM chanc@nel.nih.gov FU NEI FX This review was funded by the NEI Intramural Research Program. Only those individuals listed as authors contributed to writing this article. NR 56 TC 1 Z9 1 U1 0 U2 4 PU PROUS SCIENCE, SA-THOMSON REUTERS PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0377-8282 J9 DRUG FUTURE JI Drug Future PD SEP PY 2011 VL 36 IS 9 BP 713 EP 718 DI 10.1358/dof.2011.36.9.1678338 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 847CE UT WOS:000296948700007 ER PT J AU Brown, PN Chan, M Paley, L Betz, JM AF Brown, Paula N. Chan, Michael Paley, Lori Betz, Joseph M. TI Determination of Major Phenolic Compounds in Echinacea spp. Raw Materials and Finished Products by High-Performance Liquid Chromatography with Ultraviolet Detection: Single-Laboratory Validation Matrix Extension SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID RESPIRATORY-TRACT INFECTIONS; PLACEBO-CONTROLLED TRIAL; EXPERIMENTAL RHINOVIRUS COLDS; CAFFEIC ACID-DERIVATIVES; DOUBLE-BLIND; COMMON COLD; CICHORIC ACID; DIETARY-SUPPLEMENTS; RANDOMIZED-TRIAL; HPLC METHOD AB A method previously validated to determine caftaric acid, chlorogenic acid, cynarin, echinacoside, and cichoric acid in echinacea raw materials has been successfully applied to dry extract and liquid tincture products in response to North American consumer needs. Single-laboratory validation was used to assess the repeatability, accuracy, selectivity, LOD, LOQ, analyte stability (ruggedness), and linearity of the method, with emphasis on finished products. Repeatability precision for each phenolic compound was between 1.04 and 5.65% RSD, with HorRat values between 0.30 and 1.39 for raw and dry extract finished products. HorRat values for tinctures were between 0.09 and 1.10. Accuracy of the method was determined through spike recovery studies. Recovery of each compound from raw material negative control (ginseng) was between 90 and 114%, while recovery from the finished product negative control (maltodextrin and magnesium stearate) was between 97 and 103%. A study was conducted to determine if cichoric acid, a major phenolic component of Echinacea purpurea (L.) Moench and E. angustifolia DC, degrades during sample preparation (extraction) and HPLC analysis. No significant degradation was observed over an extended testing period using the validated method. C1 [Brown, Paula N.; Chan, Michael; Paley, Lori] British Columbia Inst Technol, Burnaby, BC V5G 3H2, Canada. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Brown, PN (reprint author), British Columbia Inst Technol, 3700 Willingdon Ave, Burnaby, BC V5G 3H2, Canada. EM paula_brown@bcit.ca FU Growing Forward Program; British Columbia Ministry of Agriculture and Lands and Agriculture; Agri-Food Canada FX This work was funded in part by the Growing Forward Program, a joint venture between the British Columbia Ministry of Agriculture and Lands and Agriculture and Agri-Food Canada. We gratefully acknowledge the National Institutes of Health Office of Dietary Supplements and the FDA for providing for the acquisition of authenticated plant material used in this study. NR 51 TC 8 Z9 8 U1 2 U2 15 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 J9 J AOAC INT JI J. AOAC Int. PD SEP-OCT PY 2011 VL 94 IS 5 BP 1400 EP 1410 DI 10.5740/jaoacint.11-142 PG 11 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 838DZ UT WOS:000296268300003 PM 22165004 ER PT J AU Kash, JC Walters, KA Davis, AS Sandouk, A Schwartzman, LM Jagger, BW Chertow, DS Qi, L Kuestner, RE Ozinsky, A Taubenberger, JK AF Kash, John C. Walters, Kathie-Anne Davis, A. Sally Sandouk, Aline Schwartzman, Louis M. Jagger, Brett W. Chertow, Daniel S. Qi, Li Kuestner, Rolf E. Ozinsky, Adrian Taubenberger, Jeffery K. TI Lethal Synergism of 2009 Pandemic H1N1 Influenza Virus and Streptococcus pneumoniae Coinfection Is Associated with Loss of Murine Lung Repair Responses SO MBIO LA English DT Article ID PNEUMOCOCCAL PNEUMONIA; PSEUDOMONAS-AERUGINOSA; BACTERIAL PNEUMONIA; EPITHELIAL REPAIR; MOUSE MODEL; MORTALITY; INFECTION; EXPANSION; BINDING; PROTEIN AB Secondary bacterial infections increase disease severity of influenza virus infections and contribute greatly to increased morbidity and mortality during pandemics. To study secondary bacterial infection following influenza virus infection, mice were inoculated with sublethal doses of 2009 seasonal H1N1 virus (NIH50) or pandemic H1N1 virus (Mex09) followed by inoculation with Streptococcus pneumoniae 48 h later. Disease was characterized by assessment of weight loss and survival, titration of virus and bacteria by quantitative reverse transcription-PCR (qRT-PCR), histopathology, expression microarray, and immunohistochemistry. Mice inoculated with virus alone showed 100% survival for all groups. Mice inoculated with Mex09 plus S. pneumoniae showed severe weight loss and 100% mortality with severe alveolitis, denuded bronchiolar epithelium, and widespread expression of apoptosis marker cleaved caspase 3. In contrast, mice inoculated with NIH50 plus S. pneumoniae showed increased weight loss, 100% survival, and slightly enhanced lung pathology. Mex09-S. pneumoniae coinfection also resulted in increased S. pneumoniae replication in lung and bacteremia late in infection. Global gene expression profiling revealed that Mex09-S. pneumoniae coinfection did not induce significantly more severe inflammatory responses but featured significant loss of epithelial cell reproliferation and repair responses. Histopathological examination for cell proliferation marker MCM7 showed significant staining of airway epithelial cells in all groups except Mex09-S. pneumoniae-infected mice. This study demonstrates that secondary bacterial infection during 2009 H1N1 pandemic virus infection resulted in more severe disease and loss of lung repair responses than did seasonal influenza viral and bacterial coinfection. Moreover, this study provides novel insights into influenza virus and bacterial coinfection by showing correlation of lethal outcome with loss of airway basal epithelial cells and associated lung repair responses. IMPORTANCE Secondary bacterial pneumonias lead to increased disease severity and have resulted in a significant percentage of deaths during influenza pandemics. To understand the biological basis for the interaction of bacterial and viral infections, mice were infected with sublethal doses of 2009 seasonal H1N1 and pandemic H1N1 viruses followed by infection with Streptococcus pneumoniae 48 h later. Only infection with 2009 pandemic H1N1 virus and S. pneumoniae resulted in severe disease with a 100% fatality rate. Analysis of the host response to infection during lethal coinfection showed a significant loss of responses associated with lung repair that was not observed in any of the other experimental groups. This group of mice also showed enhanced bacterial replication in the lung. This study reveals that the extent of lung damage during viral infection influences the severity of secondary bacterial infections and may help explain some differences in mortality during influenza pandemics. C1 [Kash, John C.; Davis, A. Sally; Sandouk, Aline; Schwartzman, Louis M.; Jagger, Brett W.; Chertow, Daniel S.; Qi, Li; Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Walters, Kathie-Anne; Kuestner, Rolf E.; Ozinsky, Adrian] Inst Syst Biol, Seattle, WA USA. RP Kash, JC (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kashj@niaid.nih.gov OI Davis, Anne/0000-0001-5711-3936 FU NIH; NIAID; Defense Threat Reduction Agency [HDTRA-1-08-C-0023] FX This work was supported by the Intramural Research Program of the NIH and the NIAID. K.-A.W., R.E.K., and A.O. were supported by Defense Threat Reduction Agency contract HDTRA-1-08-C-0023. NR 33 TC 29 Z9 30 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2011 VL 2 IS 5 AR e00172-11 DI 10.1128/mBio.00172-11 PG 9 WC Microbiology SC Microbiology GA 845SZ UT WOS:000296844300009 ER PT J AU Koli, P Sudan, S Fitzgerald, D Adhya, S Kar, S AF Koli, Preeti Sudan, Sudhanshu Fitzgerald, David Adhya, Sankar Kar, Sudeshna TI Conversion of Commensal Escherichia coli K-12 to an Invasive Form via Expression of a Mutant Histone-Like Protein SO MBIO LA English DT Article ID BH3-ONLY PROTEINS; IN-VITRO; BACTERIAL TRANSLOCATION; EPITHELIAL-CELLS; GAL PROMOTERS; DNA; TRANSCRIPTION; HU; APOPTOSIS; STRAINS AB The HU alpha(E38K,V42L) mutant of the bacterial histone-like protein HU causes a major change in the transcription profile of the commensal organism Escherichia coli K-12 (Kar S, Edgar R, Adhya S, Proc. Natl. Acad. Sci. U. S. A. 102: 16397-16402, 2005). Among the upregulated genes are several related to pathogenic interactions with mammalian cells, as evidenced by the expression of curli fibers, Ivy, and hemolysin E. When E. coli K-12/HU alpha(E38K,V42L) was added to Int-407 cells, there was host cell invasion, phagosomal disruption, and intracellular replication. The invasive trait was also retained in a murine ileal loop model and intestinal explant assays. In addition to invasion, the internalized bacteria caused a novel subversion of host cell apoptosis through modification and regulation of the BH3-only proteins Bim(EL) and Puma. Changes in the transcription profile were attributed to positive supercoiling of DNA leading to the altered availability of relevant promoters. Using the E. coli K-12/HU alpha(E38K), V42L variant as a model, we propose that traditional commensal E. coli can adopt an invasive lifestyle through reprogramming its cellular transcription, without gross genetic changes. IMPORTANCE Escherichia coli K-12 is well established as a benign laboratory strain and a human intestinal commensal. Recent evidences, however, indicate that the typical noninvasive nature of resident E. coli can be reversed under specific circumstances even in the absence of any major genomic flux. We previously engineered an E. coli strain with a mutant histone-like protein, HU, which exhibited significant changes in nucleoid organization and global transcription. Here we showed that the changes induced by the mutant HU have critical functional consequences: from a strict extracellular existence, the mutant E. coli adopts an almost obligate intracellular lifestyle. The internalized E. coli exhibits many of the prototypical characteristics of traditional intracellular bacteria, like phagosomal escape, intracellular replication, and subversion of host cell apoptosis. We suggest that E. coli K-12 can switch between widely divergent lifestyles in relation to mammalian host cells by reprogramming its cellular transcription program and without gross changes in its genomic content. C1 [Fitzgerald, David; Adhya, Sankar] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Koli, Preeti; Sudan, Sudhanshu; Kar, Sudeshna] Inst Mol Med, New Delhi, India. RP Adhya, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM sadhya@helix.nih.gov; sudeshnak@immindia.org FU NIH, National Cancer Institute, Center for Cancer Research; Department of Biotechnology, Government of India [BT/PR11351/30/137/2008] FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and in part by the Department of Biotechnology, Government of India (BT/PR11351/30/137/2008). NR 45 TC 3 Z9 3 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD SEP-OCT PY 2011 VL 2 IS 5 AR e00182 DI 10.1128/mBio.00182-11 PG 13 WC Microbiology SC Microbiology GA 845SZ UT WOS:000296844300014 ER PT J AU Sholom, S DeWitt, R Simon, SL Bouville, A McKeever, SWS AF Sholom, S. DeWitt, R. Simon, S. L. Bouville, A. McKeever, S. W. S. TI Emergency dose estimation using optically stimulated luminescence from human tooth enamel SO RADIATION MEASUREMENTS LA English DT Article DE Luminescence; Emergency dosimetry; OSL; Teeth; Fading; Radiation sensitivity ID OSL; DOSIMETRY; EXPOSURE; TRIAGE; TEETH; EPR AB Human teeth were studied for potential use as emergency Optically Stimulated Luminescence (OSL) dosimeters. By using multiple-teeth samples in combination with a custom-built sensitive OSL reader, (60)Co-equivalent doses below 0.64 Gy were measured immediately after exposure with the lowest value being 27 mGy for the most sensitive sample. The variability of OSL sensitivity, from individual to individual using multiple-teeth samples, was determined to be 53%. X-ray and beta exposure were found to produce OSL curves with the same shape that differed from those due to ultraviolet (UV) exposure: as a result, correlation was observed between OSL signals after X-ray and beta exposure and was absent if compared to OSL signals after UV exposure. Fading of the OSL signal was "typical" for most teeth with just a few of incisors showing atypical behavior. Typical fading dependences were described by a bi-exponential decay function with "fast" (decay time around of 12 min) and "slow" (decay time about 14 h) components. OSL detection limits, based on the techniques developed to-date, were found to be satisfactory from the point of view of medical triage requirements if conducted within 24 h of the exposure. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Sholom, S.] Oklahoma State Univ, Radiat Dosimetry Lab, Stillwater, OK 74074 USA. [Simon, S. L.; Bouville, A.] NCI, NIH, Bethesda, MD 20892 USA. RP Sholom, S (reprint author), Oklahoma State Univ, Radiat Dosimetry Lab, Venture I,Suite 201,1110 S Innovat Way Dr, Stillwater, OK 74074 USA. EM sergey.sholom@okstate.edu RI Rastelli, Marcio/B-8034-2011; OI DeWitt, Regina/0000-0003-2876-5489 FU National Institute of Allergy and Infectious Diseases (NIAID) [Y2-AI-5077]; National Cancer Institute (NCI) [Y3-CO-5117] FX This work was supported by the Intra-Agency agreement between the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, NIAID agreement #Y2-AI-5077 and NCI agreement #Y3-CO-5117. NR 10 TC 13 Z9 13 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1350-4487 J9 RADIAT MEAS JI Radiat. Meas. PD SEP PY 2011 VL 46 IS 9 SI SI BP 778 EP 782 DI 10.1016/j.radmeas.2011.03.008 PG 5 WC Nuclear Science & Technology SC Nuclear Science & Technology GA 835MA UT WOS:000296039300009 PM 21949479 ER PT J AU Redon, CE Nakamura, AJ Gouliaeva, K Rahman, A Blakely, WF Bonner, WM AF Redon, Christophe E. Nakamura, Asako J. Gouliaeva, Ksenia Rahman, Arifur Blakely, William F. Bonner, William M. TI Q(gamma-H2AX), an analysis method for partial-body radiation exposure using gamma-H2AX in non-human primate lymphocytes SO RADIATION MEASUREMENTS LA English DT Article DE Biological dosimetry; gamma-H2AX; Q(gamma-H2AX); F gamma-H2AX; Rhesus macaque (Macaca mulatta); Lymphocytes; Co-60 gamma-rays; Ionizing radiation; Partial-body exposure ID DOUBLE-STRAND BREAKS; BLOOD-LYMPHOCYTES; IN-VIVO; DNA; DOSIMETRY; POLY(ADP-RIBOSE); BIOMARKER; REPAIR; ASSAY AB We previously used the gamma-H2AX assay as a biodosimeter for total-body irradiation (TBI) exposure (gamma-rays) in a rhesus macaque (Macaca mulatta) model. Utilizing peripheral blood lymphocytes and plucked hairs, we obtained statistically significant gamma-H2AX responses days after total-body exposure to 1-8.5 Gy (Co-60 gamma-rays at 55 cGy min(-1)). Here, we introduce a partial-body exposure analysis method, Q(gamma-H2AX), which is based on the number of gamma-H2AX foci per damaged cells as evident by having one or more gamma-H2AX foci per cell. Results from the rhesus monkey TBI study were used to establish Q(gamma-H2AX) dose-response calibration curves to assess acute partial-body exposures. gamma-H2AX foci were detected in plucked hairs for several days after in vivo irradiation demonstrating this assay's utility for dose assessment in various body regions. The quantitation of gamma-H2AX may provide a robust biodosimeter for analyzing partial-body exposures to ionizing radiation in humans. Published by Elsevier Ltd. C1 [Redon, Christophe E.; Nakamura, Asako J.; Gouliaeva, Ksenia; Bonner, William M.] NCI, NIH, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Rahman, Arifur; Blakely, William F.] Uniformed Serv Univ Hlth Sci, Armed Forces Radiobiol Res Inst, Bethesda, MD 20889 USA. RP Redon, CE (reprint author), NCI, NIH, Mol Pharmacol Lab, Bethesda, MD 20892 USA. EM redonc@mail.nih.gov FU NIAID; National Cancer Institute, Center for Cancer Research, NIH; Armed Forces Radiobiology Research Institute [BD-13 (RBB4AR)] FX This research was supported by the NIAID Radiation/Nuclear Countermeasures Program, the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH and the Armed Forces Radiobiology Research Institute under research work unit number BD-13 (RBB4AR). Views presented in this paper are those of the authors; no endorsement by the Department of Defense has been give or should be inferred. The authors gratefully acknowledge Dr. Terry C. Pellmar (Silver Spring, MD) and Dr. Andrea L. DiCarlo-Cohen (NIAID) for their efforts to enable these studies, the assistance of the AFRRI Veterinarian, Dr. Jennifer Mitchell, and her colleagues in AFRRI's Veterinary Science Department, radiation exposure and dosimetry support from AFRRI's dosimetrist, Dr. Vitaly Nagy, and his colleagues in AFRRI's Radiation Science Department, professional assistance in the rhesus macaque radiation model from Drs. Natalia I. Ossetrova and Gregory L King, and technical support by David J. Sandgren, HM2 Sergio Gallego, Katya Kranopolsky, and Yvonne Eudy. We also thank Dr. O. Sedelnikova, NCI, for critical reading of the manuscript. NR 21 TC 15 Z9 15 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1350-4487 J9 RADIAT MEAS JI Radiat. Meas. PD SEP PY 2011 VL 46 IS 9 SI SI BP 877 EP 881 DI 10.1016/j.radmeas.2011.02.017 PG 5 WC Nuclear Science & Technology SC Nuclear Science & Technology GA 835MA UT WOS:000296039300028 PM 21949480 ER PT J AU Wilkins, RC Romm, H Oestreicher, U Marro, L Yoshida, MA Suto, Y Prasanna, PGS AF Wilkins, Ruth C. Romm, Horst Oestreicher, Ursula Marro, Leonora Yoshida, Mitsuaki A. Suto, Y. Prasanna, Pataje G. S. TI Biological dosimetry by the triage dicentric chromosome assay - Further validation of international networking SO RADIATION MEASUREMENTS LA English DT Article DE Biological dosimetry; Dicentric chromosome assay; International networking; Emergency response; Triage ID CYTOGENETIC DOSIMETRY; BIODOSIMETRY; CASUALTIES; LABORATORIES; EVENTS AB Biological dosimetry is an essential tool for estimating radiation doses received to personnel when physical dosimetry is not available or inadequate. The current preferred biodosimetry method is based on the measurement of radiation-specific dicentric chromosomes in exposed individuals' peripheral blood lymphocytes. However, this method is labor-, time- and expertise-demanding. Consequently, for mass casualty applications, strategies have been developed to increase its throughput. One such strategy is to develop validated cytogenetic biodosimetry laboratory networks, both national and international. In a previous study, the dicentric chromosome assay (DCA) was validated in our cytogenetic biodosimetry network involving five geographically dispersed laboratories. A complementary strategy to further enhance the throughput of the DCA among inter-laboratory networks is to use a triage DCA where dose assessments are made by truncating the labor-demanding and time-consuming metaphase spread analysis to 20 50 metaphase spreads instead of routine 500 - 1000 metaphase spread analysis. Our laboratory network also validated this triage DCA, however, these dose estimates were made using calibration curves generated in each laboratory from the blood samples irradiated in a single laboratory. In an emergency situation, dose estimates made using pre-existing calibration curves which may vary according to radiation type and dose rate and therefore influence the assessed dose. Here, we analyze the effect of using a pre-existing calibration curve on assessed dose among our network laboratories. The dose estimates were made by analyzing 1000 metaphase spreads as well as triage quality scoring and compared to actual physical doses applied to the samples for validation. The dose estimates in the laboratory partners were in good agreement with the applied physical doses and determined to be adequate for guidance in the treatment of acute radiation syndrome. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Wilkins, Ruth C.; Marro, Leonora] Hlth Canada, Ottawa, ON K1A 0K9, Canada. [Romm, Horst; Oestreicher, Ursula] Bundesamt Strahlenschutz, D-38226 Salzgitter, Germany. [Yoshida, Mitsuaki A.] NIRS, Res Ctr Radiat Emergency Med, Dept Dose Assessment, Biol Dosimetry Sect,Inage Ku, Chiba 2638555, Japan. [Suto, Y.] Hirosaki Univ, Grad Sch Hlth Sci, Inst Radiat Emergency Med, Dept Radiat Biol, Aomori 0368564, Japan. [Prasanna, Pataje G. S.] NCI, Div Canc Treatment & Diag, Radiat Res Program, Bethesda, MD 20892 USA. RP Wilkins, RC (reprint author), Hlth Canada, Ottawa, ON K1A 0K9, Canada. EM Ruth.Wilkins@hc-sc.gc.ca OI Romm, Horst/0000-0003-4921-685X FU National Institute of Allergies and Infectious Diseases, NIH; Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences; National Cancer Institute; Chemical, Biological, Radiological, Nuclear and Explosive Research and Technology Initiative FX Financial support was provided by an interagency agreement between the National Institute of Allergies and Infectious Diseases, NIH and the Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences. National Cancer Institute's Radiation Research Program in part supported manuscript preparation. Work at Bureau Health Canada was partially supported by the Chemical, Biological, Radiological, Nuclear and Explosive Research and Technology Initiative. Special thanks to C. Ferrarotto (Health Canada), S. Wenzel, and D. Westfahl (BFS) and M. Akiyama (NIRS) for technical assistance. NR 20 TC 17 Z9 17 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1350-4487 J9 RADIAT MEAS JI Radiat. Meas. PD SEP PY 2011 VL 46 IS 9 SI SI BP 923 EP 928 DI 10.1016/j.radmeas.2011.03.012 PG 6 WC Nuclear Science & Technology SC Nuclear Science & Technology GA 835MA UT WOS:000296039300037 PM 21949482 ER PT J AU Vorspan, F Guillem, E Bloch, V Bellais, L Sicot, R Noble, F Lepine, JP Gorelick, DA AF Vorspan, F. Guillem, E. Bloch, V. Bellais, L. Sicot, R. Noble, F. Lepine, J. -P. Gorelick, D. A. TI Cannabis withdrawal syndrome in patients with cannabis dependence only, and in patients with cannabis and opioid dependence SO ENCEPHALE-REVUE DE PSYCHIATRIE CLINIQUE BIOLOGIQUE ET THERAPEUTIQUE LA French DT Article DE Withdrawal; Cannabis; Dependence; Opiates ID ABSTINENCE SYMPTOMS; MARIJUANA USE; DRUG-USERS; MORPHINE; OPIATE; MICE; DELTA(9)-TETRAHYDROCANNABINOL; SENSITIZATION; ADOLESCENTS; ADDICTION AB Background. - The cannabis withdrawal syndrome occurs after cannabis cessation in more than 50% of dependent smokers. But although opioid-dependent patients are more frequently cannabis users and cannabis-dependent than the general population, the frequency and phenomenology of cannabis withdrawal symptoms in this specific population is unknown. Our hypothesis was that cannabis-dependent patients with current opioid dependence would experience the same withdrawal syndrome after cannabis cessation. Objective. - To describe cannabis withdrawal symptoms in cannabis-only dependent patients and in cannabis-dependent patients with current opioid dependence. Methods. - Using retrospective interviews, we evaluated the number and duration of six cannabis withdrawal symptoms in two groups: 56 cannabis-dependent patients without and 43 cannabis dependent patients with current opioid dependence. Cannabis and opioid dependence diagnoses were defined with DSM IV criteria using the MINI structured interview. Results. - The two groups were not different in terms of age of onset of cannabis use, and number of cannabis joints smoked at the time of the cannabis cessation attempt. The frequency of a cannabis withdrawal syndrome (defined as at least two different symptoms) did not differ in the two groups (65%). Neither was the proportion of subjects with the following symptoms: appetite or weight loss (30.8%), irritability (45.1%), anxiety (56%), aggression (36.3%) and restlessness (45.1%). Patients with cannabis dependence and current opioid dependence were more likely to report sleep disturbances (79.1 vs. 53.6%, chi(2) = 6.91, P = 0.007). The median duration of this cannabis withdrawal syndrome was 20 days post-cessation. Conclusion. - This is, to our knowledge, the first study describing cannabis withdrawal syndrome in cannabis-dependent patients with current opioid dependence. These patients experience a cannabis withdrawal syndrome as often as cannabis-only dependent subjects, but describe more frequently sleep disturbances. This high rate of sleep disturbances may cause relapse to cannabis use. (C) L'Encephale, Paris, 2010. C1 [Vorspan, F.; Guillem, E.; Bloch, V.; Bellais, L.; Sicot, R.; Lepine, J. -P.] Hop Fernand Widal, AP HP, Psychiat Serv, F-75475 Paris 10, France. [Vorspan, F.; Guillem, E.; Bloch, V.; Bellais, L.; Noble, F.; Lepine, J. -P.] Univ Paris 07, Inserm U705, CNRS UMR 7157, F-75010 Paris, France. [Gorelick, D. A.] NIH, NIDA Intramural Res Program, Baltimore, MD USA. RP Vorspan, F (reprint author), Hop Fernand Widal, AP HP, Psychiat Serv, 200 Rue Faubourg St Denis, F-75475 Paris 10, France. EM florence.vorspan@lrb.aphp.fr OI Vorspan, Florence/0000-0001-5168-3727 NR 38 TC 1 Z9 1 U1 4 U2 15 PU MASSON EDITEUR PI MOULINEAUX CEDEX 9 PA 21 STREET CAMILLE DESMOULINS, ISSY, 92789 MOULINEAUX CEDEX 9, FRANCE SN 0013-7006 J9 ENCEPHALE JI Enceph.-Rev. Psychiatr. Clin. Biol. Ther. PD SEP PY 2011 VL 37 IS 4 BP 266 EP 272 DI 10.1016/j.encep.2010.12.007 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 844NG UT WOS:000296753700004 PM 21981886 ER PT J AU Cuburu, N Chackerian, B AF Cuburu, Nicolas Chackerian, Bryce TI Genital delivery of virus-like particle and pseudovirus-based vaccines SO EXPERT REVIEW OF VACCINES LA English DT Editorial Material DE genital delivery; HPV; intravaginal; mucosal immunity; pseudovirus; STI; virus-like particle ID MEMORY T-CELLS; LANGERHANS CELLS; DENDRITIC CELLS; INFECTION; ACTIVATION; RESPONSES; IMMUNIZATION; CARRAGEENAN; IMMUNITY; TISSUE C1 [Chackerian, Bryce] Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Cuburu, Nicolas] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Chackerian, B (reprint author), Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. EM bchackerian@salud.unm.edu FU NCI NIH HHS [RC2 CA148982]; NIAID NIH HHS [U19 AI084081] NR 18 TC 3 Z9 3 U1 0 U2 3 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD SEP PY 2011 VL 10 IS 9 BP 1245 EP 1248 DI 10.1586/ERV.11.104 PG 4 WC Immunology SC Immunology GA 835KD UT WOS:000296034400001 PM 21919611 ER PT J AU Harunaga, JS Yamada, KM AF Harunaga, Jill S. Yamada, Kenneth M. TI Cell-matrix adhesions in 3D SO MATRIX BIOLOGY LA English DT Review DE Cell adhesion; 3D Extracellular matrix; Cytoskeleton; Integrin; Vinculin; Collagen ID 3-DIMENSIONAL COLLAGEN MATRICES; FOCAL ADHESIONS; CORNEAL FIBROBLASTS; MIGRATION; DYNAMICS; TENSION; FORCE; DIFFERENTIATION; FIBRONECTIN; RECRUITMENT AB Cells in a three-dimensional (3D) extracellular matrix environment often display different properties and behavior compared to cells cultured on a two-dimensional (2D) substrate. Recent studies characterizing the cell-matrix adhesions formed by cells within a 3D matrix have arrived at contradictory conclusions regarding the presence and composition of adhesions. Here we review this literature, and provide a comparative compilation of information found in published studies from the 3D cell-matrix adhesion field in order to identify shared and divergent conclusions and conceptually important areas that require further research. Although there is a general consensus that discrete cell-matrix adhesions exist in various 3D matrix environments, there are specific exceptions, particularly in cells undergoing amoeboid migration. There are also technical issues to consider when imaging adhesions in 3D matrix; for example, over-expression of a cytoskeletal cell adhesion component can potentially cloud the visualization of adhesions and even alter the mode of cell migration. Properties such as stiffness and local matrix topography may also affect the composition of cell-matrix adhesions. For example, even though cells contain integrin-based 3D adhesions, there can be substantial variability within these adhesions in the presence of force-dependent cytoskeletal components such as vinculin. These new findings and ideas provide promising new leads for understanding the regulation and function of cell-matrix adhesions in 3D matrix. Published by Elsevier B.V. C1 [Harunaga, Jill S.; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Yamada, KM (reprint author), 30 Convent Dr,Bldg 30,Room 426, Bethesda, MD 20892 USA. EM jill.harunaga@nih.gov; kenneth.yamada@nih.gov OI Yamada, Kenneth/0000-0003-1512-6805 FU NIH, NIDCR FX We thank Andrew Doyle, Emily Joo, and Ryan Petrie for helpful comments on the manuscript, Shelagh Johnson for editing, and the Intramural Research Program of the NIH, NIDCR for support. NR 41 TC 100 Z9 101 U1 5 U2 109 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD SEP-OCT PY 2011 VL 30 IS 7-8 BP 363 EP 368 DI 10.1016/j.matbio.2011.06.001 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 843QY UT WOS:000296688500001 PM 21723391 ER PT J AU Ida-Yonemochi, H Satokata, I Ohshima, H Sato, T Yokoyama, M Yamada, Y Saku, T AF Ida-Yonemochi, Hiroko Satokata, Ichiro Ohshima, Hayato Sato, Toshiya Yokoyama, Minesuke Yamada, Yoshihiko Saku, Takashi TI Morphogenetic roles of perlecan in the tooth enamel organ: An analysis of overexpression using transgenic mice SO MATRIX BIOLOGY LA English DT Article DE Perlecan; Enamel organ; Tooth; Overexpression; Transgenic ID HEPARAN-SULFATE PROTEOGLYCAN; DENSITY-LIPOPROTEIN-RECEPTOR; FIBROBLAST-GROWTH-FACTOR; BASEMENT-MEMBRANES; STELLATE RETICULUM; MOUSE MOLARS; EXPRESSION; LOCALIZATION; LAMININ; MOLECULE AB Perlecan, a heparan sulfate proteoglycan, is enriched in the intercellular space of the enamel organ. To understand the role of perlecan in tooth morphogenesis, we used a keratin 5 promoter to generate transgenic (Tg) mice that over-express perlecan in epithelial cells, and examined their tooth germs at tissue and cellular levels. Immunohistochemistry showed that perlecan was more strongly expressed in the enamel organ cells of Tg mice than in wild-type mice. Histopathology showed wider intercellular spaces in the stellate reticulum of the Tg molars and loss of cellular polarity in the enamel organ, especially in its cervical region. Hertwig's epithelial root sheath (HERS) cells in Tg mice were irregularly aligned due to excessive deposits of perlecan along the inner, as well as on the outer sides of the HERS. Tg molars had dull-ended crowns and outward-curved tooth roots and their enamel was poorly crystallized, resulting in pronounced attrition of molar cusp areas. In Tg mice, expression of integrin beta 1 mRNA was remarkably higher at El 8, while expression of bFGF, TGF-beta 1. DSPP and Shh was more elevated at P1. The overexpression of perlecan in the enamel organ resulted in irregular morphology of teeth, suggesting that the expression of perlecan regulates growth factor signaling in a stage-dependent manner during each step of the interaction between ameloblast-lineage cells and mesenchymal cells. (C) 2011 Elsevier B.V. All rights reserved. C1 [Ida-Yonemochi, Hiroko; Saku, Takashi] Niigata Univ, Grad Sch Med & Dent Sci, Div Oral Pathol, Dept Tissue Regenerat & Reconstruct,Chuo Ku, Niigata 9518514, Japan. [Ida-Yonemochi, Hiroko; Ohshima, Hayato] Niigata Univ, Grad Sch Med & Dent Sci, Div Anat & Cell Biol Hard Tissue, Dept Tissue Regenerat & Reconstruct,Chuo Ku, Niigata 9518514, Japan. [Sato, Toshiya; Yokoyama, Minesuke] Niigata Univ, Brain Res Inst, Dept Comparat & Expt Med, Chuo Ku, Niigata 9518585, Japan. [Yamada, Yoshihiko] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Saku, T (reprint author), Niigata Univ, Grad Sch Med & Dent Sci, Div Oral Pathol, Dept Tissue Regenerat & Reconstruct,Chuo Ku, 2-5274 Gakkocho Dori, Niigata 9518514, Japan. EM tsaku@dent.niigata-u.ac.jp FU Japan Society for the Promotion of Science; Ministry of Education, Science, Sports and Culture, Japan FX We are grateful to Mr. Shin-Ichi Kenmotsu for his technical assistance with the transmission electron microscopic analysis. This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and from the Ministry of Education, Science, Sports and Culture, Japan. NR 39 TC 14 Z9 15 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD SEP-OCT PY 2011 VL 30 IS 7-8 BP 379 EP 388 DI 10.1016/j.matbio.2011.08.001 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 843QY UT WOS:000296688500003 PM 21933708 ER PT J AU Freeman, AK Morrison, DK AF Freeman, Alyson K. Morrison, Deborah K. TI 14-3-3 Proteins: Diverse functions in cell proliferation and cancer progression SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE 14-3-3; Cell proliferation; Cell migration; Actin cytoskeleton; EMT ID COFILIN-PHOSPHATASE SLINGSHOT; BREAST-CANCER; MESENCHYMAL TRANSITION; ARGININE METHYLATION; THERAPEUTIC TARGET; ACTIN DYNAMICS; HIPPO PATHWAY; PHOSPHORYLATION; LOCALIZATION; BINDING AB The 14-3-3 proteins were the first phosphoserine/phosphothreonine-binding proteins to be discovered, a finding that provided the foundation for their prominent role in cell signaling. 14-3-3 family members interact with a wide spectrum of proteins including transcription factors, biosynthetic enzymes, cytoskeletal proteins, signaling molecules, apoptosis factors, and tumor suppressors. The interaction with 14-3-3 can have a profound effect on a target protein, altering its localization, stability, conformation, phosphorylation state, activity, and/or molecular interactions. Thus, by modulating the function of a diverse array of binding partners, 14-3-3 proteins have become key regulatory components in many vital cellular processes - processes that are crucial for normal growth and development and that often become dysregulated in human cancer. This review will examine the recent advances that further elucidate the role of 14-3-3 proteins in normal growth and cancer signaling with a particular emphasis on the signaling pathways that impact cell proliferation, cell migration, and epithelial-to-mesenchymal transition. Published by Elsevier Ltd. C1 [Freeman, Alyson K.; Morrison, Deborah K.] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Morrison, DK (reprint author), NCI, Lab Cell & Dev Signaling, POB B, Frederick, MD 21702 USA. EM morrisod@mail.nih.gov FU National Cancer Institute FX Our work is supported by federal funds from the National Cancer Institute. NR 53 TC 62 Z9 70 U1 2 U2 30 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD SEP PY 2011 VL 22 IS 7 BP 681 EP 687 DI 10.1016/j.semcdb.2011.08.009 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 842FH UT WOS:000296578000004 PM 21884813 ER PT J AU Mehedi, M Groseth, A Feldmann, H Ebihara, H AF Mehedi, Masfique Groseth, Allison Feldmann, Heinz Ebihara, Hideki TI Clinical aspects of Marburg hemorrhagic fever SO FUTURE VIROLOGY LA English DT Review DE diagnosis; disease; hemorrhagic fever; Marburg virus; pathogenesis; pathology; prevention; treatment ID EBOLA-VIRUS INFECTION; ATTENUATED RECOMBINANT VACCINE; LINKED-IMMUNOSORBENT-ASSAY; VERVET MONKEY DISEASE; NONHUMAN-PRIMATES; AGENT DISEASE; GUINEA-PIGS; IN-VITRO; POSTEXPOSURE PROTECTION; MONOCLONAL-ANTIBODIES AB Marburg virus belongs to the genus Marburgvirus in the family Filoviridae and causes a severe hemorrhagic fever, known as Marburg hemorrhagic fever (MHF), in both humans and nonhuman primates. Similar to the more widely known Ebola hemorrhagic fever, MHF is characterized by systemic viral replication, immunosuppression and abnormal inflammatory responses. These pathological features of the disease contribute to a number of systemic dysfunctions including hemorrhages, edema, coagulation abnormalities and, ultimately, multiorgan failure and shock, often resulting in death. A detailed understanding of the pathological processes that lead to this devastating disease remains elusive, a fact that contributes to the lack of licensed vaccines or effective therapeutics. This article will review the clinical aspects of MHF and discuss the pathogenesis and possible options for diagnosis, treatment and prevention. C1 [Mehedi, Masfique; Groseth, Allison; Feldmann, Heinz; Ebihara, Hideki] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. [Mehedi, Masfique; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Ebihara, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT 59840 USA. EM ebiharah@niaid.nih.gov RI Mehedi, masfique/J-6618-2014 OI Mehedi, masfique/0000-0003-1728-3126 FU NIAID, NIH FX Research on filoviruses was partially funded by the Intramural Research Program, NIAID, NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 108 TC 19 Z9 22 U1 2 U2 16 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0794 J9 FUTURE VIROL JI Future Virol. PD SEP PY 2011 VL 6 IS 9 BP 1091 EP 1106 DI 10.2217/FVL.11.79 PG 16 WC Virology SC Virology GA 841EY UT WOS:000296496500011 PM 22046196 ER PT J AU Schuetze, P Eiden, RD Colder, CR Gray, TR Huestis, MA AF Schuetze, Pamela Eiden, Rina D. Colder, Craig R. Gray, Theresa R. Huestis, Marilyn A. TI Physiological regulation in cigarette exposed infants potential moderators SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE Physiological regulation; Prenatal cigarette exposure ID FOR-GESTATIONAL-AGE; CARDIAC VAGAL TONE; MATERNAL SMOKING; PRENATAL EXPOSURE; PASSIVE SMOKING; CONDUCT PROBLEMS; TOBACCO-SMOKE; PREGNANCY; RISK; DEPRESSION AB The primary purpose of this study was to examine pathways from prenatal cigarette exposure to physiological regulation at 2 months of age. Specifically, we explored the possibility that any association between prenatal cigarette exposure and infant physiological regulation was moderated by fetal growth, prenatal or postnatal environmental tobacco smoke (ETS) exposure or maternal depressive symptomatology during pregnancy. We evaluated whether exposed infants who were also exposed to ETS after birth, were small for gestational age (SGA) or had mothers with higher depressive symptoms during pregnancy had the highest levels of physiological dysregulation. Respiratory sinus arrhythmia (RSA) was obtained from 234 (166 exposed and 68 nonexposed) infants during sleep. As expected, cigarette-exposed infants had significantly lower RSA than nonexposed infants. This association was not moderated by prenatal or postnatal ETS exposure, or maternal depressive symptomatology during pregnancy. However, small for gestational age status did moderate this association such that nonexposed infants who were not small for gestational age had a significantly higher RSA than nonexposed small for gestational age infants and exposed infants. These findings provide additional evidence that prenatal cigarette exposure is directly associated with dysregulation during infancy. (C) 2011 Elsevier Inc. All rights reserved. C1 [Schuetze, Pamela] SUNY Coll Buffalo, Dept Psychol, Buffalo, NY 14222 USA. [Schuetze, Pamela; Eiden, Rina D.] SUNY Buffalo, Res Inst Addict, Buffalo, NY 14260 USA. [Colder, Craig R.] SUNY Buffalo, Dept Psychol, Buffalo, NY 14260 USA. [Gray, Theresa R.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Chem & Drug Metab Intramural Res Program, Bethesda, MD USA. RP Schuetze, P (reprint author), SUNY Coll Buffalo, Dept Psychol, Buffalo, NY 14222 USA. EM schuetp@buffalostate.edu FU National Institute on Drug Abuse at the National Institutes of Health [1 R01 DA019632-01]; National Institute on Drug Abuse FX There is no conflict of interest. The study was funded by a grant from the National Institute on Drug Abuse.; The authors thank the parents and children who participated in this study and research staff who were responsible for conducting numerous assessments with these families. Special thanks to Dr. Amol Lele for collaboration on data collection at Women and Children's Hospital of Buffalo. This work was supported by the National Institute on Drug Abuse at the National Institutes of Health (Intramural Research Program and grant number 1 R01 DA019632-01). NR 62 TC 5 Z9 5 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD SEP-OCT PY 2011 VL 33 IS 5 BP 567 EP 574 DI 10.1016/j.ntt.2011.07.004 PG 8 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 841VY UT WOS:000296544500006 PM 21798345 ER PT J AU Mishra, A Devarajan, B Reardon, ME Dwivedi, P Krishnan, V Cisar, JO Das, A Narayana, SVL Ton-That, H AF Mishra, Arunima Devarajan, Bharanidharan Reardon, Melissa E. Dwivedi, Prabhat Krishnan, Vengadesan Cisar, John O. Das, Asis Narayana, Sthanam V. L. Ton-That, Hung TI Two autonomous structural modules in the fimbrial shaft adhesin FimA mediate Actinomyces interactions with streptococci and host cells during oral biofilm development SO MOLECULAR MICROBIOLOGY LA English DT Article ID GRAM-POSITIVE BACTERIA; INTRAMOLECULAR ISOPEPTIDE BONDS; STAPHYLOCOCCUS-AUREUS; SURFACE-PROTEINS; CORYNEBACTERIUM-DIPHTHERIAE; STABILIZING ISOPEPTIDE; NAESLUNDII; PILUS; VISCOSUS; SORTASE AB By combining X-ray crystallography and modelling, we describe here the atomic structure of distinct adhesive moieties of FimA, the shaft fimbrillin of Actinomyces type 2 fimbriae, which uniquely mediates the receptor-dependent intercellular interactions between Actinomyces and oral streptococci as well as host cells during the development of oral biofilms. The FimA adhesin is built with three IgG-like domains, each of which harbours an intramolecular isopeptide bond, previously described in several Gram-positive pilins. Genetic and biochemical studies demonstrate that although these isopeptide bonds are dispensable for fimbrial assembly, cell-cell interactions and biofilm formation, they contribute significantly to the proteolytic stability of FimA. Remarkably, FimA harbours two autonomous adhesive modules, which structurally resemble the Staphylococcus aureus Cna B domain. Each isolated module can bind the plasma glycoprotein asialofetuin as well as the polysaccharide receptors present on the surface of oral streptococci and epithelial cells. Thus, FimA should serve as an excellent paradigm for the development of therapeutic strategies and elucidating the precise molecular mechanisms underlying the interactions between cellular receptors and Gram-positive fimbriae. C1 [Devarajan, Bharanidharan; Krishnan, Vengadesan; Narayana, Sthanam V. L.] Univ Alabama, Sch Optometry, Ctr Biophys Sci & Engn, Birmingham, AL 35294 USA. [Mishra, Arunima; Reardon, Melissa E.; Dwivedi, Prabhat; Ton-That, Hung] Univ Texas Hlth Sci Ctr, Dept Microbiol & Mol Genet, Houston, TX USA. [Cisar, John O.] Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. [Das, Asis] Univ Connecticut, Ctr Hlth, Dept Mol Microbial & Struct Biol, Farmington, CT USA. RP Narayana, SVL (reprint author), Univ Alabama, Sch Optometry, Ctr Biophys Sci & Engn, Birmingham, AL 35294 USA. EM narayana@uab.edu; ton-that.hung@uth.tmc.edu OI Ton-That, Hung/0000-0003-1611-0469 FU NIH [DE017382, AI064815] FX We thank Xin Ma (University of Texas Health Science Center) for technical assistance and members of our laboratory for their critical inputs. This work was supported by the NIH grants DE017382 to Hung Ton-That and AI064815 to Sthanam V. L. Narayana. NR 54 TC 30 Z9 30 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD SEP PY 2011 VL 81 IS 5 BP 1205 EP 1220 DI 10.1111/j.1365-2958.2011.07745.x PG 16 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 811MC UT WOS:000294214100008 PM 21696465 ER PT J AU Richards, JM Stipelman, BA Bornovalova, MA Daughters, SB Sinha, R Lejuez, CW AF Richards, Jessica M. Stipelman, Brooke A. Bornovalova, Marina A. Daughters, Stacey B. Sinha, Rajita Lejuez, C. W. TI Biological mechanisms underlying the relationship between stress and smoking: State of the science and directions for future work SO BIOLOGICAL PSYCHOLOGY LA English DT Review DE HPA axis; Stress; Cortisol; Autonomic nervous system; Smoking; Nicotine dependence ID HEART-RATE-VARIABILITY; PITUITARY-ADRENAL AXIS; SALIVARY CORTISOL RESPONSES; CIGARETTE-SMOKING; HPA AXIS; HABITUAL SMOKERS; PSYCHOLOGICAL STRESS; PSYCHOSOCIAL STRESS; NUCLEUS-ACCUMBENS; NICOTINE DEPENDENCE AB Theories of addiction implicate stress as a crucial mechanism underlying initiation, maintenance, and relapse to cigarette smoking. Examinations of the biological stress systems, including functioning of the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS), have provided additional insights into the relationship between stress and smoking. To date, convergent data suggests that chronic cigarette smoking is associated with alterations in HPA and ANS functioning; however, less is known about the role of HPA and ANS functioning in smoking initiation and relapse following cessation. In order to organize existing findings and stimulate future research, the current paper summarizes the available literature on the roles of HPA axis and ANS functioning in the relationship between stress and cigarette smoking, highlights limitations within the existing literature, and suggests directions for future research to address unanswered questions in the extant literature on the biological mechanisms underlying the relationship between stress and smoking. (C) 2011 Elsevier B.V. All rights reserved. C1 [Richards, Jessica M.; Lejuez, C. W.] Univ Maryland, Dept Psychol, CAPER, College Pk, MD 20742 USA. [Stipelman, Brooke A.] NCI, Rockville, MD USA. [Bornovalova, Marina A.] Univ S Florida, Dept Psychol, Tampa, FL 33620 USA. [Bornovalova, Marina A.] Univ S Florida, Dept Mental Hlth Law & Policy, Tampa, FL 33620 USA. [Daughters, Stacey B.] Univ Maryland, Sch Publ Hlth, Dept Behav & Community Hlth, College Pk, MD 20742 USA. [Sinha, Rajita] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Sinha, Rajita; Lejuez, C. W.] Yale Child Study Ctr, New Haven, CT 06520 USA. RP Richards, JM (reprint author), Univ Maryland, Dept Psychol, CAPER, 2103 Cole Activ Bldg, College Pk, MD 20742 USA. EM jrichards@psyc.umd.edu FU NIDA NIH HHS [R01 DA015375-03S2, F31 DA027242-02, R01 DA015375, R01 DA026424] NR 170 TC 33 Z9 33 U1 4 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 EI 1873-6246 J9 BIOL PSYCHOL JI Biol. Psychol. PD SEP PY 2011 VL 88 IS 1 BP 1 EP 12 DI 10.1016/j.biopsycho.2011.06.009 PG 12 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 827QM UT WOS:000295443000001 PM 21741435 ER PT J AU Sahasrabuddhe, VV Luhn, P Wentzensen, N AF Sahasrabuddhe, Vikrant V. Luhn, Patricia Wentzensen, Nicolas TI Human papillomavirus and cervical cancer: biomarkers for improved prevention efforts SO FUTURE MICROBIOLOGY LA English DT Review DE accuracy; biomarkers; cervical cancer; HPV; prevention; risk prediction; screening ID RISK HUMAN-PAPILLOMAVIRUS; LIQUID-BASED CYTOLOGY; L1 CAPSID PROTEIN; ASC-US CYTOLOGY; SQUAMOUS INTRAEPITHELIAL LESIONS; RANDOMIZED CONTROLLED-TRIAL; DNA METHYLATION ANALYSIS; MESSENGER-RNA ASSAY; HYBRID CAPTURE 2; HPV-DNA AB While organized screening programs in industrialized countries have significantly reduced cervical cancer incidence, cytology-based screening has several limitations. Equivocal or mildly abnormal Pap tests require costly retesting or diagnostic work-up by colposcopy and biopsy. In low-resource countries, it has been difficult to establish and sustain cytology-based programs. Advances in understanding human papillomavirus biology and the natural history of human papillomavirus-related precancers and cancers have led to the discovery of a range of novel biomarkers in the past decade. In this article, we will discuss the potential role of new biomarkers for primary screening, triage and diagnosis in high-resource countries and their promise for prevention efforts in resource constrained settings. C1 [Sahasrabuddhe, Vikrant V.; Luhn, Patricia; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 5024, Rockville, MD 20852 USA. EM wentzenn@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999, ZIA CP010124-16, ZIA CP010124-17] NR 149 TC 31 Z9 32 U1 1 U2 8 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0913 J9 FUTURE MICROBIOL JI Future Microbiol. PD SEP PY 2011 VL 6 IS 9 BP 1083 EP 1098 DI 10.2217/FMB.11.87 PG 16 WC Microbiology SC Microbiology GA 836EK UT WOS:000296092300014 PM 21958146 ER PT J AU Yi, D AF Yi, Doogab TI Who Owns What? Private Ownership and the Public Interest in Recombinant DNA Technology in the 1970s SO ISIS LA English DT Article ID INTELLECTUAL PROPERTY; MOLECULAR-BIOLOGY; ESCHERICHIA-COLI; UNITED-STATES; SCIENCE; PATENT; FOUNDATION; BIOTECHNOLOGY; TRANSITION; GOVERNMENT AB This essay analyzes how academic institutions, government agencies, and the nascent biotech industry contested the legal ownership of recombinant DNA technology in the name of the public interest. It reconstructs the way a small but influential group of government officials and university research administrators introduced a new framework for the commercialization of academic research in the context of a national debate over scientific research's contributions to American economic prosperity and public health. They claimed that private ownership of inventions arising from public support would provide a powerful means to liberate biomedical discoveries for public benefit. This articulation of the causal link between private ownership and the public interest, it is argued, justified a new set of expectations about the use of research results arising from government or public support, in which commercialization became a new public obligation for academic researchers. By highlighting the broader economic and legal shifts that prompted the reconfiguration of the ownership of public knowledge in late twentieth-century American capitalism, the essay examines the threads of policy-informed legal ideas that came together to affirm private ownership of biomedical knowledge as germane to the public interest in the coming of age of biotechnology and genetic medicine. C1 NIH, Off Hist, Bethesda, MD 20892 USA. RP Yi, D (reprint author), NIH, Off Hist, 45 Ctr Dr,MSC 6330, Bethesda, MD 20892 USA. EM yid@mail.nih.gov FU National Science Foundation [SES-0522502] FX I would like to thank Paul Berg, Stanley Cohen, Katherine Ku, Norman Latker, Janet Mertz, John Morrow, and Bernard Talbot for providing their recollections and historical materials. I also thank those who attended presentations of this paper at the American Association for the History of Medicine meeting, the History of Science Society meeting, Arizona State University, Caltech, KAIST, NIH, and Seoul National University for asking insightful questions. I sincerely appreciate enlightening comments, useful questions, and corrections from Elizabeth Berman, Dan Bouk, Graham Burnett, David Cantor, Soraya de Chadarevian, Angela Creager, Michael Gordin, Sungook Hong, Myles Jackson, Chin Jou, Daniel Kevles, Robert Martensen, Bruno Strasser, the three anonymous referees for Isis, and Bernard Lightman. This research was generously supported by a dissertation research grant from the National Science Foundation (SES-0522502). I remain responsible for the interpretation offered and any errors in this essay. NR 133 TC 3 Z9 3 U1 0 U2 9 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0021-1753 J9 ISIS JI Isis PD SEP PY 2011 VL 102 IS 3 BP 446 EP 474 DI 10.1086/661619 PG 29 WC History & Philosophy Of Science SC History & Philosophy of Science GA 835TT UT WOS:000296059600003 PM 22073770 ER PT J AU Robinson, EM Iannotti, RJ Schneider, S Nansel, TR Haynie, DL Sobel, DO AF Robinson, Elizabeth M. Iannotti, Ronald J. Schneider, Stefan Nansel, Tonja R. Haynie, Denise L. Sobel, Douglas O. TI Parenting goals: Predictors of parent involvement in disease management of children with type I diabetes SO JOURNAL OF CHILD HEALTH CARE LA English DT Article DE diabetes; parenting; adolescent; chronic illness ID METABOLIC-CONTROL; ADOLESCENTS; MELLITUS; STRATEGIES; ADHERENCE; YOUTH; CARE AB The purpose of this study was to develop a measure of diabetes-specific parenting goals for parents of children with type I diabetes and to examine whether parenting goals predict a change in parenting involvement in disease management. An independent sample of primary caretakers of 87 children aged 10 to 16 years with type I diabetes completed the measure of parenting goals (diabetes-specific and general goals); both parent and child completed measures of parent responsibility for diabetes management at baseline and 6 months. Parents ranked diabetes-specific parenting goals as more important than general parenting goals, and rankings were moderately stable over time. Parenting goals were related to parent responsibility for diabetes management. The relative ranking of diabetes-specific parenting goals predicted changes in parent involvement over 6 months, with baseline ranking of goals predicting more parental involvement at follow-up. Parenting goals may play an important role in family management of type I diabetes. C1 [Robinson, Elizabeth M.] Virginia Commonwealth Univ, Dept Clin Psychol, Richmond, VA 23284 USA. [Iannotti, Ronald J.; Nansel, Tonja R.; Haynie, Denise L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Bethesda, MD 20892 USA. [Schneider, Stefan] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Sobel, Douglas O.] Georgetown Univ, Sch Med, Dept Pediat, Washington, DC 20057 USA. RP Iannotti, RJ (reprint author), 6100 Execut Blvd,Rm 7B13Q,MSC 7510, Bethesda, MD 20892 USA. EM iannottr@mail.nih.gov RI Schneider, Stefan/K-2815-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Funding was provided by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 26 TC 5 Z9 6 U1 3 U2 13 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1367-4935 J9 J CHILD HEALTH CARE JI J. Child Health Care PD SEP PY 2011 VL 15 IS 3 BP 199 EP 209 DI 10.1177/1367493511406567 PG 11 WC Nursing; Pediatrics SC Nursing; Pediatrics GA 835YD UT WOS:000296072100005 PM 21917595 ER PT J AU Carter, LG Lewis, KN Shridas, P Garcia-Cazarin, ML Andrade, FH de Cabo, R Pearson, KJ AF Carter, Lindsay G. Lewis, Kaitlyn N. Shridas, Preetha Garcia-Cazarin, Mary L. Andrade, Francisco H. de Cabo, Rafael Pearson, Kevin J. TI Maternal Exercise during Pregnancy Improves Glucose Disposal in Mice Offspring SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Meeting Abstract C1 [Carter, Lindsay G.; Pearson, Kevin J.] Univ Kentucky, Coll Med, Grad Ctr Nutr Sci, Lexington, KY 40506 USA. [Lewis, Kaitlyn N.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Bethesda, MD 20892 USA. [Lewis, Kaitlyn N.] Univ Texas Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Lewis, Kaitlyn N.] Univ Texas Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78229 USA. [Shridas, Preetha] Univ Kentucky, Coll Med, Dept Internal Med, Lexington, KY 40506 USA. [Garcia-Cazarin, Mary L.; Andrade, Francisco H.] Univ Kentucky, Coll Med, Dept Physiol, Lexington, KY 40506 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD SEP PY 2011 VL 2 SU 1 BP S79 EP S80 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 837CK UT WOS:000296168500266 ER PT J AU Swanson, JM Baker, D Aagaard, K Wadhwa, P Elaine, F Steve, H AF Swanson, James M. Baker, Dean Aagaard, Kjersti Wadhwa, Pathik Elaine, Faustman Steve, Hirschfeld TI Lessons Learned in the Vanguard Phases of the US National Children's Study SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Meeting Abstract C1 [Swanson, James M.; Baker, Dean; Wadhwa, Pathik] UC Irvine, Irvine, CA 92717 USA. [Steve, Hirschfeld] NICHD, Natl Childrens Study, NIH, Bethesda, MD 20892 USA. [Aagaard, Kjersti] Baylor Coll Med, OG GYN, Houston, TX 77030 USA. [Elaine, Faustman] Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD SEP PY 2011 VL 2 SU 1 BP S41 EP S41 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 837CK UT WOS:000296168500132 ER PT J AU Hugunin, K Herbert, R Tansey, G Amaral, J Chan, C Eckhaus, M Rockar, R Browning, M AF Hugunin, K. Herbert, R. Tansey, G. Amaral, J. Chan, C. Eckhaus, M. Rockar, R. Browning, M. TI Periocular Abnormalities in an SIV-Infected Rhesus Macaque SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Hugunin, K.; Eckhaus, M.; Rockar, R.; Browning, M.] Div Vet Resources, Bethesda, MD USA. [Tansey, G.; Amaral, J.; Chan, C.] NEI, Bethesda, MD 20892 USA. [Herbert, R.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 728 EP 728 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000045 ER EF