FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Gillman, AL Jang, H Lee, J Ramachandran, S Kagan, BL Nussinov, R Arce, FT AF Gillman, Alan L. Jang, Hyunbum Lee, Joon Ramachandran, Srinivasan Kagan, Bruce L. Nussinov, Ruth Arce, Fernando Teran TI Activity and Architecture of Pyroglutamate-Modified Amyloid-beta (A beta(pE3-42)) Pores SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID ATOMIC-FORCE MICROSCOPY; FORMS ION CHANNELS; ALL-D-ENANTIOMER; ALZHEIMERS-DISEASE; A-BETA; MOLECULAR-DYNAMICS; LIPID-BILAYERS; GRAMICIDIN CHANNEL; PEPTIDE CHANNELS; IN-VITRO AB Among the family of A beta peptides, pyroglutamate-modified A beta (A beta(pE)) peptides are particularly associated with cytotoxicity in Alzheimer's disease (AD). They represent the dominant fraction of A beta oligomers in the brains of AD patients, but their accumulation in the brains of elderly individuals with normal cognition is significantly lower. Accumulation of A beta(pE) plaques precedes the formation of plaques of full-length A beta (A beta(1.40/42)). Most of these properties appear to be associated with the higher hydrophobicity of A beta(pE) as well as an increased resistance to enzymatic degradation. However, the important question of whether A beta(pE) peptides induce pore activity in lipid membranes and their potential toxicity compared with other A beta pores is still open. Here we examine the activity of A beta(pE) pores in anionic membranes using planar bilayer electrical recording and provide their structures using molecular dynamics simulations. We find that A beta(pE) pores spontaneously induce ionic current across the membrane and have some similar properties to the other previously studied pores of the A beta family. However, there are also some significant differences. The onset of A beta(pE3-42) pore activity is generally delayed compared with A beta(1-42) pores. However, once formed, A beta(pE3-42) pores produce increased ion permeability of the membrane, as indicated by a greater occurrence of higher conductance electrical events. Structurally, the lactam ring of A beta(pE) peptides induces a change in the conformation of the N-terminal strands of the A beta(pE3-42) pores. While the N-termini of wild-type A beta(1-42) peptides normally reside in the bulk water region, the N-termini of A beta(pE3-42) peptides tend to reside in the hydrophobic lipid core. These studies provide a first step to an understanding of the enhanced toxicity attributed to A beta(pE) peptides. C1 [Gillman, Alan L.; Ramachandran, Srinivasan; Arce, Fernando Teran] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Lee, Joon; Ramachandran, Srinivasan; Arce, Fernando Teran] Univ Calif San Diego, Dept Mech & Aerosp Engn, La Jolla, CA 92093 USA. [Lee, Joon; Ramachandran, Srinivasan; Arce, Fernando Teran] Univ Calif San Diego, Mat Sci Program, La Jolla, CA 92093 USA. [Jang, Hyunbum; Nussinov, Ruth] Natl Canc Inst Frederick, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Kagan, Bruce L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. RP Arce, FT (reprint author), Univ Calif San Diego, Dept Bioengn, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM ftarce@ucsd.edu FU National Institutes of Health [R01AG028709]; National Institutes of Health Neuroplasticity of Aging Training Grant [T32 AG 000216]; Howard Hughes Medical Institute Med Into Grad Initiative; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research FX We thank Prof. Ratnesh Lal for his insight and support for this work. Support by the National Institutes of Health (R01AG028709) is acknowledged. A.L.G was supported in part by National Institutes of Health Neuroplasticity of Aging Training Grant (T32 AG 000216) and the Howard Hughes Medical Institute Med Into Grad Initiative. This project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. This research was supported [in part] by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. 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. All simulations had been performed using the high-performance computational facilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 67 TC 12 Z9 12 U1 0 U2 17 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 JUL 3 PY 2014 VL 118 IS 26 BP 7335 EP 7344 DI 10.1021/jp5040954 PG 10 WC Chemistry, Physical SC Chemistry GA AK8QL UT WOS:000338693000013 PM 24922585 ER PT J AU Crosby, J Peloso, GM Auer, PL Crosslin, DR Stitziel, NO Lange, LA Lu, YC Tang, ZZ Zhang, H Hindy, G Masca, N Stirrups, K Kanoni, S Do, R Jun, G Hu, YN Kang, HM Xue, CY Goel, A Farrall, M Duga, S Merlini, PA Asselta, R Girelli, D Olivieri, O Martinelli, N Yin, W Reilly, D Speliotes, E Fox, CS Hveem, K Holmen, OL Nikpay, M Farlow, DN Assimes, TL Franceschini, N Robinson, J North, KE Martin, LW DePristo, M Gupta, N Escher, SA Jansson, JH Van Zuydam, N Palmer, CNA Wareham, N Koch, W Meitinger, T Peters, A Lieb, W Erbel, R Konig, IR Kruppa, J Degenhardt, F Gottesman, O Bottinger, EP O'Donnell, CJ Psaty, BM Ballantyne, CM Abecasis, G Ordovas, JM Melander, O Watkins, H Orho-Melander, M Ardissino, D Loos, RJF McPherson, R Willer, CJ Erdmann, J Hall, AS Samani, NJ Deloukas, P Schunkert, H Wilson, JG Kooperberg, C Rich, SS Tracy, RP Lin, DY Altshuler, D Gabriel, S Nickerson, DA Jarvik, GP Cupples, LA Reiner, AP Boerwinkle, E Kathiresan, S AF Crosby, Jacy Peloso, Gina M. Auer, Paul L. Crosslin, David R. Stitziel, Nathan O. Lange, Leslie A. Lu, Yingchang Tang, Zheng-zheng Zhang, He Hindy, George Masca, Nicholas Stirrups, Kathleen Kanoni, Stavroula Do, Ron Jun, Goo Hu, Youna Kang, Hyun Min Xue, Chenyi Goel, Anuj Farrall, Martin Duga, Stefano Merlini, Pier Angelica Asselta, Rosanna Girelli, Domenico Olivieri, Oliviero Martinelli, Nicola Yin, Wu Reilly, Dermot Speliotes, Elizabeth Fox, Caroline S. Hveem, Kristian Holmen, Oddgeir L. Nikpay, Majid Farlow, Deborah N. Assimes, Themistocles L. Franceschini, Nora Robinson, Jennifer North, Kari E. Martin, Lisa W. DePristo, Mark Gupta, Namrata Escher, Stefan A. Jansson, Jan-Hakan Van Zuydam, Natalie Palmer, Colin N. A. Wareham, Nicholas Koch, Werner Meitinger, Thomas Peters, Annette Lieb, Wolfgang Erbel, Raimund Konig, Inke R. Kruppa, Jochen Degenhardt, Franziska Gottesman, Omri Bottinger, Erwin P. O'Donnell, Christopher J. Psaty, Bruce M. Ballantyne, Christie M. Abecasis, Goncalo Ordovas, Jose M. Melander, Olle Watkins, Hugh Orho-Melander, Marju Ardissino, Diego Loos, Ruth J. F. McPherson, Ruth Willer, Cristen J. Erdmann, Jeanette Hall, Alistair S. Samani, Nilesh J. Deloukas, Panos Schunkert, Heribert Wilson, James G. Kooperberg, Charles Rich, Stephen S. Tracy, Russell P. Lin, Dan-Yu Altshuler, David Gabriel, Stacey Nickerson, Deborah A. Jarvik, Gail P. Cupples, L. Adrienne Reiner, Alex P. Boerwinkle, Eric Kathiresan, Sekar CA Exome Sequencing Project Natl Heart Lung Blood Inst TI Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID APOLIPOPROTEIN C-III; CARDIOVASCULAR-DISEASE; PLASMA TRIGLYCERIDES; RICH LIPOPROTEINS; RARE VARIANTS; HEART-DISEASE; HUMAN EXOMES; DESIGN; ASSOCIATION; PCSK9 AB Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G -> A and IVS3+1G -> T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1x10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8x10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4x10(-6)). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.) C1 [Crosby, Jacy] Univ Texas Houston, Dept Biostat Bioinformat & Syst Biol, Grad Sch Biomed Sci, Houston, TX USA. [Crosby, Jacy; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Ballantyne, Christie M.; Boerwinkle, Eric] Baylor Coll Med, Houston, TX 77030 USA. [Ballantyne, Christie M.] Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA. [Peloso, Gina M.; Do, Ron; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Peloso, Gina M.; Do, Ron; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Peloso, Gina M.; Do, Ron; Altshuler, David; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Yin, Wu; Reilly, Dermot] Merck Sharp & Dohme Ltd, Boston, MA USA. [Ordovas, Jose M.] Tufts Univ, Nutr & Genom Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Peloso, Gina M.; Do, Ron; Farlow, Deborah N.; DePristo, Mark; Gupta, Namrata; Altshuler, David; Gabriel, Stacey; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Auer, Paul L.] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Crosslin, David R.; Nickerson, Deborah A.; Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Crosslin, David R.; Jarvik, Gail P.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Kooperberg, Charles; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Med, Cardiovasc Div, St Louis, MO 63130 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63130 USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Tang, Zheng-zheng; Lin, Dan-Yu] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Lu, Yingchang; Gottesman, Omri; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY USA. [Zhang, He; Speliotes, Elizabeth; Willer, Cristen J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Zhang, He; Xue, Chenyi; Speliotes, Elizabeth; Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Zhang, He; Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Jun, Goo; Hu, Youna; Kang, Hyun Min; Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Abecasis, Goncalo] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Hindy, George; Orho-Melander, Marju] Lund Univ, Dept Clin Sci, Clin Res Ctr, Malmo, Sweden. [Escher, Stefan A.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Melander, Olle] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. Malmo Univ Hosp, Malmo, Sweden. [Jansson, Jan-Hakan] Skelleftea Hosp, Dept Med, Skelleftea, Sweden. [Jansson, Jan-Hakan] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Masca, Nicholas; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Masca, Nicholas; Samani, Nilesh J.] Natl Inst Hlth Res Leicester, Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Stirrups, Kathleen; Kanoni, Stavroula; Deloukas, Panos] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Wellcome Trust Ctr Human Genet, Oxford, England. [Van Zuydam, Natalie; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland. [Wareham, Nicholas; Cupples, L. Adrienne] Addenbrookes Hosp, Med Res Council Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Hall, Alistair S.] Univ Leeds, Sch Med, Div Epidemiol, Leeds LS2 9JT, W Yorkshire, England. [Duga, Stefano; Asselta, Rosanna] Univ Milan, Dipartimento Biotecnol Med & Med Traslaz, Milan, Italy. [Merlini, Pier Angelica] Osped Niguarda Ca Granda, Div Cardiol, Milan, Italy. [Girelli, Domenico; Olivieri, Oliviero; Martinelli, Nicola] Univ Verona, Dept Med, Sch Med, I-37100 Verona, Italy. [Ardissino, Diego] Azienda Osped Univ Parma, Div Cardiol, Parma, Italy. [Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Hveem, Kristian; Holmen, Oddgeir L.] Norwegian Univ Sci & Technol, Nord Trondelag Hlth Study HUNT Res Ctr, Dept Publ Hlth & Gen Practice, N-7034 Trondheim, Norway. [Hveem, Kristian] Levanger Hosp, Levanger, Norway. [Holmen, Oddgeir L.] Univ Trondheim Hosp, St Olav Hosp, Trondheim, Norway. [Nikpay, Majid; McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON, Canada. [Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Robinson, Jennifer] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Ames, IA USA. [Robinson, Jennifer] Univ Iowa, Dept Med, Coll Publ Hlth, Ames, IA USA. [Martin, Lisa W.] Washington Univ, Sch Med & Hlth Sci, Div Cardiol, Washington, DC USA. [Koch, Werner; Schunkert, Heribert] Deutsch Herzzentrum Munich, Munich, Germany. [Koch, Werner] Tech Univ Munich, Klinikum Rechts Isar, Med Klin, D-80290 Munich, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Koch, Werner; Peters, Annette] German Ctr Cardiovasc Res, Munich, Germany. [Peters, Annette] Helmholtz Zentrum Munchen, Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [Lieb, Wolfgang] Univ Kiel, Inst Epidemiol & Biobank popgen, Kiel, Germany. [Erbel, Raimund] West German Heart Ctr, Dept Cardiol, Essen, Germany. [Konig, Inke R.; Kruppa, Jochen] Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Med Biometrie & Stat, Lubeck, Germany. [Erdmann, Jeanette] Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Integrat & Expt Genom, Lubeck, Germany. [Konig, Inke R.; Kruppa, Jochen] Univ Lubeck, Univ Klinikum Schleswig Holstein, Lubeck, Germany. [Erdmann, Jeanette] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany. [Degenhardt, Franziska] Univ Bonn, Inst Human Genet, Bonn, Germany. [Ordovas, Jose M.] Natl Ctr Cardiovasc Invest, Dept Cardiovasc Epidemiol & Populat Genet, Madrid, Spain. [Ordovas, Jose M.] Inst Madrileno Estudios Avanzados Alimentac, Madrid, Spain. [Deloukas, Panos] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Coll Med, Burlington, VT 05405 USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Coll Med, Burlington, VT 05405 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. EM skathiresan@partners.org RI Erdmann, Jeanette/P-7513-2014; Deloukas, Panos/B-2922-2013; Hindy, George/H-1864-2016; Jarvik, Gail/N-6476-2014; Palmer, Colin/C-7053-2008; Meitinger, Thomas/O-1318-2015; Peters, Annette/A-6117-2011; Martinelli, Nicola/J-5622-2016; Study, GoDARTS/K-9448-2016; Lieb, Wolfgang/C-1990-2012; Jun, Goo/F-1941-2017; OI Martin, Lisa Warsinger/0000-0003-4352-0914; Erdmann, Jeanette/0000-0002-4486-6231; Stitziel, Nathan/0000-0002-4963-8211; Duga, Stefano/0000-0003-3457-1410; Watkins, Hugh/0000-0002-5287-9016; Assimes, Themistocles/0000-0003-2349-0009; Deloukas, Panos/0000-0001-9251-070X; Hindy, George/0000-0002-7257-9299; Jarvik, Gail/0000-0002-6710-8708; Palmer, Colin/0000-0002-6415-6560; Martinelli, Nicola/0000-0001-6465-5119; Jun, Goo/0000-0003-0891-0204; Asselta, Rosanna/0000-0001-5351-0619 FU National Heart, Lung, and Blood Institute FX Funded by the National Heart, Lung, and Blood Institute and others. NR 40 TC 161 Z9 167 U1 4 U2 28 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 3 PY 2014 VL 371 IS 1 BP 22 EP 31 DI 10.1056/NEJMoa1307095 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AK2RA UT WOS:000338265700006 ER PT J AU Chawla, LS Eggers, PW Star, RA Kimmel, PL AF Chawla, Lakhmir S. Eggers, Paul W. Star, Robert A. Kimmel, Paul L. TI Acute Kidney Injury and Chronic Kidney Disease as Interconnected Syndromes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID ACUTE-RENAL-FAILURE; ACUTE TUBULAR-NECROSIS; LONG-TERM; HOSPITALIZED-PATIENTS; RISK; PROGRESSION; FIBROSIS; AKI; MORTALITY; OUTCOMES C1 Dept Med, Div Intens Care Med, Washington, DC USA. Div Nephrol, Washington, DC USA. [Chawla, Lakhmir S.] George Washington Univ, Med Ctr, Vet Affairs Med Ctr, Washington, DC 20037 USA. [Chawla, Lakhmir S.] George Washington Univ, Med Ctr, Dept Anesthesiol & Crit Care Med, Washington, DC 20037 USA. [Chawla, Lakhmir S.; Kimmel, Paul L.] George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, Washington, DC 20037 USA. [Eggers, Paul W.; Star, Robert A.; Kimmel, Paul L.] Natl Inst Diabet & Digest & Kidney Dis NIDDK, NIH, Bethesda, MD 20892 USA. RP Kimmel, PL (reprint author), NIDDK, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM kimmelp@extra.niddk.nih.gov FU AbbVie; AM-Pharma; Alere; Covidien; Gambro; Bard Medical; NxStage Medical; Astute Medical; Ikaria; Eli Lilly FX Dr. Chawla reports receiving fees for serving on steering committees from AbbVie and AM-Pharma, fees for serving as an adjudicator for a clinical end-point study from Alere, fees for device development from Covidien, Gambro, Bard Medical, and NxStage Medical, fees for serving as a principal investigator for trials sponsored by Astute Medical, fees for clinical-trial development and planning from Ikaria, and grant support from Eli Lilly. He also reports providing expert testimony in a case of a patient with severe rhabdomyolysis and in a case of a patient who died after intubation. No other potential conflict of interest relevant to this article was reported. NR 57 TC 202 Z9 212 U1 10 U2 40 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 3 PY 2014 VL 371 IS 1 BP 58 EP 66 DI 10.1056/NEJMra1214243 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AK2RA UT WOS:000338265700010 PM 24988558 ER PT J AU Boikos, SA Helman, LJ Stratakis, CA AF Boikos, Sosipatros A. Helman, Lee J. Stratakis, Constantine A. CA Natl Inst Hlth TI Thyroid Hormone Inactivation in Gastrointestinal Stromal Tumors SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID MUTATIONS C1 [Boikos, Sosipatros A.] Johns Hopkins Kimmel Canc Ctr, Baltimore, MD 21202 USA. [Helman, Lee J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Boikos, SA (reprint author), Johns Hopkins Kimmel Canc Ctr, Baltimore, MD 21202 USA. EM sboikos1@jhmi.edu 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 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 3 PY 2014 VL 371 IS 1 BP 85 EP 86 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AK2RA UT WOS:000338265700027 PM 24988575 ER PT J AU Yang, Z Xu, Y Xu, T Hoy, CW Handwerker, DA Chen, G Northoff, G Zuo, XN Bandettini, PA AF Yang, Zhi Xu, Yong Xu, Ting Hoy, Colin W. Handwerker, Daniel A. Chen, Gang Northoff, Georg Zuo, Xi-Nian Bandettini, Peter A. TI Brain Network Informed Subject Community Detection In Early-Onset Schizophrenia SO SCIENTIFIC REPORTS LA English DT Article ID SYNDROME SCALE PANSS; INDEPENDENT COMPONENT ANALYSIS; FUNCTIONAL CONNECTIVITY; DEFAULT NETWORK; PSYCHOSIS; DISORDERS; PRECUNEUS; FMRI; REPRODUCIBILITY; ADOLESCENCE AB Early-onset schizophrenia (EOS) offers a unique opportunity to study pathophysiological mechanisms and development of schizophrenia. Using 26 drug-naive, first-episode EOS patients and 25 age- and gender-matched control subjects, we examined intrinsic connectivity network (ICN) deficits underlying EOS. Due to the emerging inconsistency between behavior-based psychiatric disease classification system and the underlying brain dysfunctions, we applied a fully data-driven approach to investigate whether the subjects can be grouped into highly homogeneous communities according to the characteristics of their ICNs. The resultant subject communities and the representative characteristics of ICNs were then associated with the clinical diagnosis and multivariate symptom patterns. A default mode ICN was statistically absent in EOS patients. Another frontotemporal ICN further distinguished EOS patients with predominantly negative symptoms. Connectivity patterns of this second network for the EOS patients with predominantly positive symptom were highly similar to typically developing controls. Our post-hoc functional connectivity modeling confirmed that connectivity strength in this frontotemporal circuit was significantly modulated by relative severity of positive and negative syndromes in EOS. This study presents a novel subtype discovery approach based on brain networks and proposes complex links between brain networks and symptom patterns in EOS. C1 [Yang, Zhi; Xu, Ting; Zuo, Xi-Nian] Chinese Acad Sci, Inst Psychol, Key Lab Behav Sci & Magnet Resonance, Imaging Res Ctr, Beijing 100101, Peoples R China. [Yang, Zhi; Hoy, Colin W.; Handwerker, Daniel A.; Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Xu, Yong] Shanxi Med Univ, Hosp 1, Dept Psychiat, Taiyuan 030001, Peoples R China. [Chen, Gang] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. [Northoff, Georg] Univ Ottawa, Mental Hlth Res Inst, Ottawa, ON K1Z 7K4, Canada. [Yang, Zhi; Xu, Ting; Zuo, Xi-Nian] Chinese Acad Sci, Lab Funct Connectome & Dev, Inst Psychol, Beijing 100101, Peoples R China. RP Xu, Y (reprint author), Chinese Acad Sci, Inst Psychol, Key Lab Behav Sci & Magnet Resonance, Imaging Res Ctr, Beijing 100101, Peoples R China. EM xuyongsmu@vip.163.com; zuoxn@psych.ac.cn OI Zuo, Xi-Nian/0000-0001-9110-585X; Yang, Zhi/0000-0002-2222-2312 FU National Key Technologies R&D Program of China [2012BAI36B01]; Natural Science Foundation of China [81270023, 81278412, 81171409, 81000583, 81220108014]; Foundation of Beijing Key Laboratory of Mental Disorders [2014JSJB03]; Intramural Research Program of the National Institute of Mental Health; Key Research Program; Program for New Century Excellent Talents in University; Hundred Talents Program of the Chinese Academy of Sciences [KSZD-EW-TZ-002] FX This study is supported by the National Key Technologies R&D Program of China (2012BAI36B01), the Natural Science Foundation of China (81270023, 81278412, 81171409, 81000583, 81220108014), the Foundation of Beijing Key Laboratory of Mental Disorders (2014JSJB03), the Intramural Research Program of the National Institute of Mental Health, the Key Research Program and the Hundred Talents Program of the Chinese Academy of Sciences (KSZD-EW-TZ-002), and the Program for New Century Excellent Talents in University. All of the authors declare no conflict of interest. The computations were performed on the NIH Biowulf Cluster System (http://biowulf.nih.gov) and the Dell Blade Cluster System at the Institute of Psychology, Chinese Academy of Sciences. We acknowledge the comments on the manuscript from Dr. F. Xavier Castellanos. NR 58 TC 13 Z9 14 U1 4 U2 16 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 JUL 3 PY 2014 VL 4 AR 5549 DI 10.1038/srep05549 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK4VI UT WOS:000338421800001 PM 24989351 ER PT J AU Huang, BL Mackem, S AF Huang, Bau-Lin Mackem, Susan TI EVOLUTIONARY DEVELOPMENTAL BIOLOGY Use it or lose it SO NATURE LA English DT Editorial Material ID VERTEBRATE LIMB; DIGIT LOSS; REDUCTION C1 [Huang, Bau-Lin; Mackem, Susan] NCI, Ctr Canc Res, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RP Huang, BL (reprint author), NCI, Ctr Canc Res, Canc & Dev Biol Lab, Frederick, MD 21702 USA. EM mackems@mail.nih.gov NR 12 TC 0 Z9 0 U1 0 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 3 PY 2014 VL 511 IS 7507 BP 34 EP 35 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK1TN UT WOS:000338199400024 PM 24990735 ER PT J AU Mayer-Barber, KD Andrade, BB Oland, SD Amaral, EP Barber, DL Gonzales, J Derrick, SC Shi, RR Kumar, NP Wei, W Yuan, X Zhang, GL Cai, Y Babu, S Catalfamo, M Salazar, AM Via, LE Barry, CE Sher, A AF Mayer-Barber, Katrin D. Andrade, Bruno B. Oland, Sandra D. Amaral, Eduardo P. Barber, Daniel L. Gonzales, Jacqueline Derrick, Steven C. Shi, Ruiru Kumar, Nathella Pavan Wei, Wang Yuan, Xing Zhang, Guolong Cai, Ying Babu, Subash Catalfamo, Marta Salazar, Andres M. Via, Laura E. Barry, Clifton E., III Sher, Alan TI Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk SO NATURE LA English DT Article ID NECROSIS-FACTOR-ALPHA; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; LIPID MEDIATORS; INDUCTION; INFECTION; SUSCEPTIBILITY; INFLAMMATION; IMMUNITY; INNATE AB Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent(1). Despite chemotherapy, the global tuberculosis epidemic has intensified because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria(2-5). Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality(6). The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target(7). Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy. C1 [Mayer-Barber, Katrin D.; Andrade, Bruno B.; Oland, Sandra D.; Amaral, Eduardo P.; Sher, Alan] NIAID, Immunobiol Sect, LPD, NIH, Bethesda, MD 20892 USA. [Amaral, Eduardo P.] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, BR-05508900 Sao Paulo, Brazil. [Barber, Daniel L.] NIAID, Lymphocyte Biol Unit T, LPD, NIH, Bethesda, MD 20892 USA. [Gonzales, Jacqueline; Via, Laura E.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Derrick, Steven C.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Shi, Ruiru; Wei, Wang; Yuan, Xing] Henan Chest Hosp, Zhengzhou 450003, Peoples R China. [Kumar, Nathella Pavan; Babu, Subash] Int Ctr Excellence Res, NIH, Madras 600031, Tamil Nadu, India. [Kumar, Nathella Pavan] NIRT, Madras 600031, Tamil Nadu, India. [Zhang, Guolong] SinoUS Int Res Ctr TB, Zhengzhou 450003, Peoples R China. [Zhang, Guolong] Henan Publ Hlth Ctr, Zhengzhou 450003, Peoples R China. [Babu, Subash] NIAID, Helminth Immunol Sect, LPD, NIH, Bethesda, MD 20892 USA. [Catalfamo, Marta] NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Salazar, Andres M.] Oncovir Inc, Washington, DC 20008 USA. RP Mayer-Barber, KD (reprint author), NIAID, Immunobiol Sect, LPD, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mayerk@niaid.nih.gov RI Andrade, Bruno/J-9111-2012; Amaral, Eduardo/M-2456-2014; Barry, III, Clifton/H-3839-2012; OI Andrade, Bruno/0000-0001-6833-3811; Amaral, Eduardo/0000-0001-5465-8113; Via, Laura/0000-0001-6074-9521 FU NIAID Intramural Research program; Concept Acceleration Program-Award from DMID, NIAID FX This work was supported by the NIAID Intramural Research program and a Concept Acceleration Program-Award (K.D.M.-B., B.B.A. and A.S.) from DMID, NIAID. We are grateful to K. Elkins, S. Morris, M. Belcher as well as the NIAID ABSL3 support staff for facilitating our animal studies. We thank R. Chen, L. Goldfeder and Q. Gao for sharing their clinical trial expertise and research facilities, respectively. We also thank K. Kauffman, R. Thompson, S. Hieny, P. Dayal, D. Surman, L. Meng, Z. Li, L. Lifa, Q. Shen and Z. Huang for technical assistance, H. Boshoff for help with direct anti-mycobacterial activity assays and M. S. Jawahar, V. V. Banurekha and R. Sridhar for recruitment and clinical evaluation of patients in Chennai, India. We are grateful to F. Andrade Neto, H. Remold, K. Arora, J. Aliberti, M. Moayeri, P. Murphy, A. O'Garra, R. Germain and C. Serhan for discussion or critical reading of the manuscript. Finally, we thank the patients, volunteer participants, and clinical staff of the Tuberculosis department of Henan Chest Hospital in Zhengzhou, China and the Department of Clinical Research (NIRT) and Department of Thoracic Medicine (Government Stanley Medical Hospital) in Chennai, India for their participation in our clinical studies. NR 32 TC 164 Z9 167 U1 11 U2 92 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 3 PY 2014 VL 511 IS 7507 BP 99 EP U491 DI 10.1038/nature13489 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK1TN UT WOS:000338199400044 PM 24990750 ER PT J AU Portnoy, DB Ferrer, RA Bergman, HE Klein, WMP AF Portnoy, David B. Ferrer, Rebecca A. Bergman, Hannah E. Klein, William M. P. TI Changing deliberative and affective responses to health risk: a meta-analysis SO HEALTH PSYCHOLOGY REVIEW LA English DT Article DE perceived risk; perceived susceptibility; affect; worry; meta-analysis ID BREAST-CANCER SUSCEPTIBILITY; BELIEF MODEL; PERCEIVED SUSCEPTIBILITY; INFLUENZA VACCINATION; OVARIAN-CANCER; COLON-CANCER; WORRY; PERCEPTIONS; BEHAVIOR; INTENTIONS AB Perceptions of risk for health outcomes are integral to many theories of health behaviour, and are often targeted in interventions. Evidence suggests that affective responses to risk, including worry, are empirically distinguishable from commonly used perceived risk measures such as perceived susceptibility. The aims of this meta-analysis were to (1) examine if perceived susceptibility and worry can be independently influenced, and what manipulation types are most effective at changing each construct and (2) examine the efficacy of interventions to change worry and perceived susceptibility. Thirty-eight studies using 43 separate samples provided 78 independent comparisons that were meta-analysed using the inverse variance method with random-effects modelling. The overall effect size (d) was 0.50, 95% CI [0.362, 0.632] for perceived susceptibility; and 0.25, 95% CI [0.148, 0.349] for worry. Effect sizes for perceived susceptibility were significantly related to those for worry, B=0.495, p < 0.001. Moderators of these effects are discussed. The present meta-analysis provides further evidence that perceived susceptibility and worry are distinguishable but related constructs, and that it is possible to perturb one and not the other. C1 [Portnoy, David B.] NCI, Canc Prevent Fellowship Program, Rockville, MD USA. [Portnoy, David B.; Ferrer, Rebecca A.; Bergman, Hannah E.; Klein, William M. P.] NCI, Behav Res Program, Rockville, MD USA. RP Portnoy, DB (reprint author), US FDA, Ctr Tobacco Prod, Rockville, MD 20857 USA. EM david.portnoy@fda.hhs.gov OI Portnoy, David/0000-0003-2175-9457 NR 71 TC 7 Z9 7 U1 4 U2 15 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1743-7199 EI 1743-7202 J9 HEALTH PSYCHOL REV JI Health Psychol. Rev. PD JUL 3 PY 2014 VL 8 IS 3 BP 296 EP 318 DI 10.1080/17437199.2013.798829 PG 23 WC Psychology, Clinical SC Psychology GA AH2IH UT WOS:000335944200004 PM 25053216 ER PT J AU Wang, HK Lupica, CR AF Wang, Huikun Lupica, Carl R. TI Release of endogenous cannabinoids from ventral tegmental area dopamine neurons and the modulation of synaptic processes SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Article DE CB1 receptor; Dopamine neuron; Endocannabinoid; Synaptic modulation; Ventral tegmental area ID CONDITIONED PLACE PREFERENCE; METABOTROPIC GLUTAMATE; RECEPTOR ACTIVATION; ENDOCANNABINOID RELEASE; PRESYNAPTIC INHIBITION; PLASTICITY; SYNAPSES; TRANSMISSION; RAT; 2-ARACHIDONOYLGLYCEROL AB Endogenous cannabinoids play important roles in a variety of functions in the mammalian brain, including the regulation reward-related information processing. The primary mechanism through which this is achieved is the presynaptic modulation of synaptic transmission. During reward-and reinforcement-related behavior dopamine levels increase in forebrain areas and this has recently been shown to be modulated by the endocannabinoid system. Therefore, understanding how endocannabinoids are mobilized to modulate synaptic inputs impinging on midbrain dopamine neurons is crucial to a complete understanding of the roles that these molecules play in reward behavior, drug abuse and addiction. Here we summarize the literature describing short-term and long-term regulation of afferent connections on dopamine neurons in the ventral tegmental area via endocannabinoid activation of cannabinoid CB1 receptors, and describe the mechanisms through which these molecules are released during reward-based behavior and exposure to abused drugs. Published by Elsevier Inc. C1 [Wang, Huikun; Lupica, Carl R.] Natl Inst Drug Abuse, Electrophysiol Res Sect, Intramural Res Program, NIH,US DEPT HHS, Baltimore, MD 21224 USA. RP Lupica, CR (reprint author), 251 Bayview Blvd, Baltimore, MD 21224 USA. EM clupica@mail.nih.gov OI Wang, Huikun/0000-0001-8556-3504 FU National Institute on Drug Abuse Intramural Research Program; U.S. Department of Health and Human Services FX This work was supported by the National Institute on Drug Abuse Intramural Research Program and the U.S. Department of Health and Human Services. NR 52 TC 15 Z9 15 U1 1 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD JUL 3 PY 2014 VL 52 BP 24 EP 27 DI 10.1016/j.pnpbp.2014.01.019 PG 4 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AG5EM UT WOS:000335442100005 PM 24495779 ER PT J AU Napper, LE Harris, PR Klein, WMP AF Napper, Lucy E. Harris, Peter R. Klein, William M. P. TI Combining Self-Affirmation With the Extended Parallel Process Model: The Consequences for Motivation to Eat More Fruit and Vegetables SO HEALTH COMMUNICATION LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; HEALTH BEHAVIOR-CHANGE; FEAR APPEALS; INTERVENTION; METAANALYSIS; INFORMATION; APPRAISAL; RISK AB There is potential for fruitful integration of research using the Extended Parallel Process Model (EPPM) with research using Self-affirmation Theory. However, to date no studies have attempted to do this. This article reports an experiment that tests whether (a) the effects of a self-affirmation manipulation add to those of EPPM variables in predicting intentions to improve a health behavior and (b) self-affirmation moderates the relationship between EPPM variables and intentions. Participants (N = 80) were randomized to either a self-affirmation or control condition prior to receiving personally relevant health information about the risks of not eating at least five portions of fruit and vegetables per day. A hierarchical regression model revealed that efficacy, threat x efficacy, self-affirmation, and self-affirmation x efficacy all uniquely contributed to the prediction of intentions to eat at least five portions per day. Self-affirmed participants and those with higher efficacy reported greater motivation to change. Threat predicted intentions at low levels of efficacy, but not at high levels. Efficacy had a stronger relationship with intentions in the nonaffirmed condition than in the self-affirmed condition. The findings indicate that self-affirmation processes can moderate the impact of variables in the EPPM and also add to the variance explained. We argue that there is potential for integration of the two traditions of research, to the benefit of both. C1 [Napper, Lucy E.; Harris, Peter R.] Univ Sheffield, Dept Psychol, Sheffield S10 2TN, S Yorkshire, England. [Klein, William M. P.] NCI, Bethesda, MD 20892 USA. RP Napper, LE (reprint author), Loyola Marymount Univ, Dept Psychol, 1 LMU Dr, Los Angeles, CA 90045 USA. EM lucy.napper@lmu.edu NR 39 TC 2 Z9 2 U1 4 U2 39 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1041-0236 EI 1532-7027 J9 HEALTH COMMUN JI Health Commun. PD JUL 3 PY 2014 VL 29 IS 6 BP 610 EP 618 DI 10.1080/10410236.2013.791962 PG 9 WC Communication; Health Policy & Services SC Communication; Health Care Sciences & Services GA AE5XC UT WOS:000334061600008 PM 24138335 ER PT J AU Gladwin, MT Barst, RJ Gibbs, JSR Hildesheim, M Sachdev, V Nouraie, M Hassell, KL Little, JA Schraufnagel, DE Krishnamurti, L Novelli, E Girgis, RE Morris, CR Rosenzweig, EB Badesch, DB Lanzkron, S Castro, OL Taylor, JG Goldsmith, JC Kato, GJ Gordeuk, VR Machado, RF AF Gladwin, Mark T. Barst, Robyn J. Gibbs, J. Simon R. Hildesheim, Mariana Sachdev, Vandana Nouraie, Mehdi Hassell, Kathryn L. Little, Jane A. Schraufnagel, Dean E. Krishnamurti, Lakshmanan Novelli, Enrico Girgis, Reda E. Morris, Claudia R. Rosenzweig, Erika Berman Badesch, David B. Lanzkron, Sophie Castro, Oswaldo L. Taylor, James G. Goldsmith, Jonathan C. Kato, Gregory J. Gordeuk, Victor R. Machado, Roberto F. CA Walk-PHaSST Investigators Patients TI Risk Factors for Death in 632 Patients with Sickle Cell Disease in the United States and United Kingdom SO PLOS ONE LA English DT Article ID NATRIURETIC PEPTIDE LEVELS; PULMONARY-HYPERTENSION; ASSOCIATION; ADOLESCENTS; MORTALITY; ADULTS AB Background: The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial. Methods and Results: We evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)>= 3.0 m/s cuttof, which has a 67-75% positive predictive value for mean pulmonary artery pressure >= 25 mm Hg was used. Among 572 subjects, 11.2% had TRV >= 3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values >= 160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV<3.0 m/sec. At 24 months the cumulative survival was 83% with TRV >= 3.0 m/sec and 98% with TRV, 3.0 m/sec (p<0.0001). The hazard ratios for death were 11.1 (95% CI 4.1-30.1; p, 0.0001) for TRV >= 3.0 m/sec, 4.6 (1.8-11.3; p = 0.001) for NT-proBNP >= 160 pg/mL, and 14.9 (5.5-39.9; p<0.0001) for both TRV >= 3.0 m/sec and NT-proBNP >= 160 pg/mL. Age >47 years, male gender, chronic transfusions, WHO class III-IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death. Conclusions: A TRV >= 3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable. C1 [Gladwin, Mark T.; Hildesheim, Mariana; Krishnamurti, Lakshmanan; Novelli, Enrico] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15260 USA. [Gladwin, Mark T.; Hildesheim, Mariana] Univ Pittsburgh, Med Ctr, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Barst, Robyn J.; Rosenzweig, Erika Berman] Columbia Univ, New York, NY USA. [Gibbs, J. Simon R.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Sachdev, Vandana; Taylor, James G.; Kato, Gregory J.] NHLBI, Cardiovasc Branch, Bethesda, MD 20892 USA. [Nouraie, Mehdi; Castro, Oswaldo L.] Howard Univ, Washington, DC 20059 USA. [Hassell, Kathryn L.; Badesch, David B.] Univ Colorado HSC, Denver, CO USA. [Little, Jane A.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Schraufnagel, Dean E.; Gordeuk, Victor R.; Machado, Roberto F.] Univ Illinois, Chicago, IL USA. [Krishnamurti, Lakshmanan] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Girgis, Reda E.; Lanzkron, Sophie] Johns Hopkins Univ, Baltimore, MD USA. [Morris, Claudia R.] Emory Univ, Sch Med, Atlanta, GA USA. [Goldsmith, Jonathan C.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15260 USA. EM gladwinmt@upmc.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 National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services [HHSN268200617182C] FX This project has been founded with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under contract HHSN268200617182C. NHLBI was involved in the design and conduct of the original study and their staff had input in the writing of the manuscript. NR 20 TC 20 Z9 20 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 JUL 2 PY 2014 VL 9 IS 7 AR e99489 DI 10.1371/journal.pone.0099489 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5BA UT WOS:000341354100014 PM 24988120 ER PT J AU Gourraud, PA Khankhanian, P Cereb, N Yang, SY Feolo, M Maiers, M Rioux, JD Hauser, S Oksenberg, J AF Gourraud, Pierre-Antoine Khankhanian, Pouya Cereb, Nezih Yang, Soo Young Feolo, Michael Maiers, Martin Rioux, John D. Hauser, Stephen Oksenberg, Jorge TI HLA Diversity in the 1000 Genomes Dataset SO PLOS ONE LA English DT Article ID HIGH-RESOLUTION HLA; EXTENDED HUMAN MHC; MULTIPLE-SCLEROSIS; LINKAGE DISEQUILIBRIUM; LOCI; ASSOCIATION; ALLELES; MAP; IMMUNOGENETICS; INFORMATION AB The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation by sequencing at a level that should allow the genome-wide detection of most variants with frequencies as low as 1%. However, in the major histocompatibility complex (MHC), only the top 10 most frequent haplotypes are in the 1% frequency range whereas thousands of haplotypes are present at lower frequencies. Given the limitation of both the coverage and the read length of the sequences generated by the 1000 Genomes Project, the highly variable positions that define HLA alleles may be difficult to identify. We used classical Sanger sequencing techniques to type the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 genes in the available 1000 Genomes samples and combined the results with the 103,310 variants in the MHC region genotyped by the 1000 Genomes Project. Using pairwise identity-by-descent distances between individuals and principal component analysis, we established the relationship between ancestry and genetic diversity in the MHC region. As expected, both the MHC variants and the HLA phenotype can identify the major ancestry lineage, informed mainly by the most frequent HLA haplotypes. To some extent, regions of the genome with similar genetic or similar recombination rate have similar properties. An MHC-centric analysis underlines departures between the ancestral background of the MHC and the genome-wide picture. Our analysis of linkage disequilibrium (LD) decay in these samples suggests that overestimation of pairwise LD occurs due to a limited sampling of the MHC diversity. This collection of HLA-specific MHC variants, available on the dbMHC portal, is a valuable resource for future analyses of the role of MHC in population and disease studies. C1 [Gourraud, Pierre-Antoine; Khankhanian, Pouya; Hauser, Stephen; Oksenberg, Jorge] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Cereb, Nezih; Yang, Soo Young] Histogenetics Inc, Ossining, NY USA. [Feolo, Michael] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Maiers, Martin] Natl Marrow Donor Program, Minneapolis, MN USA. [Rioux, John D.] Univ Montreal, Inst Cardiol Montreal, Montreal, PQ, Canada. RP Gourraud, PA (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. EM pierreantoine.gourraud@ucsf.edu RI Rioux, John/A-9599-2015; Gourraud, Pierre-Antoine/O-3024-2015; OI Rioux, John/0000-0001-7560-8326; Maiers, Martin/0000-0002-0198-2064 FU National Institute of Health [U19AI067152, RO1NS076492, RO1NS046297]; Office of Naval Research [N00014-11-1-0339]; Race to erase MS Junior Investigator Award; European Federation for Immunogenetics Julia Bodmer Award FX This work was supported by grants from the National Institute of Health U19AI067152 (ARRA administrative supplement), RO1NS076492, RO1NS046297, and from the Office of Naval Research N00014-11-1-0339. PAG is a recipient of the Race to erase MS Junior Investigator Award and the European Federation for Immunogenetics Julia Bodmer Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 23 Z9 23 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 2 PY 2014 VL 9 IS 7 AR e97282 DI 10.1371/journal.pone.0097282 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5BA UT WOS:000341354100006 PM 24988075 ER PT J AU Hobbs, CV Neal, J Conteh, S Donnelly, L Chen, JY Marsh, K Lambert, L Orr-Gonzalez, S Hinderer, J Healy, S Borkowsky, W Penzak, SR Chakravarty, S Hoffman, SL Duffy, PE AF Hobbs, Charlotte V. Neal, Jillian Conteh, Solomon Donnelly, Liam Chen, Jingyang Marsh, Kennan Lambert, Lynn Orr-Gonzalez, Sachy Hinderer, Jessica Healy, Sara Borkowsky, William Penzak, Scott R. Chakravarty, Sumana Hoffman, Stephen L. Duffy, Patrick E. TI HIV Treatments Reduce Malaria Liver Stage Burden in a Non-Human Primate Model of Malaria Infection at Clinically Relevant Concentrations In Vivo SO PLOS ONE LA English DT Article ID PLASMODIUM-CYNOMOLGI; PROTEASE INHIBITORS; SULFAMETHOXAZOLE; TRANSMISSION; FALCIPARUM; PROGUANIL; KNOWLESI AB We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium liver stages in rodent malarias and in vitro in P. falciparum. Since clinically relevant levels are better achieved in the non-human-primate model, and since Plasmodium knowlesi is an accepted animal model for the study of liver stages of malaria as a surrogate for P. falciparum infection, we investigated the antimalarial activity of these drugs on Plasmodium knowlesi liver stages in rhesus macaques. We demonstrate that TMP-SMX and TMP-SMX+LPV-RTV (in combination), but not LPV-RTV alone, inhibit liver stage parasite development. Because drugs that inhibit the clinically silent liver stages target parasites when they are present in lower numbers, these results may have implications for eradication efforts. C1 [Hobbs, Charlotte V.; Neal, Jillian; Conteh, Solomon; Donnelly, Liam; Chen, Jingyang; Lambert, Lynn; Orr-Gonzalez, Sachy; Hinderer, Jessica; Healy, Sara; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. [Marsh, Kennan] AbbVie Inc, N Chicago, IL USA. [Borkowsky, William] NYU, Sch Med, Dept Pediat, Div Infect Dis & Immunol, New York, NY USA. [Penzak, Scott R.] NIAID, Ctr Clin, Dept Pharm, Clin Pharmacokinet Res Lab,NIH, Bethesda, MD 20892 USA. [Chakravarty, Sumana; Hoffman, Stephen L.] Sanaria Inc, Rockville, MD USA. RP Hobbs, CV (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. EM charlotte.hobbs@nih.gov FU National Institutes of Health Division of Intramural Research FX This work was supported by the National Institutes of Health Division of Intramural Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 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 JUL 2 PY 2014 VL 9 IS 7 AR e100138 DI 10.1371/journal.pone.0100138 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5BA UT WOS:000341354100025 PM 24988386 ER PT J AU White, MR Kandel, R Tripathi, S Condon, D Qi, L Taubenberger, J Hartshorn, KL AF White, Mitchell R. Kandel, Ruth Tripathi, Shweta Condon, David Qi, Li Taubenberger, Jeffrey Hartshorn, Kevan L. TI Alzheimer's Associated beta-Amyloid Protein Inhibits Influenza A Virus and Modulates Viral Interactions with Phagocytes SO PLOS ONE LA English DT Article ID HUMAN NEUTROPHIL DEFENSINS; DISEASE; PEPTIDE; RESPONSES; RECEPTOR AB Accumulation of beta-Amyloid (beta A) is a key pathogenetic factor in Alzheimer's disease; however, the normal function of beta A is unknown. Recent studies have shown that beta A can inhibit growth of bacteria and fungi. In this paper we show that beta A also inhibits replication of seasonal and pandemic strains of H3N2 and H1N1 influenza A virus (IAV) in vitro. The 42 amino acid fragment of beta A (beta A42) had greater activity than the 40 amino acid fragment. Direct incubation of the virus with beta A42 was needed to achieve optimal inhibition. Using quantitative PCR assays beta A42 was shown to reduce viral uptake by epithelial cells after 45 minutes and to reduce supernatant virus at 24 hours post infection. beta A42 caused aggregation of IAV particles as detected by light transmission assays and electron and confocal microscopy. beta A42 did not stimulate neutrophil H2O2 production or extracellular trap formation on its own, but it increased both responses stimulated by IAV. In addition, beta A42 increased uptake of IAV by neutrophils. beta A42 reduced viral protein synthesis in monocytes and reduced IAV-induced interleukin-6 production by these cells. Hence, we demonstrate for the first time that beta A has antiviral activity and modulates viral interactions with phagocytes. C1 [White, Mitchell R.; Tripathi, Shweta; Condon, David; Hartshorn, Kevan L.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Kandel, Ruth] Harvard Univ, Sch Med, Hebrew Senior Life, Boston, MA USA. [Qi, Li; Taubenberger, Jeffrey] NIAID, Bethesda, MD 20892 USA. RP Hartshorn, KL (reprint author), Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. EM khartsho@bu.edu FU National Institutes of Health [AI-83222, HL 069031]; NIH FX Funding came from the National Institutes of Health Grant numbers AI-83222 (KLH)and HL 069031 (KLH) and NIH intramural funds (JKT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 16 Z9 16 U1 2 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 JUL 2 PY 2014 VL 9 IS 7 AR e101364 DI 10.1371/journal.pone.0101364 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5BA UT WOS:000341354100079 PM 24988208 ER PT J AU Graydon, CW Zhang, J Oesch, NW Sousa, AA Leapman, RD Diamond, JS AF Graydon, Cole W. Zhang, Jun Oesch, Nicholas W. Sousa, Alioscka A. Leapman, Richard D. Diamond, Jeffrey S. TI Passive Diffusion as a Mechanism Underlying Ribbon Synapse Vesicle Release and Resupply SO JOURNAL OF NEUROSCIENCE LA English DT Article DE diffusion; tether; vesicle ID RETINAL BIPOLAR NEURONS; HAIR CELL SYNAPSES; TRANSMITTER RELEASE; PHOTORECEPTOR TERMINALS; MULTIVESICULAR RELEASE; RANA-CATESBEIANA; EXOCYTOSIS; TRANSMISSION; MOBILITY; DEPOLARIZATION AB Synaptic ribbons are presynaptic protein structures found at many synapses that convey graded, "analog" sensory signals in the visual, auditory, and vestibular pathways. Ribbons, typically anchored to the presynaptic membrane and surrounded by tethered synaptic vesicles, are thought to regulate or facilitate vesicle delivery to the presynaptic membrane. No direct evidence exists, however, to indicate how vesicles interact with the ribbon or, once attached, move along the ribbon's surface to reach the presynaptic release sites at its base. To address these questions, we have created, validated, and tested a passive vesicle diffusion model of retinal rod bipolar cell ribbon synapses. We used axial (bright-field) electron tomography in the scanning transmission electron microscopy to obtain 3D structures of rat rod bipolar cell terminals in 1-mu m-thick sections of retinal tissue at an isotropic spatial resolution of similar to 3 nm. The resulting structures were then incorporated with previously published estimates of vesicle diffusion dynamics into numerical simulations that accurately reproduced electrophysiologically measured vesicle release/replenishment rates and vesicle pool sizes. The simulations suggest that, under physiologically realistic conditions, diffusion of vesicles crowded on the ribbon surface gives rise to a flow field that enhances delivery of vesicles to the presynaptic membrane without requiring an active transport mechanism. Numerical simulations of ribbon-vesicle interactions predict that transient binding and unbinding of multiple tethers to each synaptic vesicle may achieve sufficiently tight association of vesicles to the ribbon while permitting the fast diffusion along the ribbon that is required to sustain high release rates. C1 [Graydon, Cole W.; Zhang, Jun; Oesch, Nicholas W.; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. [Sousa, Alioscka A.; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Diamond, JS (reprint author), 35 Convent Dr,Bldg 35,Room 3C-1000, Bethesda, MD 20892 USA. EM diamond@ninds.nih.gov RI Diamond, Jeffrey/C-1835-2015 OI Diamond, Jeffrey/0000-0002-1770-2629 FU National Institute of Neurological Disorders and Stroke [NS003039] FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program Grant NS003039 to J.S.D. We thank the National Institute of Neurological Disorders and Stroke EM facility for sample assistance. NR 53 TC 7 Z9 7 U1 2 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 2 PY 2014 VL 34 IS 27 BP 8948 EP 8962 DI 10.1523/JNEUROSCI.1022-14.2014 PG 15 WC Neurosciences SC Neurosciences & Neurology GA AL5DJ UT WOS:000339153400004 PM 24990916 ER PT J AU Pitcher, D AF Pitcher, David TI Facial Expression Recognition Takes Longer in the Posterior Superior Temporal Sulcus than in the Occipital Face Area SO JOURNAL OF NEUROSCIENCE LA English DT Article DE face perception; occipital face area; superior temporal sulcus; transcranial magnetic stimulation ID HUMAN NEURAL SYSTEM; DISTINCT REPRESENTATIONS; OCCIPITOTEMPORAL CORTEX; PERCEPTION; IDENTITY; POTENTIALS; FMRI; REVEALS; EMOTION; REGIONS AB Neuroimaging studies have identified a face-selective region in the right posterior superior temporal sulcus (rpSTS) that responds more strongly during facial expression recognition tasks than during facial identity recognition tasks, but precisely when the rpSTS begins to causally contribute to expression recognition is unclear. The present study addressed this issue using transcranial magnetic stimulation (TMS). In Experiment 1, repetitive TMS delivered over the rpSTS of human participants, at a frequency of 10 Hz for 500 ms, selectively impaired a facial expression task but had no effect on a matched facial identity task. In Experiment 2, participants performed the expression task only while double-pulse TMS (dTMS) was delivered over the rpSTS or over the right occipital face area (rOFA), a face-selective region in lateral occipital cortex, at different latencies up to 210 ms after stimulus onset. Task performance was selectively impaired when dTMS was delivered over the rpSTS at 60-100 ms and 100-140 ms. dTMS delivered over the rOFA impaired task performance at 60-100 ms only. These results demonstrate that the rpSTS causally contributes to expression recognition and that it does so over a longer time-scale than the rOFA. This difference in the length of the TMS induced impairment between the rpSTS and the rOFA suggests that the neural computations that contribute to facial expression recognition in each region are functionally distinct. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Pitcher, D (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. EM david.pitcher@nih.gov NR 38 TC 19 Z9 19 U1 4 U2 12 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 JUL 2 PY 2014 VL 34 IS 27 BP 9173 EP 9177 DI 10.1523/JNEUROSCI.5038-13.2014 PG 5 WC Neurosciences SC Neurosciences & Neurology GA AL5DJ UT WOS:000339153400025 PM 24990937 ER PT J AU Choi, H Lee, M Chen, RY Kim, Y Yoon, S Joh, JS Park, SK Dodd, LE Lee, J Song, T Cai, Y Goldfeder, LC Via, LE Carroll, MW Barry, CE Cho, SN AF Choi, Hongjo Lee, Myungsun Chen, Ray Y. Kim, Youngran Yoon, Soyoung Joh, Joon Sung Park, Seung Kyu Dodd, Lori E. Lee, Jongseok Song, Taeksun Cai, Ying Goldfeder, Lisa C. Via, Laura E. Carroll, Matthew W. Barry, Clifton E., III Cho, Sang-Nae TI Predictors of pulmonary tuberculosis treatment outcomes in South Korea: a prospective cohort study, 2005-2012 SO BMC INFECTIOUS DISEASES LA English DT Article DE Multidrug-resistant tuberculosis; Tuberculosis; Diabetes; Unfavorable outcome; Long-term follow up; South Korea ID MULTIDRUG-RESISTANT TUBERCULOSIS; RISK-FACTORS; ANTITUBERCULOSIS TREATMENT; DEFAULT; ADHERENCE; SMOKING AB Background: Tuberculosis remains an important health concern in many countries. The aim of this study was to identify predictors of unfavorable outcomes at the end of treatment (EOT) and at the end of study (EOS; 40 months after EOT) in South Korea. Methods: New or previously treated tuberculosis patients were recruited into a prospective observational cohort study at two hospitals in South Korea. To identify predictors of unfavorable outcomes at EOT and EOS, logistic regression analysis was performed. Results: The proportion of multidrug-resistant tuberculosis (MDR-TB) was 8.2% in new cases and 57.9% in previously treated cases. Of new cases, 68.6% were cured, as were 40.7% of previously treated cases. At EOT, diabetes, >= 3 previous TB episodes, >= 1 significant regimen change, and MDR-TB were significantly associated with treatment failure or death. At EOS, age >= 35, body-mass index (BMI) < 18.5, diabetes, and MDR-TB were significantly associated with treatment failure, death, or relapse. Among cases that were cured at EOT, age >= 50 and a BMI < 18.5 were associated with subsequent death or relapse during follow-up to EOS. Treatment interruption was associated with service sector employees or laborers, bilateral lesions on chest X-ray, and previous treatment failure or treatment interruption history. Conclusions: Risk factors for poor treatment outcomes at EOT and EOS include both patient factors (diabetes status, age, BMI) and disease factors (history of multiple previous treatment episodes, MDR-TB). In this longitudinal, observational cohort study, diabetes mellitus and MDR-TB were risk factors for poor treatment outcomes and relapse. Measures to help ensure that the first tuberculosis treatment episode is also the last one may improve treatment outcomes. C1 [Choi, Hongjo; Lee, Myungsun; Kim, Youngran; Yoon, Soyoung; Lee, Jongseok; Song, Taeksun; Cho, Sang-Nae] Int TB Res Ctr, Chang Won, South Korea. [Choi, Hongjo] Korea Univ, Dept Hlth Sci, Grad Sch, Program Publ Hlth Sci BK21PLUS, Seoul, South Korea. [Chen, Ray Y.; Cai, Ying; Goldfeder, Lisa C.; Via, Laura E.; Carroll, Matthew W.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Joh, Joon Sung] Natl Med Ctr, Dept Internal Med, Seoul, South Korea. [Park, Seung Kyu] Natl Masan TB Hosp, Chang Won, South Korea. [Dodd, Lori E.] NIAID, Biostat Res Branch, NIH, Bethesda, MD USA. [Cho, Sang-Nae] Yonsei Univ, Coll Med, Dept Microbiol, Seoul, South Korea. [Cho, Sang-Nae] Yonsei Univ, Coll Med, Inst Immunol & Immunol Dis, Brain Korea Project Med Sci 21, Seoul, South Korea. RP Cho, SN (reprint author), Int TB Res Ctr, Chang Won, South Korea. EM raycho@yonsei.kr RI Barry, III, Clifton/H-3839-2012; OI Via, Laura/0000-0001-6074-9521; Chen, Ray/0000-0001-6344-1442 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) FX This study was supported (in part) by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), and (in part) by continuous support from the Korean Centers for Disease Control of the Korean Ministry of Health and Welfare to the International Tuberculosis Research Center. Through authors RYC, LED, YC, LCG, LEV, MWC, and CEB, the NIAID, NIH was involved in the design, collection, analysis, and interpretation of data; in writing the manuscript; and in the decision to submit for publication. The Korean Centers for Disease Control was not involved in the design, collection, analysis, and interpretation of data; in writing the manuscript; and in the decision to submit for publication. We would like to thank the patients who enrolled in this research study and the clinical staff who supported the trial. NR 26 TC 12 Z9 12 U1 0 U2 9 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 JUL 2 PY 2014 VL 14 AR 360 DI 10.1186/1471-2334-14-360 PG 12 WC Infectious Diseases SC Infectious Diseases GA AL0CI UT WOS:000338794500001 PM 24990578 ER PT J AU Pegu, A Yang, ZY Boyington, JC Wu, L Ko, SY Schmidt, SD Mckee, K Kong, WP Shi, W Chen, XJ Todd, JP Letvin, NL Huang, JH Nason, MC Hoxie, JA Kwong, PD Connors, M Rao, SS Mascola, JR Nabel, GJ AF Pegu, Amarendra Yang, Zhi-yong Boyington, Jeffrey C. Wu, Lan Ko, Sung-Youl Schmidt, Stephen D. Mckee, Krisha Kong, Wing-Pui Shi, Wei Chen, Xuejun Todd, John-Paul Letvin, Norman L. Huang, Jinghe Nason, Martha C. Hoxie, James A. Kwong, Peter D. Connors, Mark Rao, Srinivas S. Mascola, John R. Nabel, Gary J. TI Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MUCOSAL SHIV CHALLENGE; ANTI-CD4 MONOCLONAL-ANTIBODY; VACCINE DESIGN; POTENT NEUTRALIZATION; VAGINAL TRANSMISSION; 2F5-LIKE ANTIBODIES; STRUCTURAL BASIS; CELL-FUSION; X-RAY AB HIV-1 infection depends on effective viral entry mediated by the interaction of its envelope (Env) glycoprotein with specific cell surface receptors. Protective antiviral antibodies generated by passive or active immunization must prevent these interactions. Because the HIV-1 Env is highly variable, attention has also focused on blocking the HIV-1 primary cell receptor CD4. We therefore analyzed the in vivo protective efficacy of three potent neutralizing monoclonal antibodies (mAbs) to HIV-1 Env compared to an antibody against the CD4 receptor. Protection was assessed after mucosal challenge of rhesus macaques with simian/HIV (SHIV). Despite its comparable or greater neutralization potency in vitro, the anti-CD4 antibody did not provide effective protection in vivo, whereas the HIV-1-specific mAbs VRC01, 10E8, and PG9, targeting the CD4 binding site, membrane-proximal, and V1V2 glycan Env regions, respectively, conferred complete protection, albeit at different relative potencies. These findings demonstrate the protective efficacy of broadly neutralizing antibodies directed to the HIV-1 Env and suggest that targeting the HIV-1 Env is preferable to the cell surface receptor CD4 for the prevention of HIV-1 transmission. C1 [Pegu, Amarendra; Yang, Zhi-yong; Boyington, Jeffrey C.; Wu, Lan; Ko, Sung-Youl; Schmidt, Stephen D.; Mckee, Krisha; Kong, Wing-Pui; Shi, Wei; Chen, Xuejun; Todd, John-Paul; Kwong, Peter D.; Rao, Srinivas S.; Mascola, John R.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Letvin, Norman L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Div Viral Pathogenesis, Boston, MA 02115 USA. [Huang, Jinghe; Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Hoxie, James A.] Univ Penn, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM jmascola@nih.gov; gary.nabel@sanofi.com RI Schmidt, Stephen/B-5398-2012; Huang, Jinghe/O-1986-2015; OI Pegu, Amarendra/0000-0003-3564-6453 FU Intramural Research Program of the Vaccine Research Center; NIAID; NIH; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX This research was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, NIH. Use of SER-CAT sector 22 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. The findings and conclusions in this report are those of the authors and do not necessarily reflect the views of the funding agency. NR 60 TC 12 Z9 12 U1 2 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 2 PY 2014 VL 6 IS 243 AR 243ra88 DI 10.1126/scitranslmed.3008992 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AK8XN UT WOS:000338712200010 PM 24990883 ER PT J AU Berezovskaya, FS Wolf, YI Koonin, EV Karev, GP AF Berezovskaya, Faina S. Wolf, Yuri I. Koonin, Eugene V. Karev, Georgy P. TI Pseudo-chaotic oscillations in CRISPR-virus coevolution predicted by bifurcation analysis SO BIOLOGY DIRECT LA English DT Article ID ADAPTIVE IMMUNITY SYSTEM; CAS SYSTEMS; EVOLUTION; BACTERIA; PHAGE; ARCHAEA; DIVERSIFICATION; EPIGENETICS; DYNAMICS; MEMORY AB Background: The CRISPR-Cas systems of adaptive antivirus immunity are present in most archaea and many bacteria, and provide resistance to specific viruses or plasmids by inserting fragments of foreign DNA into the host genome and then utilizing transcripts of these spacers to inactivate the cognate foreign genome. The recent development of powerful genome engineering tools on the basis of CRISPR-Cas has sharply increased the interest in the diversity and evolution of these systems. Comparative genomic data indicate that during evolution of prokaryotes CRISPR-Cas loci are lost and acquired via horizontal gene transfer at high rates. Mathematical modeling and initial experimental studies of CRISPR-carrying microbes and viruses reveal complex coevolutionary dynamics. Results: We performed a bifurcation analysis of models of coevolution of viruses and microbial host that possess CRISPR-Cas hereditary adaptive immunity systems. The analyzed Malthusian and logistic models display complex, and in particular, quasi-chaotic oscillation regimes that have not been previously observed experimentally or in agent-based models of the CRISPR-mediated immunity. The key factors for the appearance of the quasi-chaotic oscillations are the non-linear dependence of the host immunity on the virus load and the partitioning of the hosts into the immune and susceptible populations, so that the system consists of three components. Conclusions: Bifurcation analysis of CRISPR-host coevolution model predicts complex regimes including quasi-chaotic oscillations. The quasi-chaotic regimes of virus-host coevolution are likely to be biologically relevant given the evolutionary instability of the CRISPR-Cas loci revealed by comparative genomics. The results of this analysis might have implications beyond the CRISPR-Cas systems, i.e. could describe the behavior of any adaptive immunity system with a heritable component, be it genetic or epigenetic. These predictions are experimentally testable. C1 [Berezovskaya, Faina S.] Howard Univ, Washington, DC 20059 USA. [Wolf, Yuri I.; Koonin, Eugene V.; Karev, Georgy P.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services FX We thank Alex Lobkovsky for helpful discussions. YIW, EVK and GPK are supported through intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 60 TC 1 Z9 1 U1 2 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD JUL 2 PY 2014 VL 9 AR 13 DI 10.1186/1745-6150-9-13 PG 17 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AL1KB UT WOS:000338883200001 PM 24986220 ER PT J AU Fagan-Solis, KD Reaves, DK Rangel, MC Popoff, MR Stiles, BG Fleming, JM AF Fagan-Solis, Katerina D. Reaves, Denise K. Rangel, M. Cristina Popoff, Michel R. Stiles, Bradley G. Fleming, Jodie M. TI Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer SO MOLECULAR CANCER LA English DT Article DE Clostridium perfringens iota toxin; Lipolysis stimulated lipoprotein receptor; CD44; Breast cancer; Endocytosis; Cytotoxicity; Tamoxifen resistance ID AROMATASE INHIBITOR-RESISTANCE; N-GLYCOSYLATION AFFECTS; INCREASED CELL MOTILITY; GENE-THERAPY; REMNANT RECEPTOR; TUMOR SUBTYPES; E-CADHERIN; HYALURONAN; BINDING; METASTASIS AB Background: Translational exploration of bacterial toxins has come to the forefront of research given their potential as a chemotherapeutic tool. Studies in select tissues have demonstrated that Clostridium perfringens iota toxin binds to CD44 and lipolysis stimulated lipoprotein receptor (LSR) cell-surface proteins. We recently demonstrated that LSR expression correlates with estrogen receptor positive breast cancers and that LSR signaling directs aggressive, tumor-initiating cell behaviors. Herein, we identify the mechanisms of iota toxin cytotoxicity in a tissue-specific, breast cancer model with the ultimate goal of laying the foundation for using iota toxin as a targeted breast cancer therapy. Methods: In vitro model systems were used to determine the cytotoxic effect of iota toxin on breast cancer intrinsic subtypes. The use of overexpression and knockdown technologies confirmed the roles of LSR and CD44 in regulating iota toxin endocytosis and induction of cell death. Lastly, cytotoxicity assays were used to demonstrate the effect of iota toxin on a validated set of tamoxifen resistant breast cancer cell lines. Results: Treatment of 14 breast cancer cell lines revealed that LSR+/CD44-lines were highly sensitive, LSR+/CD44+ lines were slightly sensitive, and LSR-/CD44+ lines were resistant to iota cytotoxicity. Reduction in LSR expression resulted in a significant decrease in toxin sensitivity; however, overexpression of CD44 conveyed toxin resistance. CD44 overexpression was correlated with decreased toxin-stimulated lysosome formation and decreased cytosolic levels of iota toxin. These findings indicated that expression of CD44 drives iota toxin resistance through inhibition of endocytosis in breast cancer cells, a role not previously defined for CD44. Moreover, tamoxifen-resistant breast cancer cells exhibited robust expression of LSR and were highly sensitive to iota-induced cytotoxicity. Conclusions: Collectively, these data are the first to show that iota toxin has the potential to be an effective, targeted therapy for breast cancer. C1 [Fagan-Solis, Katerina D.; Reaves, Denise K.; Fleming, Jodie M.] N Carolina Cent Univ, Dept Biol, Durham, NC 27707 USA. [Rangel, M. Cristina] Frederick Natl Lab Canc Res, Lab Canc Prevent, Tumor Growth Factor Sect, Frederick, MD USA. [Popoff, Michel R.] Inst Pasteur, Anaerob Bacteria & Toxins Unit, Paris, France. [Stiles, Bradley G.] Wilson Coll, Dept Biol, Chambersburg, PA USA. RP Fleming, JM (reprint author), N Carolina Cent Univ, Dept Biol, Durham, NC 27707 USA. EM Jodie.fleming@nccu.edu RI Rangel, Maria Cristina/P-7216-2014; Popoff, Michel/O-7719-2016 OI Rangel, Maria Cristina/0000-0002-8002-9617; Popoff, Michel/0000-0001-9305-8989 FU National Cancer Institute [U54 CA156735, R21 CA175783]; National Institute to General Medical Sciences [SC2 GM102012] FX This work was supported by the National Cancer Institute (U54 CA156735 and R21 CA175783) and the National Institute to General Medical Sciences (SC2 GM102012). The authors thank Dr. Kathleen Arcaro from the University of Massachusetts Amherst for kindly provided TMX2-4, TMX2-11, and TMX2-28 cell lines. NR 73 TC 3 Z9 3 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD JUL 2 PY 2014 VL 13 AR 163 DI 10.1186/1476-4598-13-163 PG 15 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AK9EA UT WOS:000338729200001 PM 24990559 ER PT J AU Kobayashi, T Takeuchi, JS Ren, FR Matsuda, K Sato, K Kimura, Y Misawa, N Yoshikawa, R Nakano, Y Yamada, E Tanaka, H Hirsch, VM Koyanagi, Y AF Kobayashi, Tomoko Takeuchi, Junko S. Ren, Fengrong Matsuda, Kenta Sato, Kei Kimura, Yuichi Misawa, Naoko Yoshikawa, Rokusuke Nakano, Yusuke Yamada, Eri Tanaka, Hiroshi Hirsch, Vanessa M. Koyanagi, Yoshio TI Characterization of red-capped mangabey tetherin: implication for the co-evolution of primates and their lentiviruses SO SCIENTIFIC REPORTS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MAXIMUM-LIKELIHOOD; RESTRICTION FACTORS; POSITIVE SELECTION; NONPANDEMIC HIV-1; VPU; EVOLUTION; RELEASE; PROTEIN; ORIGIN AB Primate lentiviruses including human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses (SIVs) evolved through the acquisition of antagonists against intrinsic host restriction factors, such as tetherin. It is widely accepted that HIV-1 has emerged by zoonotic transmission of SIV in chimpanzee (SIVcpz), and that SIVcpz Nef protein antagonizes chimpanzee tetherin. Although Nef of SIVcpz shares a common ancestor with that of SIVrcm, an SIV in red-capped mangabey (Cercocebus torquatus), it remains unclear whether SIVrcm Nef can antagonize tetherin of its natural host. In this study, we determine the sequence of red-capped mangabey tetherin for the first time and directly demonstrate that SIVrcm Nef is the bona fide antagonist of red-capped mangabey tetherin. These findings suggest that SIVrcm Nef is the functional ancestor of SIVcpz Nef. Moreover, molecular phylogenetic analyses reveal that tetherins of the genus Cercocebus have experienced adaptive evolution, which is presumably promoted by primate lentiviruses. C1 [Kobayashi, Tomoko; Takeuchi, Junko S.; Sato, Kei; Kimura, Yuichi; Misawa, Naoko; Yoshikawa, Rokusuke; Nakano, Yusuke; Yamada, Eri; Koyanagi, Yoshio] Kyoto Univ, Inst Virus Res, Lab Viral Pathogenesis, Kyoto 6068507, Japan. [Ren, Fengrong; Tanaka, Hiroshi] Tokyo Med & Dent Univ, Med Res Inst, Dept Bioinformat, Tokyo 1138510, Japan. [Matsuda, Kenta; Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Nakano, Yusuke] Kumamoto Univ, Dept Med Virol, Fac Life Sci, Kumamoto 8608556, Japan. RP Sato, K (reprint author), Kyoto Univ, Inst Virus Res, Lab Viral Pathogenesis, Kyoto 6068507, Japan. EM ksato@virus.kyoto-u.ac.jp FU Aihara Innovative Mathematical Modeling Project; Japan Society for the Promotion of Science through the "Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program)"; Takeda Science Foundation; Sumitomo Foundation Research Grant; Senshin Medical Research Foundation; intramural research program of NIAID, NIH; JSPS [B24390112, S22220007]; Ministry of Education, Culture, Sports, Science and Technology of Japan [24115008]; Ministry of Health, Labor and Welfare of Japan FX We would like to thank Drs. Takashi Fujita (Institute for Virus Research, Kyoto University, Japan), Klaus Strebel (National Institute of Allergy and Infectious Diseases, NIH, USA), Frank Kirchhoff (University of Ulm, Germany), and Beatrice Hahn (University of Pennsylvania, USA) for providing p55A2-Luc, pNL43-Udel, pCGCG-IRES-EGFP, and pMB897, respectively. This study was supported in-part by grants from the following: the Aihara Innovative Mathematical Modeling Project, the Japan Society for the Promotion of Science through the "Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program)," initiated by the Council for Science and Technology Policy of Japan (to K.S.); Takeda Science Foundation (to K.S.); Sumitomo Foundation Research Grant (to K.S.); Senshin Medical Research Foundation (to K.S.); the intramural research program of NIAID, NIH (to K.M. and V.M.H.); Grants-in-Aid for Scientific Research B24390112 (to Y.Koyanagi) and S22220007 (to Y.Koyanagi) from JSPS; a Grant-in-Aid for Scientific Research on Innovative Areas 24115008 (to Y.Koyanagi) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and Research on HIV/AIDS (to Y.Koyanagi) from the Ministry of Health, Labor and Welfare of Japan. NR 58 TC 8 Z9 8 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 2 PY 2014 VL 4 AR 5529 DI 10.1038/srep05529 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK4VA UT WOS:000338421000002 PM 24984862 ER PT J AU Hsieh, MM Fitzhugh, CD Weitzel, RP Link, ME Coles, WA Zhao, XC Rodgers, GP Powell, JD Tisdale, JF AF Hsieh, Matthew M. Fitzhugh, Courtney D. Weitzel, R. Patrick Link, Mary E. Coles, Wynona A. Zhao, Xiongce Rodgers, Griffin P. Powell, Jonathan D. Tisdale, John F. TI Nonmyeloablative HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Severe Sickle Cell Phenotype SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BONE-MARROW-TRANSPLANTATION; LONG-TERM; MIXED CHIMERISM; MAMMALIAN TARGET; DISEASE; ANEMIA; THALASSEMIA; SURVIVAL; FAILURE; INDIVIDUALS AB IMPORTANCE Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicitymay be prohibitive for adults. Nonmyeloablative transplantation has been attempted with degrees of preparative regimen intensity, but graft rejection and graft-vs-host disease remain significant. OBJECTIVE To determine the efficacy, safety, and outcome on end-organ function with this low-intensity regimen for sickle cell phenotype with or without thalassemia. DESIGN, SETTING, AND PARTICIPANTS From July 16, 2004, to October 25, 2013, 30 patients aged 16-65 years with severe disease enrolled in this nonmyeloablative transplant study, consisting of alemtuzumab (1mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells (5.5-31.7 x 10(6) cells/kg) from human leukocyte antigen-matched siblings. MAIN OUTCOMES AND MEASURES The primary end point was treatment success at 1 year after the transplant, defined as a full donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. The secondary end points were the level of donor leukocyte chimerism; incidence of acute and chronic graft-vs-host disease; and sickle cell-thalassemia disease-free survival, immunologic recovery, and changes in organ function, assessed by annual brain imaging, pulmonary function, echocardiographic image, and laboratory testing. RESULTS Twenty-nine patients survived a median 3.4 years (range, 1-8.6), with no nonrelapse mortality. One patient died from intracranial bleeding after relapse. As of October 25, 2013, 26 patients (87%) had long-term stable donor engraftment without acute or chronic graft-vs-host disease. The mean donor T-cell levelwas 48%(95% CI, 34%-62%); the myeloid chimerism levels, 86%(95% CI, 70%-100%). Fifteen engrafted patients discontinued immunosuppression medication with continued stable donor chimerism and no graft-vs-host disease. The normalized hemoglobin and resolution of hemolysis among engrafted patients were accompanied by stabilization in brain imaging, a reduction of echocardiographic estimates of pulmonary pressure, and allowed for phlebotomy to reduce hepatic iron. The mean annual hospitalization rate was 3.23 (95% CI, 1.83-4.63) the year before, 0.63 (95% CI, 0.26-1.01) the first year after, 0.19 (95% CI, 0-0.45) the second year after, and0.11 (95% CI, 0.04-0.19) the third year after transplant. For patients taking long-term narcotics, the mean use per week was 639 mg (95% CI, 220-1058) of intravenous morphine-equivalent dose the week of their transplants and 140 mg (95% CI, 56225) 6 months after transplant. There were 38 serious adverse events: pain and related management, infections, abdominal events, and sirolimus related toxic effects. CONCLUSIONS AND RELEVANCE Among 30 patients with sickle cell phenotype with or without thalassemia who underwent nonmyeloablative allogeneic HSCT, the rate of stable mixed-donor chimerism was high and allowed for complete replacement with circulating donor red blood cells among engrafted participants. Further accrual and follow-up are required to assess longer-term clinical outcomes, adverse events, and transplant tolerance. C1 [Hsieh, Matthew M.; Fitzhugh, Courtney D.; Weitzel, R. Patrick; Link, Mary E.; Coles, Wynona A.; Rodgers, Griffin P.; Tisdale, John F.] NIDDK, Mol & Clin Hematol Branch, Bethesda, MD USA. [Hsieh, Matthew M.; Fitzhugh, Courtney D.; Weitzel, R. Patrick; Link, Mary E.; Coles, Wynona A.; Rodgers, Griffin P.; Tisdale, John F.] NHLBI, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, Off Clin Director, Bethesda, MD USA. [Powell, Jonathan D.] Johns Hopkins Med Inst, Sidney Kimmel Canc Ctr, Baltimore, MD 21205 USA. RP Tisdale, JF (reprint author), NIH, 9000 Rockville Pike,Bldg 10,9N 112, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov FU intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH) FX This work is supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH). NR 36 TC 55 Z9 55 U1 0 U2 8 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 JUL 2 PY 2014 VL 312 IS 1 BP 48 EP 56 DI 10.1001/jama.2014.7192 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AK0UK UT WOS:000338131100020 PM 25058217 ER PT J AU Mertins, P Clauser, KR Mani, DR Gillette, M Fenyo, D Wang, P Paulovich, A Ellis, M Carr, SA AF Mertins, P. Clauser, K. R. Mani, D. R. Gillette, M. Fenyo, D. Wang, P. Paulovich, A. Ellis, M. Carr, S. A. CA Clinical Proteomic Tumor Anal TI Proffered Paper: Proteogenomic analysis of human breast cancer connects genetic alterations to phosphorylation networks SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Mertins, P.; Clauser, K. R.; Mani, D. R.; Gillette, M.; Carr, S. A.] Broad Inst MIT & Harvard, Prote Platform, Cambridge, MA USA. [Fenyo, D.] NYU, Sch Med, New York, NY USA. [Wang, P.] Icahn Sch Med Mt Sinai, Genet & Genom Sci, New York, NY 10029 USA. [Paulovich, A.] Fred Hutchinson Canc Res Ctr, Div Oncol, Dept Med, Seattle, WA 98104 USA. [Ellis, M.] Washington Univ, Sch Med, Div Med Oncol, St Louis, MO USA. [Clinical Proteomic Tumor Anal] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2014 VL 50 SU 5 MA 36 BP S10 EP S10 PG 1 WC Oncology SC Oncology GA CE1RN UT WOS:000351589700034 ER PT J AU Rota, R Carcarino, E De Salvo, M Adesso, L Ciarapica, R Marquez, VE Mai, A Puri, PL Palacios, D Locatelli, F AF Rota, R. Carcarino, E. De Salvo, M. Adesso, L. Ciarapica, R. Marquez, V. E. Mai, A. Puri, P. L. Palacios, D. Locatelli, F. TI Enhancer of Zeste Homolog 2 (EZH2) modulation in either embryonal or PAX3-FOXO1 alveolar rhabdomyosarcoma shows different anti-tumoral effects SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Rota, R.; De Salvo, M.; Adesso, L.; Ciarapica, R.; Locatelli, F.] Osped Pediat Bambino Gesu, Oncohematol, Rome, Italy. [Carcarino, E.; Palacios, D.] EBRI Santa Lucia, Dulbecco Telethon Inst, Muscle Dis, Rome, Italy. [Marquez, V. E.] NCI, CCR, NIH, Frederick Natl Lab Canc Res, Frederick, MA USA. [Mai, A.] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, I-00185 Rome, Italy. [Puri, P. L.] Sanford Burnham Med Res Inst, Muscle Dev & Regenerat Program, La Jolla, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2014 VL 50 SU 5 MA 453 BP S109 EP S110 PG 2 WC Oncology SC Oncology GA CE1RN UT WOS:000351589701044 ER PT J AU Sharma, V Bisio, A Ciribilli, Y Jordan, J Resnick, MA Inga, A AF Sharma, V. Bisio, A. Ciribilli, Y. Jordan, J. Resnick, M. A. Inga, A. TI Quantitative analysis of NF kappa B transactivation abilities using a yeast-based in vivo functional assay SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Sharma, V.; Bisio, A.; Ciribilli, Y.; Jordan, J.; Inga, A.] Univ Trento, Lab Transcript Networks, Ctr Integrat Biol CIBIO, Trento, Italy. [Resnick, M. A.] NIEHS, Res Triangle Pk, NC 27709 USA. [Resnick, M. A.] Chromosome Stabil Grp, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2014 VL 50 SU 5 MA 542 BP S131 EP S131 PG 1 WC Oncology SC Oncology GA CE1RN UT WOS:000351589701121 ER PT J AU Srivastava, S AF Srivastava, S. TI The NCI early detection research network: Charting the course of biomarker research SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Srivastava, S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2014 VL 50 SU 5 MA 56 BP S14 EP S14 PG 1 WC Oncology SC Oncology GA CE1RN UT WOS:000351589700051 ER PT J AU Chen, KG Hamilton, RS Robey, PG Mallon, BS AF Chen, Kevin G. Hamilton, Rebecca S. Robey, Pamela G. Mallon, Barbara S. TI Alternative Cultures for Human Pluripotent Stem Cell Production, Maintenance, and Genetic Analysis SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Stem Cell Biology; Issue 89; Pluripotent stem cells; human embryonic stem cells; induced pluripotent stem cells; cell culture; non-colony type monolayer; single cell; plating efficiency; Rho-associated kinase; Y-27632; transfection; transduction ID IN-VITRO; SELF-RENEWAL; DIFFERENTIATION; MANIPULATION; LAMININ-511; ADAPTATION; SUSPENSION; EXPANSION; NICHE; VIVO AB Human pluripotent stem cells (hPSCs) hold great promise for regenerative medicine and biopharmaceutical applications. Currently, optimal culture and efficient expansion of large amounts of clinical-grade hPSCs are critical issues in hPSC-based therapies. Conventionally, hPSCs are propagated as colonies on both feeder and feeder-free culture systems. However, these methods have several major limitations, including low cell yields and generation of heterogeneously differentiated cells. To improve current hPSC culture methods, we have recently developed a new method, which is based on non-colony type monolayer (NCM) culture of dissociated single cells. Here, we present detailed NCM protocols based on the Rho-associated kinase (ROCK) inhibitor Y-27632. We also provide new information regarding NCM culture with different small molecules such as Y-39983 (ROCK I inhibitor), phenylbenzodioxane (ROCK II inhibitor), and thiazovivin (a novel ROCK inhibitor). We further extend our basic protocol to cultivate hPSCs on defined extracellular proteins such as the laminin isoform 521 (LN-521) without the use of ROCK inhibitors. Moreover, based on NCM, we have demonstrated efficient transfection or transduction of plasmid DNAs, lentiviral particles, and oligonucleotide-based microRNAs into hPSCs in order to genetically modify these cells for molecular analyses and drug discovery. The NCM-based methods overcome the major shortcomings of colony-type culture, and thus may be suitable for producing large amounts of homogeneous hPSCs for future clinical therapies, stem cell research, and drug discovery. C1 [Chen, Kevin G.; Hamilton, Rebecca S.; Mallon, Barbara S.] NINDS, NIH Stem Cell Unit, NIH, Bethesda, MD 20892 USA. [Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Chen, KG (reprint author), NINDS, NIH Stem Cell Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM cheng@mail.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Intramural Research Program of the National Institutes of Health (NIH) at the National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) at the National Institute of Neurological Disorders and Stroke. We would like to thank Dr. Ronald D. McKay for his discussion and comments on this project. NR 28 TC 0 Z9 0 U1 2 U2 13 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUL PY 2014 IS 89 AR e51519 DI 10.3791/51519 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB0DR UT WOS:000349296100034 ER PT J AU Hipp, JD Cheng, J Hanson, JC Rosenberg, AZ Emmert-Buck, MR Tangrea, MA Balis, UJ AF Hipp, Jason D. Cheng, Jerome Hanson, Jeffrey C. Rosenberg, Avi Z. Emmert-Buck, Michael R. Tangrea, Michael A. Balis, Ulysses J. TI SIVQ-LCM Protocol for the ArcturusXT Instrument SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Bioengineering; Issue 89; SIVQ; LCM; personalized medicine; digital pathology; image analysis; ArcturusXT ID LASER-CAPTURE MICRODISSECTION; TISSUE; EXPRESSION AB SIVQ-LCM is a new methodology that automates and streamlines the more traditional, user-dependent laser dissection process. It aims to create an advanced, rapidly customizable laser dissection platform technology. In this report, we describe the integration of the image analysis software Spatially Invariant Vector Quantization (SIVQ) onto the ArcturusXT instrument. The ArcturusXT system contains both an infrared (IR) and ultraviolet (UV) laser, allowing for specific cell or large area dissections. The principal goal is to improve the speed, accuracy, and reproducibility of the laser dissection to increase sample throughput. This novel approach facilitates microdissection of both animal and human tissues in research and clinical workflows. C1 [Hipp, Jason D.; Hanson, Jeffrey C.; Rosenberg, Avi Z.; Emmert-Buck, Michael R.; Tangrea, Michael A.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Cheng, Jerome; Balis, Ulysses J.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. RP Tangrea, MA (reprint author), NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. EM tangream@mail.nih.gov OI Rosenberg, Avi/0000-0003-2356-950X FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX The study was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 23 TC 0 Z9 0 U1 1 U2 4 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUL PY 2014 IS 89 AR e51662 DI 10.3791/51662 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB0DR UT WOS:000349296100057 ER PT J AU Lerit, DA Plevock, KM Rusan, NM AF Lerit, Dorothy A. Plevock, Karen M. Rusan, Nasser M. TI Live Imaging of Drosophila Larval Neuroblasts SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Neuroscience; Issue 89; live imaging; Drosophila; neuroblast; stem cell; asymmetric division; centrosome; brain; cell cycle; mitosis ID CENTRAL-NERVOUS-SYSTEM; GANGLION MOTHER CELLS; NEURAL STEM-CELLS; SPINDLE ORIENTATION; EXTRINSIC CUES; CENTROSOME; MELANOGASTER; ASYMMETRY; CENTRIOLE; DIVISION AB Stem cells divide asymmetrically to generate two progeny cells with unequal fate potential: a self-renewing stem cell and a differentiating cell. Given their relevance to development and disease, understanding the mechanisms that govern asymmetric stem cell division has been a robust area of study. Because they are genetically tractable and undergo successive rounds of cell division about once every hour, the stem cells of the Drosophila central nervous system, or neuroblasts, are indispensable models for the study of stem cell division. About 100 neural stem cells are located near the surface of each of the two larval brain lobes, making this model system particularly useful for live imaging microscopy studies. In this work, we review several approaches widely used to visualize stem cell divisions, and we address the relative advantages and disadvantages of those techniques that employ dissociated versus intact brain tissues. We also detail our simplified protocol used to explant whole brains from third instar larvae for live cell imaging and fixed analysis applications. C1 [Lerit, Dorothy A.; Plevock, Karen M.; Rusan, Nasser M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Rusan, NM (reprint author), NHLBI, NIH, Bethesda, MD 20892 USA. EM nasser@nih.gov RI Rusan, Nasser/P-3511-2016 FU division of intramural research at the National Institutes of Health/NHLBI [1ZIAHL006126]; Lenfant Biomedical Postdoctoral Fellowship FX This work was supported by the division of intramural research at the National Institutes of Health/NHLBI (1ZIAHL006126) and a Lenfant Biomedical Postdoctoral Fellowship awarded to DAL. NR 38 TC 3 Z9 3 U1 1 U2 1 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUL PY 2014 IS 89 AR e51756 DI 10.3791/51756 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB0DR UT WOS:000349296100073 ER PT J AU Daar, I AF Daar, Ira TI Foreword SO CELL ADHESION & MIGRATION LA English DT Editorial Material C1 NCI, Dev Signal Transduct Sect, Lab Cell & Dev Signaling, Frederick, MD 21701 USA. RP Daar, I (reprint author), NCI, Dev Signal Transduct Sect, Lab Cell & Dev Signaling, Frederick, MD 21701 USA. EM daar@ncifcrf.gov OI Daar, Ira/0000-0003-2657-526X NR 0 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1933-6918 EI 1933-6926 J9 CELL ADHES MIGR JI Celll Adhes. Migr. PD JUL-AUG PY 2014 VL 8 IS 4 SI SI BP 293 EP 293 DI 10.4161/19336918.2014.987059 PG 1 WC Cell Biology SC Cell Biology GA AZ6HL UT WOS:000348320500001 PM 25482614 ER PT J AU Kwon-Chung, KJ Fraser, JA Doering, TL Wang, ZA Janbon, G Idnurm, A Bahn, YS AF Kwon-Chung, Kyung J. Fraser, James A. Doering, Tamara L. Wang, Zhuo A. Janbon, Guilhem Idnurm, Alexander Bahn, Yong-Sun TI Cryptococcus neoformans and Cryptococcus gattii, the Etiologic Agents of Cryptococcosis SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID FUNGAL PATHOGEN CRYPTOCOCCUS; TEMPERATURE-REGULATED GENES; UDP-GLUCOSE DEHYDROGENASE; GDP-MANNOSE TRANSPORTERS; CENTRAL-NERVOUS-SYSTEM; VIRULENCE FACTORS; BRITISH-COLUMBIA; AMPHOTERICIN-B; FILOBASIDIELLA-NEOFORMANS; CAPSULAR POLYSACCHARIDE AB Cryptococcus neoformans and Cryptococcus gattii are the two etiologic agents of cryptococcosis. They belong to the phylum Basidiomycota and can be readily distinguished from other pathogenic yeasts such as Candida by the presence of a polysaccharide capsule, formation of melanin, and urease activity, which all function as virulence determinants. Infection proceeds via inhalation and subsequent dissemination to the central nervous system to cause meningoencephalitis. The most common risk for cryptococcosis caused by C. neoformans is AIDS, whereas infections caused by C. gattii are more often reported in immunocompetent patients with undefined risk than in the immunocompromised. There have been many chapters, reviews, and books written on C. neoformans. The topicswe focus on in this article include species description, pathogenesis, life cycle, capsule, and stress response, which serve to highlight the specializations in virulence that have occurred in this unique encapsulated melanin-forming yeast that causes global deaths estimated at more than 600,000 annually. C1 [Kwon-Chung, Kyung J.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Fraser, James A.] Univ Queensland, Australian Infect Dis Res Ctr, Brisbane, Qld 4072, Australia. [Doering, Tamara L.; Wang, Zhuo A.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Janbon, Guilhem] Inst Pasteur, Unite Biol & Pathogen Fong, F-75015 Paris, France. [Idnurm, Alexander] Univ Missouri, Sch Biol Sci, Div Cell Biol & Biophys, Kansas City, MO 64110 USA. [Bahn, Yong-Sun] Yonsei Univ, Coll Life Sci & Biotechnol, Dept Biotechnol, Seoul 120749, South Korea. RP Kwon-Chung, KJ (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jkchung@niaid.nih.gov RI Idnurm, Alexander/K-8558-2013; OI Idnurm, Alexander/0000-0001-5995-7040; Janbon, Guilhem/0000-0002-4788-1154 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD; National Research Foundation of Korea Grant from MEST [20080061963, 2010-0029117]; NIAID [78795, 87794, 102882, 109623] FX K.J.K-C. is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD and Y.-S.B. is supported by the National Research Foundation of Korea Grant Nos. 20080061963 and 2010-0029117 from MEST. T.L.D. is supported by NIAID Grant Nos. 78795, 87794, 102882, and 109623. NR 252 TC 29 Z9 31 U1 3 U2 17 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD JUL PY 2014 VL 4 IS 7 AR a019760 DI 10.1101/cshperspect.a019760 PG 27 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AW8NB UT WOS:000346518000003 PM 24985132 ER PT J AU Nakao, K Nakazawa, K AF Nakao, Kazuhito Nakazawa, Kazu TI Brain state-dependent abnormal LFP activity in the auditory cortex of a schizophrenia mouse model SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE auditory steady-state responses; GABAergic interneurons; gamma oscillation; local field potentials; NMDA receptors; parvalbumin; schizophrenia; mouse models ID STEADY-STATE; NEOCORTICAL NEURONS; GAMMA-OSCILLATIONS; NEURAL SYNCHRONY; WORKING-MEMORY; VISUAL-CORTEX; FREQUENCY; EEG; RAT; HALLUCINATIONS AB In schizophrenia, evoked 40-Hz auditory steady-state responses (ASSRs) are impaired, which reflects the sensory deficits in this disorder, and baseline spontaneous oscillatory activity also appears to be abnormal. It has been debated whether the evoked ASSR impairments are due to the possible increase in baseline power. GABAergic interneuron-specific NMDA receptor (NMDAR) hypofunction mutant mice mimic some behavioral and pathophysiological aspects of schizophrenia. To determine the presence and extent of sensory deficits in these mutant mice, we recorded spontaneous local field potential (LFP) activity and its click-train evoked ASSRs from primary auditory cortex of awake, head-restrained mice. Baseline spontaneous LFP power in the pre-stimulus period before application of the first click trains was augmented at a wide range of frequencies. However, when repetitive ASSR stimuli were presented every 20s, averaged spontaneous LFP power amplitudes during the inter-ASSR stimulus intervals in the mutant mice became indistinguishable from the levels of control mice. Nonetheless, the evoked 40-Hz ASSR power and their phase locking to click trains were robustly impaired in the mutants, although the evoked 20-Hz ASSRs were also somewhat diminished. These results suggested that NMDAR hypofunction in cortical GABAergic neurons confers two brain state-dependent LFP abnormalities in the auditory cortex; (1) a broadband increase in spontaneous LFP power in the absence of external inputs, and (2) a robust deficit in the evoked ASSR power and its phase-locking despite of normal baseline LFP power magnitude during the repetitive auditory stimuli. The "paradoxically" high spontaneous LFP activity of the primary auditory cortex in the absence of external stimuli may possibly contribute to the emergence of schizophrenia-related aberrant auditory perception. C1 [Nakao, Kazuhito; Nakazawa, Kazu] Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA. [Nakao, Kazuhito; Nakazawa, Kazu] NIMH, Unit Genet Cognit & Behav, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Nakazawa, K (reprint author), Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Shelby Bldg 1105,1825 Univ Blvd, Birmingham, AL 35294 USA. EM nakazawk@uab.edu OI Nakazawa, Kazutoshi/0000-0001-5699-9093 FU NIH [K22MH099164]; NIH Intramural Research Program FX This work was supported by an NIH grant K22MH099164 (Kazu Nakazawa) and by NIH Intramural Research Program. We thank Stefan Kolata and Kentaroh Takagaki for their advice on the earlier version of manuscript. NR 79 TC 10 Z9 10 U1 2 U2 8 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD JUL 1 PY 2014 VL 8 AR 168 DI 10.3389/fnins.2014.00168 PG 12 WC Neurosciences SC Neurosciences & Neurology GA AW8FK UT WOS:000346496200002 PM 25018691 ER PT J AU Keselman, A Smith, CA Hundal, S AF Keselman, Alla Smith, Catherine Arnott Hundal, Savreen TI Library workers' personal beliefs about childhood vaccination and vaccination information provision SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article ID CHILDREN; PARENTS AB This is a report on the impact of library workers' personal beliefs on provision of vaccination information. Nine public librarians were interviewed about a hypothetical scenario involving a patron who is concerned about possible vaccination-autism connections. The analysis employed thematic coding. Results suggested that while most participants supported childhood vaccination, tension between their personal views and neutrality impacted their ability to conduct the interaction. The neutrality stance, though consonant with professional guidelines, curtails librarians' ability to provide accurate health information. Outreach and communication between public and health sciences libraries can help librarians provide resources to address health controversies. C1 [Keselman, Alla] US Natl Lib Med, Div Specialized Informat Serv, Bethesda, MD 20892 USA. [Smith, Catherine Arnott] Univ Wisconsin, Sch Lib & Informat Studies, Madison, WI 53706 USA. [Hundal, Savreen] Ctr Publ Serv Commun, Claiborne, MD 21624 USA. RP Keselman, A (reprint author), US Natl Lib Med, Div Specialized Informat Serv, 6707 Democracy Blvd,Suite 510, Bethesda, MD 20892 USA. EM keselmana@mail.nih.gov; casmith24@wisc.edu; savreenhundal@gmail.com FU Intramural NIH HHS NR 16 TC 2 Z9 2 U1 1 U2 5 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD JUL PY 2014 VL 102 IS 3 BP 205 EP U73 DI 10.3163/1536-5050.102.3.012 PG 6 WC Information Science & Library Science SC Information Science & Library Science GA AW2UW UT WOS:000346145700012 PM 25031563 ER PT J AU Tiro, JA Kamineni, A Levin, TR Zheng, YY Schottinger, JS Rutter, CM Corley, DA Skinner, CS Chubak, J Doubeni, CA Halm, EA Gupta, S Wemli, KJ Klabunde, C AF Tiro, Jasmin A. Kamineni, Aruna Levin, Theodore R. Zheng, Yingye Schottinger, Joanne S. Rutter, Carolyn M. Corley, Douglas A. Skinner, Celette S. Chubak, Jessica Doubeni, Chyke A. Halm, Ethan A. Gupta, Samir Wemli, Karen J. Klabunde, Carrie TI The Colorectal Cancer Screening Process in Community Settings: A Conceptual Model for the Population-Based Research Optimizing Screening through Personalized Regimens Consortium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID COLLEGE-OF-RADIOLOGY; SERVICES TASK-FORCE; INSTRUMENTAL VARIABLES; CERVICAL-CANCER; CARE CONTINUUM; FOLLOW-UP; PERFORMANCE-CHARACTERISTICS; COLONOSCOPY INDICATION; MULTILEVEL FACTORS; RISK-FACTORS AB Reducing colorectal cancer mortality by promoting screening has been a national goal for two decades. The NCI's Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium is the first federal initiative to foster coordinated, transdisciplinary research evaluating the entire cancer screening process in community settings. PROSPR is creating a central data repository to facilitate research evaluating the breast, cervical, and colorectal cancer screening process across different patient populations, provider types, and delivery systems. Data are being collected and organized at the multiple levels in which individuals are nested (e.g., healthcare systems, facilities, providers, and patients). Here, we describe a conceptual model of the colorectal cancer screening process guiding data collection and highlight critical research questions that will be addressed through pooled data. We also describe the three research centers focused on colorectal cancer screening with respect to study populations, practice settings, and screening policies. PROSPR comprehensively elucidates the complex screening process through observational study, and has potential to improve care delivery beyond the healthcare systems studied. Findings will inform intervention designs and policies to optimize colorectal cancer screening delivery and advance the Institute of Medicine's goals of effective, efficient, coordinated, timely, and safe health care with respect to evidence-based cancer screening. (C) 2014 AACR. C1 [Tiro, Jasmin A.; Skinner, Celette S.; Halm, Ethan A.] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Tiro, Jasmin A.; Skinner, Celette S.; Wemli, Karen J.] Harold C Simmons Canc Ctr, Dallas, TX USA. [Kamineni, Aruna; Rutter, Carolyn M.; Chubak, Jessica; Wemli, Karen J.] Fred Hutchinson Canc Res Ctr, Grp Hlth Res Inst, Seattle, WA 98104 USA. [Zheng, Yingye] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Corley, Douglas A.] Kaiser Permanente, Div Res, Oakland, CA USA. [Schottinger, Joanne S.] Kaiser Permanente Southern Calif, Pasadena, CA USA. [Gupta, Samir] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Gupta, Samir] Univ Calif San Diego, Div Gastroenterol, La Jolla, CA 92093 USA. [Klabunde, Carrie] NCI, NIH, Bethesda, MD 20892 USA. [Doubeni, Chyke A.] Univ Penn, Perelman Sch Med, Dept Family Med & Community Hlth, Philadelphia, PA 19104 USA. RP Tiro, JA (reprint author), Univ Texas SW Med Ctr Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM jasmin.tiro@utsouthwestern.edu OI Doubeni, Chyke/0000-0001-7495-0285; Tiro, Jasmin/0000-0001-8300-0441 FU NCI [5U54CA163308, 5U54CA163261, 5U54CA163262, 5U01CA163304] FX This research was funded by the NCI. J.A. Tiro, C.S. Skinner, E.A. Halm, and S. Gupta were supported by grant 5U54CA163308. A. Kamineni, C.M. Rutter, J. Chubak, and K.J. Wernli were supported by 5U54CA163261. T.R. Levin, J.S. Schottinger, D.A. Corley, and C.A. Doubeni were supported by 5U54CA163262. Y. Zheng was supported by 5U01CA163304. NR 64 TC 17 Z9 17 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2014 VL 23 IS 7 BP 1147 EP 1158 DI 10.1158/1055-9965.EPI-13-1217 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WE UT WOS:000345273700002 PM 24917182 ER PT J AU Coghill, AE Hsu, WL Pfeiffer, RM Juwana, H Yu, KJ Lou, PJ Wang, CP Chen, JY Chen, CJ Middeldorp, JM Hildesheim, A AF Coghill, Anna E. Hsu, Wan-Lun Pfeiffer, Ruth M. Juwana, Hedy Yu, Kelly J. Lou, Pei-Jen Wang, Cheng-Ping Chen, Jen-Yang Chen, Chien-Jen Middeldorp, Jaap M. Hildesheim, Allan TI Epstein-Barr Virus Serology as a Potential Screening Marker for Nasopharyngeal Carcinoma among High-Risk Individuals from Multiplex Families in Taiwan SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ANTIBODY-POSITIVE PERSONS; WUZHOU-CITY; CHINA; PATHOGENESIS; INFECTION; NPC AB Background: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated cancer that is highly treatable when diagnosed early, with 5-year disease-free survival of approximately 90%. However, NPC is typically diagnosed at advanced stages, in which disease-free survival is <50%. There is, therefore, a need for clinical tools to assist in early NPC detection, particularly among high-risk individuals. Methods: We evaluated the ability of anti-EBV IgA antibodies to detect incident NPC among high-risk Taiwanese individuals. NPC cases (N = 21) and age-and sex-matched controls (N = 84) were selected. Serum collected before NPC diagnosis was tested for ELISA-based IgA antibodies against the following EBV peptides: EBNA1, VCAp18, EAp138, Ead_p47, and VCAp18 _EBNA1 peptide mixture. The sensitivity, specificity, and screening program parameters were calculated. Results: EBNA1 IgA had the best performance characteristics. At an optimized threshold value, EBNA1 IgA measured at baseline identified 80% of the high-risk individuals who developed NPC during follow-up (80% sensitivity). However, approximately 40% of high-risk individuals who did not develop NPC also tested positive (false positives). Application of EBNA1 IgA as a biomarker to detect incident NPC in a previously unscreened, high-risk population revealed that 164 individuals needed to be screened to detect 1 NPC and that 69 individuals tested positive per case detected. Conclusions: EBNA1 IgA proved to be a sensitive biomarker for identifying incident NPC, but future work is warranted to develop more specific screening tools to decrease the number of false positives. Impact: Results from this study could inform decisions about screening biomarkers and referral thresholds for future NPC early-detection program evaluations. (C) 2014 AACR. C1 [Coghill, Anna E.; Pfeiffer, Ruth M.; Yu, Kelly J.; Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Yu, Kelly J.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Hsu, Wan-Lun; Chen, Chien-Jen] Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol, Taipei 10764, Taiwan. [Hsu, Wan-Lun; Chen, Chien-Jen] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan. [Lou, Pei-Jen; Wang, Cheng-Ping] Natl Taiwan Univ Hosp, Dept Otolaryngol, Taipei, Taiwan. [Lou, Pei-Jen; Wang, Cheng-Ping] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. [Chen, Jen-Yang] Natl Hlth Res Inst, Natl Inst Canc Res, Miaoli, Taiwan. [Middeldorp, Jaap M.] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands. RP Coghill, AE (reprint author), NCI, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM anna.coghill@nih.gov RI Chen, Chien-Jen/C-6976-2008; Hildesheim, Allan/B-9760-2015; Chen, Jen-Yang/D-2085-2010; OI Hildesheim, Allan/0000-0003-0257-2363; WANG, CHENG-PING/0000-0001-7872-1463; LOU, PEI-JEN/0000-0002-3383-8593; Middeldorp, Jaap/0000-0002-0765-4125 FU intramural program at the National Cancer Institute FX This work was funded by the intramural program at the National Cancer Institute. NR 28 TC 5 Z9 6 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2014 VL 23 IS 7 BP 1213 EP 1219 DI 10.1158/1055-9965.EPI-13-1262 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WE UT WOS:000345273700009 PM 24769890 ER PT J AU Stott-Miller, M Zhao, SS Wright, JL Kolb, S Bibikova, M Klotzle, B Ostrander, EA Fan, JB Feng, ZD Stanford, JL AF Stott-Miller, Marni Zhao, Shanshan Wright, Jonathan L. Kolb, Suzanne Bibikova, Marina Klotzle, Brandy Ostrander, Elaine A. Fan, Jian-Bing Feng, Ziding Stanford, Janet L. TI Validation Study of Genes with Hypermethylated Promoter Regions Associated with Prostate Cancer Recurrence SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID DNA METHYLATION; CLINICOPATHOLOGICAL FEATURES; BIOCHEMICAL RECURRENCE; RADICAL PROSTATECTOMY; HOMEOBOX GENES; PROGRESSION; HOXB13; RISK; DISEASE; CD44 AB Background: One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed. Methods: We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the Surveillance, Epidemiology, and End Results (SEER) registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared with those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined. Results: During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46 x 10(-6)), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2 x 10(-4)). DNA methylation profiles did not differ by recurrence status for the other genes. Conclusions: These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and prostate cancer recurrence. Impact: Tumor DNA methylation profiling may help to distinguish patients with prostate cancer at higher risk for disease recurrence. (C)2014 AACR. C1 [Stott-Miller, Marni; Zhao, Shanshan; Wright, Jonathan L.; Kolb, Suzanne; Feng, Ziding; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Wright, Jonathan L.] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Feng, Ziding] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Stanford, Janet L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Bibikova, Marina; Klotzle, Brandy; Fan, Jian-Bing] Illumina Inc, San Diego, CA USA. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Stanford, JL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,M4-B874, Seattle, WA 98109 USA. EM jstanfor@fhcrc.org OI Ostrander, Elaine/0000-0001-6075-9738 FU National Cancer Institute [R01 CA056678, R01 CA092579, P50 CA097186]; Fred Hutchinson Cancer Research Center; Prostate Cancer Foundation FX This work was supported by grants from the National Cancer Institute (R01 CA056678, R01 CA092579, and P50 CA097186 to J.L. Stanford), with additional support provided by the Fred Hutchinson Cancer Research Center and the Prostate Cancer Foundation. NR 52 TC 10 Z9 10 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2014 VL 23 IS 7 BP 1331 EP 1339 DI 10.1158/1055-9965.EPI-13-1000 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WE UT WOS:000345273700023 PM 24718283 ER PT J AU Kweon, SS Shu, XO Xiang, YB Yang, G Ji, BT Li, HL Gao, YT Zheng, W Shrubsole, MJ AF Kweon, Sun-Seog Shu, Xiao-Ou Xiang, Yongbing Yang, Gong Ji, Bu-Tian Li, Honglan Gao, Yu-Tang Zheng, Wei Shrubsole, Martha J. TI One-Carbon Metabolism Dietary Factors and Distal Gastric Cancer Risk in Chinese Women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FOLIC-ACID SUPPLEMENTATION; B VITAMIN; METHYLENETETRAHYDROFOLATE-REDUCTASE; SHANGHAI WOMENS; DNA METHYLATION; NUTRIENT INTAKE; RIBOFLAVIN DEFICIENCY; ESOPHAGEAL CANCER; FOLATE-DEFICIENCY; STOMACH-CANCER AB Background: Previous studies on the association between one-carbon dietary factors and gastric cancer risk have been inconsistent. Methods: We investigated this association using data from a prospective study, the Shanghai Women's Health Study (1997-2010), including 323 distal gastric cancer cases identified from 73,009 Chinese women. HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression after adjusting for confounders. Results: Overall, no statistically significant association of gastric cancer was observed with dietary intake of folate, methionine, or B vitamins. However, when stratified by menopausal status, higher intake of riboflavin was associated with decreased gastric cancer risk in premenopausal women with HR of 0.35 (95% CI, 0.17-0.73), 0.48 (0.24-0.97), 0.28 (0.12-0.65), and 0.23 (0.07-0.91), respectively, for the quintiles 2 to 5 intake groups compared with the lowest quintile intake (P for trend = 0.02). Among premenopausal women, highest intake of folate was associated with increased gastric cancer risk (HR, 2.62; 95% CI, 1.04-6.59). There were no statistically significant associations observed among postmenopausal women. Conclusions: These results suggest that dietary factors involved in one-carbon metabolism are associated with gastric cancer risk among premenopausal women. Impact: Riboflavin may be a protective factor and folate may be a risk factor for premenopausal gastric cancer. (C)2014 AACR. C1 [Kweon, Sun-Seog; Shu, Xiao-Ou; Yang, Gong; Zheng, Wei; Shrubsole, Martha J.] Vanderbilt Univ, Sch Med, Dept Med, Vanderbilt Ingram Canc Ctr,Div Epidemiol, Nashville, TN 37203 USA. [Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Xiang, Yongbing; Li, Honglan; Gao, Yu-Tang] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Shanghai Canc Inst,Dept Epidemiol, Shanghai 200030, Peoples R China. [Kweon, Sun-Seog] Chonnam Natl Univ, Sch Med, Dept Prevent Med, Kwangju, South Korea. RP Shrubsole, MJ (reprint author), Vanderbilt Univ, Sch Med, Eighth Floor,Suite 800,2525 West End Ave, Nashville, TN 37203 USA. EM martha.shrubsole@vanderbilt.edu RI Shrubsole, Martha/K-5052-2015 OI Shrubsole, Martha/0000-0002-5591-7575 FU NCI [R37 CA70867, K07CA122451] FX This project was supported by R37 CA70867 ( to W. Zheng) and K07CA122451 ( to M.J. Shrubsole) from the NCI. NR 66 TC 2 Z9 2 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2014 VL 23 IS 7 BP 1374 EP 1382 DI 10.1158/1055-9965.EPI-14-0038 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WE UT WOS:000345273700028 PM 24789845 ER PT J AU Olson, SH Hsu, M Wiemels, JL Bracci, PM Zhou, M Patoka, J Reisacher, WR Wang, J Kurtz, RC Silverman, DT Stolzenberg-Solomon, RZ AF Olson, Sara H. Hsu, Meier Wiemels, Joseph L. Bracci, Paige M. Zhou, Mi Patoka, Joseph Reisacher, William R. Wang, Julie Kurtz, Robert C. Silverman, Debra T. Stolzenberg-Solomon, Rachael Z. TI Serum Immunoglobulin E and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NUTRITION EXAMINATION SURVEY; FOOD ALLERGY; NATIONAL-HEALTH; IGE LEVELS; COHORT; GLIOMA; ADULTS; SENSITIZATION; EPIDEMIOLOGY; PREVALENCE AB Epidemiologic studies have consistently found that self-reported allergies are associated with reduced risk of pancreatic cancer. Our aim was to prospectively assess the relationship between serum immunoglobulin E (IgE), a marker of allergy, and risk. This nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) included subjects enrolled in 1994 to 2001 and followed through 2010. There were 283 cases of pancreatic cancer and 544 controls matched on age, gender, race, and calendar date of blood draw. Using the ImmunoCAP system, we measured total IgE (normal, borderline, elevated), IgE to respiratory allergens, and IgE to food allergens (negative or positive) in serum collected at baseline. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. We assessed interactions with age, gender, smoking, body mass index, and time between randomization and case diagnosis. Overall, there was no association between the IgE measures and risk. We found a statistically significant interaction by baseline age: in those aged >= 65 years, elevated risks were observed for borderline total IgE (OR, 1.43; 95% CI, 0.88-2.32) and elevated total IgE (OR, 1.98; 95% CI, 1.16-3.37) and positive IgE to food allergens (OR, 2.83; 95% CI, 1.29-6.20); among participants <65 years, ORs were <1. Other interactions were not statistically significant. The reduced risk of pancreatic cancer associated with self-reported allergies is not reflected in serum IgE. (C)2014 AACR. C1 [Olson, Sara H.; Hsu, Meier] Weill Cornell Med Coll, Dept Epidemiol & Biostat, New York, NY USA. [Kurtz, Robert C.] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY USA. [Wang, Julie] Weill Cornell Med Coll, Mt Sinai Med Ctr, Div Pediat Allergy & Immunol, New York, NY USA. [Reisacher, William R.] Weill Cornell Med Coll, Dept Otolaryngol Head & Neck Surg, New York, NY USA. [Wiemels, Joseph L.; Bracci, Paige M.; Zhou, Mi; Patoka, Joseph] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. [Silverman, Debra T.] NCI, Occupat & Environm Epidemiol Branch, Rockville, MD USA. [Stolzenberg-Solomon, Rachael Z.] NCI, Div Canc Epidemiol & Genet, Branch Nutr Epidemiol, Rockville, MD USA. RP Olson, SH (reprint author), 307 East 63rd St, New York, NY 10065 USA. EM olsons@mskcc.org FU [U01CA150138] FX This project was supported by U01CA150138 to Dr. S.H. Olson. NR 23 TC 4 Z9 4 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2014 VL 23 IS 7 BP 1414 EP 1420 DI 10.1158/1055-9965.EPI-13-1359 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WE UT WOS:000345273700032 PM 24718282 ER PT J AU Block, MS Charbonneau, B Vierkant, RA Fogarty, Z Bamlet, WR Pharoah, PDP Chenevix-Trench, G Rossing, MA Cramer, D Pearce, CL Schildkraut, J Menon, U Kjaer, SK Levine, DA Gronwald, J Culver, HA Whittemore, AS Karlan, BY Lambrechts, D Wentzensen, N Kupryjanczyk, J Chang-Claude, J Bandera, EV Hogdall, E Heitz, F Kaye, SB Fasching, PA Campbell, I Goodman, MT Pejovic, T Bean, YT Hays, LE Lurie, G Eccles, D Hein, A Beckmann, MW Ekici, AB Paul, J Brown, R Flanagan, JM Harter, P du Bois, A Schwaab, I Hogdall, CK Lundvall, L Olson, SH Orlow, I Paddock, LE Rudolph, A Eilber, U Dansonka-Mieszkowska, A Rzepecka, IK Ziolkowska-Seta, I Brinton, LA Yang, HN Garcia-Closas, M Despierre, E Lambrechts, S Vergote, I Walsh, CS Lester, J Sieh, W McGuire, V Rothstein, JH Ziogas, A Lubinski, J Cybulski, C Menkiszak, J Jensen, A Gayther, SA Ramus, SJ Gentry-Maharaj, A Berchuck, A Wu, AH Pike, MC Van Den Berg, D Terry, KL Vitonis, AF Ramirez, SM Rider, DN Knutson, KL Sellers, TA Phelan, CM Doherty, JA Johnatty, SE deFazio, A Song, HL Tyrer, J Kalli, KR Fridley, BL Cunningham, JM Goode, EL AF Block, Matthew S. Charbonneau, Bridget Vierkant, Robert A. Fogarty, Zachary Bamlet, William R. Pharoah, Paul D. P. Chenevix-Trench, Georgia Rossing, Mary Anne Cramer, Daniel Pearce, Celeste Leigh Schildkraut, Joellen Menon, Usha Kjaer, Susanne K. Levine, Douglas A. Gronwald, Jacek Culver, Hoda Anton Whittemore, Alice S. Karlan, Beth Y. Lambrechts, Diether Wentzensen, Nicolas Kupryjanczyk, Jolanta Chang-Claude, Jenny Bandera, Elisa V. Hogdall, Estrid Heitz, Florian Kaye, Stanley B. Fasching, Peter A. Campbell, Ian Goodman, Marc T. Pejovic, Tanja Bean, Yukie T. Hays, Laura E. Lurie, Galina Eccles, Diana Hein, Alexander Beckmann, Matthias W. Ekici, Arif B. Paul, James Brown, Robert Flanagan, James M. Harter, Philipp du Bois, Andreas Schwaab, Ira Hogdall, Claus K. Lundvall, Lene Olson, Sara H. Orlow, Irene Paddock, Lisa E. Rudolph, Anja Eilber, Ursula Dansonka-Mieszkowska, Agnieszka Rzepecka, Iwona K. Ziolkowska-Seta, Izabela Brinton, Louise A. Yang, Hannah Garcia-Closas, Montserrat Despierre, Evelyn Lambrechts, Sandrina Vergote, Ignace Walsh, Christine S. Lester, Jenny Sieh, Weiva McGuire, Valerie Rothstein, Joseph H. Ziogas, Argyrios Lubinski, Jan Cybulski, Cezary Menkiszak, Janusz Jensen, Allan Gayther, Simon A. Ramus, Susan J. Gentry-Maharaj, Aleksandra Berchuck, Andrew Wu, Anna H. Pike, Malcolm C. Van Den Berg, David Terry, Kathryn L. Vitonis, Allison F. Ramirez, Starr M. Rider, David N. Knutson, Keith L. Sellers, Thomas A. Phelan, Catherine M. Doherty, Jennifer A. Johnatty, Sharon E. deFazio, Anna Song, Honglin Tyrer, Jonathan Kalli, Kimberly R. Fridley, Brooke L. Cunningham, Julie M. Goode, Ellen L. CA AOCS ACS Grp TI Variation in NF-kappa B Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FAMILY MEMBERS; BCL10; RISK; SUSCEPTIBILITY; POLYMORPHISMS; INFLAMMATION; ASSOCIATION; STATISTICS; VARIANTS; CARD11 AB Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-kappa B (NF-kappa B) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-kappa B family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 x 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 x 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 x 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 x 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 x 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. (C)2014 AACR. C1 [Block, Matthew S.; Kalli, Kimberly R.] Mayo Clin, Dept Med Oncol, Rochester, MN 55905 USA. [Charbonneau, Bridget; Ramirez, Starr M.; Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN 55905 USA. [Vierkant, Robert A.; Fogarty, Zachary; Bamlet, William R.; Rider, David N.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Knutson, Keith L.] Mayo Clin, Dept Immunol, Rochester, MN 55905 USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN 55905 USA. [Rossing, Mary Anne] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98195 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Cramer, Daniel; Terry, Kathryn L.; Vitonis, Allison F.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Cramer, Daniel; Terry, Kathryn L.; Vitonis, Allison F.] Harvard Univ, Sch Med, Boston, MA USA. [Cramer, Daniel; Terry, Kathryn L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Pearce, Celeste Leigh; Gayther, Simon A.; Ramus, Susan J.; Wu, Anna H.; Pike, Malcolm C.; Van Den Berg, David] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Keck Sch Med, Los Angeles, CA USA. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Culver, Hoda Anton; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Ctr Canc Genet Res & Prevent, Dept Epidemiol, Irvine, CA 92717 USA. [Whittemore, Alice S.; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Palo Alto, CA 94304 USA. [Karlan, Beth Y.; Walsh, Christine S.; Lester, Jenny] Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Wentzensen, Nicolas; Brinton, Louise A.; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Schildkraut, Joellen] Duke Univ, Med Ctr, Duke Canc Inst, Canc Prevent Detect & Res Program, Durham, NC USA. [Schildkraut, Joellen] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Kjaer, Susanne K.; Hogdall, Claus K.; Lundvall, Lene] Rigshosp, Juliane Marie Ctr, Dept Obstet & Gynecol, DK-2100 Copenhagen, Denmark. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Olson, Sara H.; Orlow, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Bandera, Elisa V.] Univ Med & Dent New Jersey, Canc Inst New Jersey, New Brunswick, NJ USA. [Paddock, Lisa E.] New Jersey Dept Hlth, Trenton, NJ USA. [Pejovic, Tanja; Bean, Yukie T.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja; Bean, Yukie T.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Hays, Laura E.] Dept Hematol & Oncol, Portland, OR USA. [Hays, Laura E.] Knight Canc Inst, Portland, OR USA. [Lurie, Galina] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Sellers, Thomas A.; Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Div Populat Sci, Tampa, FL USA. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Epidemiol & Biostat Sect, Lebanon, NH USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA. [Pharoah, Paul D. P.; Song, Honglin; Tyrer, Jonathan] Univ Cambridge, Dept Oncol, Cambridge CB2 1TN, England. [Pharoah, Paul D. P.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB2 1TN, England. [Menon, Usha; Gentry-Maharaj, Aleksandra] UCL, Inst Womens Hlth, Gynaecol Canc Res Ctr, London WC1E 6BT, England. [Brown, Robert; Flanagan, James M.] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London SW7 2AZ, England. [Garcia-Closas, Montserrat] Break Breast Canc Res Ctr, London, England. [Eccles, Diana] Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton SO9 5NH, Hants, England. [Kaye, Stanley B.] Inst Canc Res, Div Clin Studies, Sutton, Surrey, England. [Kaye, Stanley B.] Royal Marsden Hosp, Sutton, Surrey, England. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Paul, James] Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland. [Chenevix-Trench, Georgia; Johnatty, Sharon E.] Queensland Inst Med Res, Canc Div, Herston, Qld 4006, Australia. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Melbourne, Vic, Australia. [Campbell, Ian] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [deFazio, Anna] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Dept Gynaecol Oncol, Westmead, NSW 2145, Australia. [deFazio, Anna] Univ Sydney, Westmead Inst Canc Res, Westmead Millennium Inst, Westmead, NSW 2145, Australia. [Kjaer, Susanne K.; Hogdall, Estrid; Jensen, Allan] Univ Copenhagen, Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Gronwald, Jacek; Lubinski, Jan; Cybulski, Cezary] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol, Warsaw, Poland. [Ziolkowska-Seta, Izabela] Maria Sklodowska Curie Mem Canc Ctr, Dept Gynecol Oncol, Warsaw, Poland. [Ziolkowska-Seta, Izabela] Inst Oncol, Warsaw, Poland. [Menkiszak, Janusz] Pomeranian Med Univ, Clin Gynaecol Surg & Oncol, Szczecin, Poland. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace] Univ Hosp Leuven, Dept Obstet & Gynecol, Div Gynecol Oncol, Leuven, Belgium. [Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace] Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. [Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Ctr Comprehens Canc, Univ Hosp Erlangen, Dept Gynecol & Obstet, D-91054 Erlangen, Germany. [Chang-Claude, Jenny; Rudolph, Anja; Eilber, Ursula] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Heitz, Florian; Harter, Philipp; du Bois, Andreas] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Schwaab, Ira] Inst Humangenet Wiesbaden, Wiesbaden, Germany. [Heitz, Florian; Harter, Philipp; du Bois, Andreas] Huyssens Stiftung Knappschaft GmbH, Kliniken Essen Mitte Evang, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany. RP Goode, EL (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 First St SW, Rochester, MN 55905 USA. EM egoode@mayo.edu RI Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; deFazio, Anna/D-3939-2013; Bowtell, David/H-1007-2016; Menkiszak, Janusz/I-4036-2014; Johnatty, Sharon/R-8890-2016; Gronwald, Jacek/A-4576-2017; Hein, Alexander/F-6999-2010; Bandera, Elisa/M-4169-2014; Fridley, Brooke/D-8315-2015 OI Ramus, Susan/0000-0003-0005-7798; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; deFazio, Anna/0000-0003-0057-4744; Bowtell, David/0000-0001-9089-7525; Johnatty, Sharon/0000-0002-7888-1966; Gronwald, Jacek/0000-0002-3643-2871; Kjaer, Susanne/0000-0002-8347-1398; Hein, Alexander/0000-0003-2601-3398; Bandera, Elisa/0000-0002-8789-2755; Fridley, Brooke/0000-0001-7739-7956 FU Ovarian Cancer Research Fund [PPD/RPCI.07]; Genetic Associations and Mechanisms in Oncology (GAME-ON): an NCI Cancer Post-GWAS Initiative [U19-CA148112, U19-CA148537]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; Canadian Institutes for Health Research (CIHR) [MOP-86727]; CIHR Team in Familial Risks of Breast Cancer; American Cancer Society [CRTG-00-196-01-CCE, SIOP-06-090-06]; California Cancer Research Program [00-01389V20170, N01-CN25403, 2II0200]; Canadian Institutes for Health Research; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; Cancer Institute of New Jersey; Cancer Research UK [C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689, C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692]; Celma Mastry Ovarian Cancer Foundation; Danish Cancer Society [94-222-52]; ELAN Program of the University of Erlangen-Nuremberg; Eve Appeal; Helsinki University Central Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre [C1312/A15589]; Norwegian Cancer Society; Norwegian Research Council; Ovarian Cancer Research Fund; National Kankerplan of Belgium; L. & S. Milken Foundation; Polish Ministry of Science and Higher Education; US National Cancer Institute [K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P20-GM103418, P30-CA072720, P30CA15083, P30-CA168524]; Intramural research funds; US Army Medical Research and Material Command [DAMD17-98-1-8659, DAMD17-01-10729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280, W81XWH-10-1-0341]; National Health and Medical Research Council of Australia [199600, 400413, 400281]; German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]; state of Baden-W_urttemberg through Medical Faculty of the University of Ulm [P.685]; Minnesota Ovarian Cancer Alliance; Mayo Foundation; Fred C. and Katherine B. Andersen Foundation; Lon V. Smith Foundation [LVS-39420]; Polish Committee for Scientific Research [4P05C 028 14, 2P05A 068 27]; Oak Foundation; OHSU Foundation; Mermaid I project; Rudolf-Bartling Foundation; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College Hospital "Womens Health Theme"; Royal Marsden Hospital; WorkSafeBC; Komen Foundation for the Cure; Breast Cancer Research Foundation; Australian National Health and Medical Research Council; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; [R01CA074850]; [R01-CA076016]; [R01-CA080742]; [R01-CA080978]; [R01-CA128978]; [R01-CA083918]; [R01-CA087538]; [R01-CA092044]; [R01-095023]; [P50-CA105009]; [P50-CA136393]; [R01-CA014089]; [R01-CA016056]; [R01-CA017054]; [R01-CA049449]; [R01-CA050385]; [R01CA054419]; [R01-CA058598]; [R01-CA058860]; [R01-CA061107]; [R01-CA061132]; [R01-CA063682]; [R01-CA064277]; [R01-CA067262]; [R01-CA071766]; [R01CA106414]; [R01-CA122443]; [R01-CA61107]; [R01-CA112523]; [R01-CA114343]; [R01-CA126841]; [R01-CA136924]; [R01-CA149429]; [R03-CA113148]; [R03CA115195]; [R21-GM86689]; [R37-CA070867]; [R37-CA70867]; [U01-CA069417]; [U01-CA071966] FX This study was supported by funding from several sources including the Ovarian Cancer Research Fund thanks to donations by the family and friends of K.S. Smith (PPD/RPCI.07); the Genetic Associations and Mechanisms in Oncology (GAME-ON): an NCI Cancer Post-GWAS Initiative (U19-CA148112 and U19-CA148537); the European Community's Seventh Framework Programme under grant agreement No. 223175 (HEALTH-F2-2009-223175); the Canadian Institutes for Health Research (CIHR) MOP-86727 and the CIHR Team in Familial Risks of Breast Cancer; the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V20170, N01-CN25403, 2II0200); the Canadian Institutes for Health Research; Cancer Council Victoria; Cancer Council Queensland; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; Cancer Foundation of Western Australia; the Cancer Institute of New Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689, C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Central Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/A15589); the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; National Kankerplan of Belgium; the L. & S. Milken Foundation; the Polish Ministry of Science and Higher Education; the US National Cancer Institute (K07-CA095666, K07-CA143047, K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137, P01-CA017054, P01-CA087696, P20-GM103418, P30-CA072720, P30CA15083, P30-CA168524, P50-CA105009, P50-CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01-CA049449, R01-CA050385, R01CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA128978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01CA106414, R01-CA122443, R01-CA61107, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03-CA113148, R03CA115195, R21-GM86689, R37-CA070867, R37-CA70867, U01-CA069417, U01-CA071966, and Intramural research funds); the US Army Medical Research and Material Command (DAMD17-98-1-8659, DAMD17-01-10729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280, W81XWH-10-1-0341); the National Health and Medical Research Council of Australia (199600, 400413, and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the state of Baden-W_urttemberg through Medical Faculty of the University of Ulm (P.685); the Minnesota Ovarian Cancer Alliance; the ayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Polish Committee for Scientific Research (4P05C 028 14 and 2P05A 068 27); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial College London; University College Hospital "Womens Health Theme" and the Royal Marsden Hospital; WorkSafeBC; Komen Foundation for the Cure; and the Breast Cancer Research Foundation. G. Chenevix-Trench and P. M. Webb are supported by the Australian National Health and Medical Research Council, B.; Karlan holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN), and A. Berchuck holds the Barbara Thomason Ovarian Cancer Research Professorship from the American Cancer Society (SIOP-06-090-06). NR 26 TC 4 Z9 5 U1 0 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2014 VL 23 IS 7 BP 1421 EP 1427 DI 10.1158/1055-9965.EPI-13-0962 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WE UT WOS:000345273700033 PM 24740199 ER PT J AU Ryan, BM Wang, Y Jen, J Yi, ES Olivo-Marston, S Yang, P Harris, CC AF Ryan, Brid M. Wang, Yi Jen, Jin Yi, Eunhee S. Olivo-Marston, Susan Yang, Ping Harris, Curtis C. TI Evidence that the Lung Adenocarcinoma EML4-ALK Fusion Gene Is not Caused by Exposure to Secondhand Tobacco Smoke During Childhood SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CANCER AB Background: The EML4-ALK fusion gene is more frequently found in younger, never smoking patients with lung cancer. Meanwhile, never smokers exposed to secondhand tobacco smoke (SHS) during childhood are diagnosed at a younger age compared with never smoking patients with lung cancer who are not exposed. We, therefore, hypothesized that SHS, which can induce DNA damage, is associated with the EML4-ALK fusion gene. Methods: We compared the frequency of the EML4-ALK fusion gene among 197 never smoker patients with lung cancer with and without a history of exposure to SHS during childhood at Mayo Clinic. Results: The EML4-ALK fusion gene was detected in 33% of cases from never smokers with a history of SHS exposure during childhood, whereas 47% of never smoking lung cancer cases without a history of childhood SHS exposure tested positive for the fusion gene. Conclusions: The EML4-ALK fusion gene is not enriched in tumors from individuals exposed to SHS during childhood. Impact: These data suggest that childhood exposure to SHS is not a significant etiologic cause of the EML4ALK fusion gene in lung cancer. (C)2014 AACR. C1 [Ryan, Brid M.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Wang, Yi; Yang, Ping] Mayo Clin, Ctr Individualized Med, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Jen, Jin; Yi, Eunhee S.] Mayo Clin, Ctr Individualized Med, Dept Lab Med & Pathol, Rochester, MN USA. [Jen, Jin] Mayo Clin, Ctr Individualized Med, Gene Express Core, Med Genome Facil, Rochester, MN USA. [Olivo-Marston, Susan] Ohio State Univ, Coll Publ Hlth, Div Epidemiol, Columbus, OH 43210 USA. [Wang, Yi] Wenzhou Med Univ, Div Prevent Med, Sch Environm Sci & Publ Hlth, Wenzhou, Zhejiang, Peoples R China. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Bldg 37,Room 3068,37 Convent Dr,MSC 4258, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov FU Intramural Program of the Centre for Cancer Research, National Cancer Institute, NIH [NIH-R01-CA80127, NIH-R01-CA84354, NIH-R01-CA115857]; American Cancer Society; Mayo Clinic Cancer Center; Center for Individualized Medicine; Mayo Clinic Foundation FX This work was supported by the Intramural Program of the Centre for Cancer Research, National Cancer Institute, NIH grants NIH-R01-CA80127, NIH-R01-CA84354, and NIH-R01-CA115857 (all to P. Yang). J. Jen is a recipient of the New Investigator Award from the American Cancer Society and supported by funding from Mayo Clinic Cancer Center and the Center for Individualized Medicine. P. Yang, J. Jen, E. S. Yi, and Y. Wang received support from The Mayo Clinic Foundation. NR 8 TC 2 Z9 3 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2014 VL 23 IS 7 BP 1432 EP 1434 DI 10.1158/1055-9965.EPI-14-0224 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WE UT WOS:000345273700035 PM 24755712 ER PT J AU Kellner, CH McClintock, SM McCall, WV Petrides, G Knapp, RG Weiner, RD Young, RC Greenberg, RM Rudorfer, MV Ahle, GM Liebman, LS Lisanby, SH AF Kellner, Charles H. McClintock, Shawn M. McCall, W. Vaughn Petrides, George Knapp, Rebecca G. Weiner, Richard D. Young, Robert C. Greenberg, Robert M. Rudorfer, Matthew V. Ahle, Gabriella M. Liebman, Lauren S. Lisanby, Sarah H. CA CORE PRIDE Grp TI Brief Pulse and Ultrabrief Pulse Right Unilateral Electroconvulsive Therapy (ECT) for Major Depression: Efficacy, Effectiveness, and Cognitive Effects SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Letter C1 [Kellner, Charles H.; Ahle, Gabriella M.; Liebman, Lauren S.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [McClintock, Shawn M.; Weiner, Richard D.; Lisanby, Sarah H.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. [McCall, W. Vaughn] Georgia Regents Univ, Dept Psychiat & Human Hlth, Augusta, GA USA. [Petrides, George] Northshore LIJ Hlth Syst, Zucker Hillside Hosp, Dept Psychiat, Glen Oaks, NY USA. [Knapp, Rebecca G.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC USA. [Young, Robert C.] Weill Cornell Med Coll, Dept Psychiat, White Plains, NY USA. [Greenberg, Robert M.] Lutheran Med Ctr, Dept Psychiat, Brooklyn, NY USA. [Rudorfer, Matthew V.] NIMH, Somat Treatments Program, Bethesda, MD 20892 USA. RP Kellner, CH (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. EM charles.kellner@mssm.edu OI Young, Robert/0000-0002-6380-6314; Greenberg, Robert/0000-0001-7078-8970 NR 3 TC 2 Z9 2 U1 0 U2 4 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 2014 VL 75 IS 7 BP 777 EP 777 DI 10.4088/JCP.14lr08997 PG 1 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AU3PX UT WOS:000345526900020 PM 25093475 ER PT J AU Jensen, MD Ryan, DH Donato, KA Apovian, CM Ard, JD Comuzzie, AG Hu, FB Hubbard, VS Jakicic, JM Kushner, RF Loria, CM Millen, BE Nonas, CA Pi-Sunyer, FX Stevens, J Stevens, VJ Wadden, TA Wolfe, BM Yanovski, SZ AF Jensen, Michael D. Ryan, Donna H. Donato, Karen A. Apovian, Caroline M. Ard, Jamy D. Comuzzie, Anthony G. Hu, Frank B. Hubbard, Van S. Jakicic, John M. Kushner, Robert F. Loria, Catherine M. Millen, Barbara E. Nonas, Cathy A. Pi-Sunyer, F. Xavier Stevens, June Stevens, Victor J. Wadden, Thomas A. Wolfe, Bruce M. Yanovski, Susan Z. CA Amer Coll Cardiology Amer Heart TI Executive Summary: Guidelines (2013) for the Management of Overweight and Obesity in Adults SO OBESITY LA English DT Article ID RANDOMIZED-CONTROLLED-TRIAL; LIFE-STYLE INTERVENTION; WEIGHT-LOSS MAINTENANCE; CARDIOVASCULAR RISK-FACTORS; QUALITY-OF-LIFE; FINNISH DIABETES PREVENTION; IMPAIRED GLUCOSE-TOLERANCE; BODY-MASS INDEX; LOW-FAT DIET; STRUCTURED COMMERCIAL PROGRAM C1 [Jensen, Michael D.] Mayo Clin, Endocrine Res Unit, Endocrinol Metab Diabet Nutr & Internal Med Div, Rochester, MN 55902 USA. [Ryan, Donna H.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Apovian, Caroline M.] Boston Med Ctr, Boston, MA USA. [Apovian, Caroline M.] Ctr Nutr & Weight Management, Los Angeles, CA USA. [Ard, Jamy D.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Ard, Jamy D.] Weight Management Ctr, Baltimore, MD USA. [Comuzzie, Anthony G.] Southwest Fdn Biomed Res, Dept Genet, San Antonio, TX USA. [Donato, Karen A.] NHLBI, Div Applicat Res Discoveries, Bethesda, MD USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Hubbard, Van S.] NIDDK, NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. [Jakicic, John M.] Univ Pittsburgh, Phys Act & Weight Management Res Ctr, Pittsburgh, PA 15260 USA. [Kushner, Robert F.] Northwestern Univ, Feinberg Sch Med, Div Gen Internal Med, Evanston, IL 60208 USA. [Loria, Catherine M.] NHLBI, Bethesda, MD USA. [Millen, Barbara E.] Boston Nutr Fdn, Boston, MA USA. [Nonas, Cathy A.] NYC Dept Hlth & Mental Hyg, Bur Chron Dis Prevent & Tobacco Control, New York, NY USA. [Pi-Sunyer, F. Xavier] Columbia Univ, Coll Phys & Surg, New York, NY 10027 USA. [Stevens, June] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Stevens, June] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Stevens, June] Univ N Carolina, Sch Med, Dept Epidemiol, Chapel Hill, NC USA. [Stevens, Victor J.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Wadden, Thomas A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wadden, Thomas A.] Ctr Weight & Eating Disorders, Philadelphia, PA USA. [Wolfe, Bruce M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Yanovski, Susan Z.] NIDDK, Off Obes Res, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. RP Jensen, MD (reprint author), Mayo Clin, Endocrine Res Unit, Endocrinol Metab Diabet Nutr & Internal Med Div, Rochester, MN 55902 USA. NR 178 TC 17 Z9 17 U1 4 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JUL PY 2014 VL 22 SU 2 SI SI BP S5 EP S39 DI 10.1002/oby.20821 PG 35 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AT6CR UT WOS:000345027100003 ER PT J AU Kuan, CT Pastan, IH Bigner, DD AF Kuan, Chien-Tsun Pastan, Ira H. Bigner, Darell D. TI NEXT-GENERATION RECOMBINANT IMMUNOTOXINS FOR GLIOBLASTOMAS AND MELANOMAS TREATMENT SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 20th International Conference on Brain Tumor Research and Therapy CY JUL 20-22, 2014 CL CA C1 Duke Univ, Med Ctr, Durham, NC 27706 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUL PY 2014 VL 16 SU 3 DI 10.1093/neuonc/nou209.6 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AS4IB UT WOS:000344236400156 ER PT J AU Lonser, RR Frerich, J Huntoon, K Yang, CZ Merrill, M Abdullaev, Z Pack, S Shively, S Stamp, G Zhuang, ZP AF Lonser, Russell R. Frerich, Jason Huntoon, Kristin Yang, Chunzhang Merrill, Marsha Abdullaev, Ziedulla Pack, Svetlana Shively, Sharon Stamp, Gordon Zhuang, Zhengping TI VASCULOGENESIS IN VON HIPPEL-LINDAU DISEASE ASSOCIATED TUMORS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 20th International Conference on Brain Tumor Research and Therapy CY JUL 20-22, 2014 CL CA C1 [Lonser, Russell R.; Frerich, Jason; Huntoon, Kristin; Yang, Chunzhang; Merrill, Marsha; Abdullaev, Ziedulla; Pack, Svetlana; Shively, Sharon; Stamp, Gordon; Zhuang, Zhengping] Ohio State Univ, Wexner Med Ctr, NINDS, NIH, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUL PY 2014 VL 16 SU 3 DI 10.1093/neuonc/nou206.32 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AS4IB UT WOS:000344236400033 ER PT J AU Raynor, HA Bond, DS Steeves, J Thompson, DL AF Raynor, Hollie A. Bond, Dale S. Steeves, Jeremy Thompson, Dixie L. TI Physical Activity Variety, Energy Expenditure, and Body Mass Index SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article DE variety; physical activity; maintenance; weight loss ID RANDOMIZED-CONTROLLED-TRIAL; LIFE-STYLE INTERVENTION; WEIGHT REGAIN; TELEVISION; CHOICE; ADULTS; TIME; OVERWEIGHT; MORTALITY; CHILDREN AB Objectives: To examine if physical activity (PA) variety was associated with moderate- to vigorous-intensity PA (MVPA) energy expenditure and body mass index (BMI) at 18 months during an obesity intervention. Methods: Participants with >= 10 minutes/week of MVPA at 6 months and complete PA data were included. Participants were classified into Variety (N = 30), >= 2 different activities/week, or Less Variety (N = 65), only 1 activity/week. Results: Weekly MVPA-related energy expenditure was higher for Variety than Less Variety (3674.7 +/- 1934.6 kcal/week vs 2197.3 +/- 1841.4 kcal/week, p < .05) at 18 months, with no difference in BMI. Conclusions: Greater weekly PA variety during obesity treatment was related to greater 18-month MVPA energy expenditure. C1 [Raynor, Hollie A.; Thompson, Dixie L.] Univ Tennessee, Knoxville, TN 37996 USA. [Bond, Dale S.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Steeves, Jeremy] NCI, Rockville, MD USA. RP Raynor, HA (reprint author), Univ Tennessee, Knoxville, TN 37996 USA. EM hraynor@utk.edu OI Thompson, Dixie/0000-0001-9944-0206 FU NIDDK NIH HHS [R01 DK074721] NR 28 TC 3 Z9 3 U1 1 U2 5 PU PNG PUBLICATIONS PI OAK RIDGE PA 2205-K OAK RIDGE RD, #115, OAK RIDGE, NC 27310 USA SN 1945-7359 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PD JUL PY 2014 VL 38 IS 4 BP 624 EP 630 DI 10.5993/AJHB.38.4.16 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AS1JC UT WOS:000344036400016 PM 24636125 ER PT J AU Mierzwa, AJ Sullivan, GM Beer, LA Ahn, S Armstrong, RC AF Mierzwa, Amanda J. Sullivan, Genevieve M. Beer, Laurel A. Ahn, Sohyun Armstrong, Regina C. TI Comparison of Cortical and White Matter Traumatic Brain Injury Models Reveals Differential Effects in the Subventricular Zone and Divergent Sonic Hedgehog Signaling Pathways in Neuroblasts and Oligodendrocyte Progenitors SO ASN NEURO LA English DT Article DE neuroblast; oligodendrocyte progenitor; sonic hedgehog; stem cell; subventricular zone; traumatic brain injury ID NEURAL STEM-CELL; IMPACT INJURY; ADULT BRAIN; MICE; MOUSE; PROLIFERATION; DEMYELINATION; MAINTENANCE; POPULATIONS; ASTROCYTES AB The regenerative capacity of the central nervous system must be optimized to promote repair following traumatic brain injury (TBI) and may differ with the site and form of damage. Sonic hedgehog (Shh) maintains neural stem cells and promotes oligodendrogenesis. We examined whether Shh signaling contributes to neuroblast (doublecortin) or oligodendrocyte progenitor (neural/glial antigen 2 [NG2]) responses in two distinct TBI models. Shh-responsive cells were heritably labeled in vivo using Gli1-CreER (T2); R26-YFP bitransgenic mice with tamoxifen administration on Days 2 and 3 post-TBI. Injury to the cerebral cortex was produced with mild controlled cortical impact. Yellow fluorescent protein (YFP) cells decreased in cortical lesions. Total YFP cells increased in the subventricular zone (SVZ), indicating Shh pathway activation in SVZ cells, including doublecortin-labeled neuroblasts. The alternate TBI model produced traumatic axonal injury in the corpus callosum. YFP cells decreased within the SVZ and were rarely double labeled as NG2 progenitors. NG2 progenitors increased in the cortex, with a similar pattern in the corpus callosum. To further test the potential of NG2 progenitors to respond through Shh signaling, Smoothened agonist was microinjected into the corpus callosum to activate Shh signaling. YFP cells and NG2 progenitors increased in the SVZ but were not double labeled. This result indicates that either direct Smoothened activation in NG2 progenitors does not signal through Gli1 or that Smoothened agonist acts indirectly to increase NG2 progenitors. Therefore, in all conditions, neuroblasts exhibited differential Shh pathway utilization compared with oligodendrocyte progenitors. Notably, cortical versus white matter damage from TBI produced opposite responses of Shh-activated cells within the SVZ. C1 [Mierzwa, Amanda J.; Sullivan, Genevieve M.; Beer, Laurel A.; Armstrong, Regina C.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Mierzwa, Amanda J.; Sullivan, Genevieve M.; Beer, Laurel A.; Armstrong, Regina C.] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Sullivan, Genevieve M.; Armstrong, Regina C.] Uniformed Serv Univ Hlth Sci, Program Mol & Cell Biol, Bethesda, MD 20814 USA. [Ahn, Sohyun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Armstrong, RC (reprint author), Uniformed Serv Univ Hlth Sci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM regina.armstrong@usuhs.edu FU National Multiple Sclerosis Society [RG4675]; Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM) FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Multiple Sclerosis Society (RG4675) and the Department of Defense in the Center for Neuroscience and Regenerative Medicine (CNRM). NR 30 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 1759-0914 J9 ASN NEURO JI ASN Neuro PD JUL-SEP PY 2014 VL 6 IS 5 AR 1759091414551782 DI 10.1177/1759091414551782 PG 16 WC Neurosciences SC Neurosciences & Neurology GA AR7IP UT WOS:000343753200001 ER PT J AU Qin, M Huang, TJ Liu, ZH Kader, M Burlin, T Xia, ZY Zeidler, Z Hukema, RK Smith, CB AF Qin, Mei Huang, Tianjian Liu, Zhonghua Kader, Michael Burlin, Thomas Xia, Zengyan Zeidler, Zachary Hukema, Renate K. Smith, Carolyn B. TI Cerebral Protein Synthesis in a Knockin Mouse Model of the Fragile X Premutation SO ASN NEURO LA English DT Article DE Fmr1; FMRP; fragile X premutation; fragile X syndrome; FXTAS; protein synthesis ID TREMOR/ATAXIA SYNDROME FXTAS; MENTAL-RETARDATION PROTEIN; TREMOR-ATAXIA-SYNDROME; FMR1 MESSENGER-RNA; CGG-REPEAT; FULL MUTATION; IN-VIVO; TRANSLATION; MICE; EXPRESSION AB The (CGG) n-repeat in the 50-untranslated region of the fragile X mental retardation gene (FMR1) gene is polymorphic and may become unstable on transmission to the next generation. In fragile X syndrome, CGG repeat lengths exceed 200, resulting in silencing of FMR1 and absence of its protein product, fragile X mental retardation protein (FMRP). CGG repeat lengths between 55 and 200 occur in fragile X premutation (FXPM) carriers and have a high risk of expansion to a full mutation on maternal transmission. FXPM carriers have an increased risk for developing progressive neurodegenerative syndromes and neuropsychological symptoms. FMR1 mRNA levels are elevated in FXPM, and it is thought that clinical symptoms might be caused by a toxic gain of function due to elevated FMR1 mRNA. Paradoxically, FMRP levels decrease moderately with increasing CGG repeat length in FXPM. Lowered FMRP levels may also contribute to the appearance of clinical problems. We previously reported increases in regional rates of cerebral protein synthesis (rCPS) in the absence of FMRP in an Fmr1 knockout mouse model and in a FXPM knockin (KI) mouse model with 120 to 140 CGG repeats in which FMRP levels are profoundly reduced (80%-90%). To explore whether the concentration of FMRP contributes to the rCPS changes, we measured rCPS in another FXPM KI model with a similar CGG repeat length and a 50% reduction in FMRP. In all 24 brain regions examined, rCPS were unaffected. These results suggest that even with 50% reductions in FMRP, normal protein synthesis rates are maintained. C1 [Qin, Mei; Huang, Tianjian; Liu, Zhonghua; Kader, Michael; Burlin, Thomas; Xia, Zengyan; Zeidler, Zachary; Smith, Carolyn B.] NIMH, Sect Neuroadaptat & Prot Metab, NIH, Bethesda, MD 20892 USA. [Hukema, Renate K.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. RP Smith, CB (reprint author), NIMH, Sect Neuroadaptat & Prot Metab, NIH, 10 Ctr Dr,Bldg 10,Room 2D54, Bethesda, MD 20892 USA. EM beebe@mail.nih.gov RI Hukema, Renate/E-1422-2013 OI Zeidler, Zachary/0000-0001-6539-4360; Hukema, Renate/0000-0002-1580-4154 FU Intramural Research Program, National Institute of Mental Health FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Intramural Research Program, National Institute of Mental Health. NR 44 TC 0 Z9 0 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1759-0914 J9 ASN NEURO JI ASN Neuro PD JUL-SEP PY 2014 VL 6 IS 5 AR 1759091414551957 DI 10.1177/1759091414551957 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AR7IP UT WOS:000343753200002 ER PT J AU Lee, J Jo, DG Park, D Chung, HY Mattson, MP AF Lee, Jaewon Jo, Dong-Gyu Park, Daeui Chung, Hae Young Mattson, Mark P. TI Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System SO PHARMACOLOGICAL REVIEWS LA English DT Review ID NF-KAPPA-B; HYPOXIA-INDUCIBLE FACTOR; PROLIFERATOR-ACTIVATED-RECEPTOR; GREEN TEA POLYPHENOL; GLYCOGEN-SYNTHASE KINASE-3; FOCAL-CEREBRAL-ISCHEMIA; HIGH-FAT DIET; AMYOTROPHIC-LATERAL-SCLEROSIS; HEPATIC STELLATE CELLS; PROSTATE-CANCER CELLS AB During the past 5 decades, it has been widely promulgated that the chemicals in plants that are good for health act as direct scavengers of free radicals. Here we review evidence that favors a different hypothesis for the health benefits of plant consumption, namely, that some phytochemicals exert disease-preventive and therapeutic actions by engaging one or more adaptive cellular response pathways in cells. The evolutionary basis for the latter mechanism is grounded in the fact that plants produce natural antifeedant/noxious chemicals that discourage insects and other organisms from eating them. However, in the amounts typically consumed by humans, the phytochemicals activate one or more conserved adaptive cellular stress response pathways and thereby enhance the ability of cells to resist injury and disease. Examples of such pathways include those involving the transcription factors nuclear factor erythroid 2-related factor 2, nuclear factor-kappa B, hypoxia-inducible factor 1a, peroxisome proliferator-activated receptor gamma, and forkhead box subgroup O, as well as the production and action of trophic factors and hormones. Translational research to develop interventions that target these pathways may lead to new classes of therapeutic agents that act by stimulating adaptive stress response pathways to bolster endogenous defenses against tissue injury and disease. Because neurons are particularly sensitive to potentially noxious phytochemicals, we focus on the nervous system but also include findings from other cell types in which actions of phytochemicals on specific signal transduction pathways have been more thoroughly studied. C1 [Lee, Jaewon; Park, Daeui; Chung, Hae Young] Pusan Natl Univ, Dept Pharm, Coll Pharm, Pusan 609735, South Korea. [Lee, Jaewon; Park, Daeui; Chung, Hae Young] Pusan Natl Univ, Mol Inflammat Res Ctr Aging Intervent, Pusan 609735, South Korea. [Jo, Dong-Gyu] Sungkyunkwan Univ, Sch Pharm, Suwon, South Korea. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Lee, J (reprint author), Pusan Natl Univ, Dept Pharm, Coll Pharm, Pusan 609735, South Korea. EM neuron@pusan.ac.kr; mark.mattson@nih.gov RI Lee, Jaewon/N-9064-2013 FU National Institutes of Health [National Institute on Aging]; Korean National Research Foundation - Korea Ministry of Science, ICT and Future Planning [2009-0083538] FX This research was supported by the Intramural Research Program of the National Institutes of Health [National Institute on Aging]; and the Korean National Research Foundation [Grant 2009-0083538 funded by the Korea Ministry of Science, ICT and Future Planning]. NR 770 TC 19 Z9 19 U1 3 U2 27 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 EI 1521-0081 J9 PHARMACOL REV JI Pharmacol. Rev. PD JUL PY 2014 VL 66 IS 3 BP 815 EP 868 DI 10.1124/pr.113.007757 PG 54 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AR6UR UT WOS:000343719100002 PM 24958636 ER PT J AU Brandt, SD Baumann, MH Partilla, JS Kavanagh, PV Power, JD Talbot, B Twamley, B Mahony, O O'Brien, J Elliott, SP Archer, RP Patrick, J Singh, K Dempster, NM Cosbey, SH AF Brandt, Simon D. Baumann, Michael H. Partilla, John S. Kavanagh, Pierce V. Power, John D. Talbot, Brian Twamley, Brendan Mahony, Olivia O'Brien, John Elliott, Simon P. Archer, Roland P. Patrick, Julian Singh, Kuldip Dempster, Nicola M. Cosbey, Simon H. TI Characterization of a novel and potentially lethal designer drug (+/-)-cis-para-methyl-4-methylaminorex (4,4 '-DMAR, or 'Serotoni') SO DRUG TESTING AND ANALYSIS LA English DT Article DE aminorex; 4-methylaminorex; para-methyl-4-methylaminorex; new psychoactive substances; psychostimulants; Internet; monoamine transporters; synaptosomes ID PULMONARY-HYPERTENSION; MONOAMINE TRANSPORTERS; STIMULUS PROPERTIES; 4-METHYLAMINOREX; AMINOREX; STEREOISOMERS; PSYCHOSTIMULANT; RAT; CIS-4-METHYLAMINOREX; METHCATHINONE AB During the second half of 2013, a total of 26 deaths involving para-methyl-4-methylaminorex (4,4'-DMAR) were reported to the European Monitoring Centre for Drugs and Drug Addiction. While aminorex and 4-methylaminorex (4-MAR) are known psychostimulants, nothing is known about the comparatively new para-methyl analog. Analytical characterization of two independent samples obtained from online vendors confirmed the presence of the (+/-)-cis isomer that also appeared to be associated with at least 18 of the 26 deaths. Extensive characterizations included crystal structure analysis, single, tandem, and high-resolution mass spectrometry, liquid and gas chromatography, and nuclear magnetic resonance spectroscopy. For the work described here, both the (+/-)-cis and (+/-)-trans racemates were also synthesized, confirming that the differentiation between these two forms was straight-forward. Monoamine transporter activity was studied using rat brain synaptosomes which included the comparison with d-amphetamine, aminorex and (+/-)-cis-4-MAR. (+/-)-cis-4,4'-DMAR was a potent, efficacious substrate-type releaser at transporters for dopamine, norepinephrine and serotonin with EC50 values of 8.6 +/- 1.1 nM (DAT), 26.9 +/- 5.9 nM (NET) and 18.5 +/- 2.8 nM (SERT), respectively. The potency of (+/-)-cis-4,4'-DMAR at DAT and NET rivalled that of other psychomotor stimulant drugs like d-amphetamine and aminorex. However, (+/-)-cis-4,4'-DMAR had much more potent actions at SERT and activity at SERT varied more than 100-fold across the four drugs. The potent releasing activity of (+/-)-cis4,4'-DMAR at all three monoamine transporters predicts a potential for serious side-effects such as psychotic symptoms, agitation, hyperthermia and cardiovascular stimulation, especially after high-dose exposure or following combination with other psychostimulants. Copyright (C) 2014 John Wiley & Sons, Ltd. C1 [Brandt, Simon D.; Dempster, Nicola M.] Liverpool John Moores Univ, Sch Pharm & Biomol Sci, Liverpool L3 3AF, Merseyside, England. [Baumann, Michael H.; Partilla, John S.] NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, Baltimore, MD USA. [Kavanagh, Pierce V.; Power, John D.; Talbot, Brian; Twamley, Brendan] St James Hosp, Dept Pharmacol & Therapeut, Sch Med, Trinity Ctr Hlth Sci, Dublin 8, Ireland. [Twamley, Brendan; O'Brien, John] Trinity Coll Dublin, Sch Chem, Dublin 2, Ireland. [Mahony, Olivia] Dublin Inst Technol, Sch Chem Sci & Pharmaceut Sci, Dublin 2, Ireland. [Elliott, Simon P.] ROAR Forens, Barbados WR14 3SZ, Ireland. [Archer, Roland P.] State Analysts Lab, St Martin GY4 6LD, Guernsey, England. [Patrick, Julian] Sci Supplies Ltd, London W1S 1YH, England. [Singh, Kuldip] Univ Leicester, Dept Chem, Leicester LE1 7RH, Leics, England. [Cosbey, Simon H.] Forens Sci Northern Ireland, Carrickfergus BT38 8PL, Ireland. RP Brandt, SD (reprint author), Liverpool John Moores Univ, Sch Pharm & Biomol Sci, Byrom St, Liverpool L3 3AF, Merseyside, England. EM s.brandt@ljmu.ac.uk OI Brandt, Simon/0000-0001-8632-5372 FU National Institute on Drug Abuse, National Institutes of Health, U.S.A FX Portions of this research were generously supported by the National Institute on Drug Abuse, National Institutes of Health, U.S.A NR 48 TC 8 Z9 8 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD JUL-AUG PY 2014 VL 6 IS 7-8 SI SI BP 684 EP 695 DI 10.1002/dta.1668 PG 12 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA AQ6YR UT WOS:000342960300010 PM 24841869 ER PT J AU Ellefsen, KN Anizan, S Castaneto, MS Desrosiers, NA Martin, TM Klette, KL Huestis, MA AF Ellefsen, Kayla N. Anizan, Sebastien Castaneto, Marisol S. Desrosiers, Nathalie A. Martin, Thomas M. Klette, Kevin L. Huestis, Marilyn A. TI Validation of the only commercially available immunoassay for synthetic cathinones in urine: Randox Drugs of Abuse V Biochip Array Technology SO DRUG TESTING AND ANALYSIS LA English DT Article DE synthetic cathinones; mephedrone; MDPV; Randox; immunoassay ID TANDEM MASS-SPECTROMETRY; DESIGNER DRUGS; BATH SALTS; FATAL INTOXICATIONS; RECREATIONAL DRUGS; UNITED-STATES; MEPHEDRONE; METHYLONE; TOXICITY; 3,4-METHYLENEDIOXYPYROVALERONE AB Deterrence of synthetic cathinone abuse is hampered by the lack of a high-throughput immunoassay screen. The Randox Drugs of Abuse V (DOA-V) Biochip Array Technology contains two synthetic cathinone antibodies: Bath Salt I (BSI) targets mephedrone/methcathinone and Bath Salt II (BSII) targets 3',4'-methylenedioxypyrovalerone (MDPV)/3',4'-methylenedioxy-alpha-pyrrolidinobutiophenone (MDPBP). We evaluated DOA-V synthetic cathinones performance and conducted a full validation on the original assay with calibrators reconstituted in water, and the new assay with calibrators prepared in lyophilized urine; both utilized the same antibodies and were run on the fully automated Evidence (R) Analyzer. We screened 20 017 authentic military urine specimens and confirmed positives by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for 28 synthetic cathinones. Limits of detection (LOD) for the original and new assays were 0.35 and 0.18 (BSI), and 8.5 and 9.2 mu g/L (BSII), respectively. Linearity was acceptable (R-2 > 0.98); however, a large negative bias was observed with in-house prepared calibrators. Intra-assay imprecision was < 20% BSI-II, while inter-assay imprecision was 18-42% BSI and < 22% BSII. Precision was acceptable for Randox controls. Cross-reactivities of many additional synthetic cathinones were determined. Authentic drug-free negative urine pH < 4 produced false positive results for BSI (6.3 mu g/L) and BSII (473 mu g/L). Oxidizing agents reduced BSI and increased BSII results. Sensitivity, specificity, and efficiency of 100%, 52.1%, and 53.0% were obtained at manufacturer's proposed cut-offs (BSI 5 mu g/L, BSII 30 mu g/L). Performance improved if cut-off concentrations increased (BSI 7.5 mu g/L, BSII 40 mu g/L); however, there were limited confirmed positive specimens. Currently, this is the first and only fully validated immunoassay for preliminary detection of synthetic cathinones in urine. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Ellefsen, Kayla N.; Anizan, Sebastien; Castaneto, Marisol S.; Desrosiers, Nathalie A.; Huestis, Marilyn A.] NIDA, NIH, Baltimore, MD 21224 USA. [Ellefsen, Kayla N.; Castaneto, Marisol S.; Desrosiers, Nathalie A.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Martin, Thomas M.; Klette, Kevin L.] Off Secretary Def Operat Readiness & Safety, Washington, DC USA. RP Huestis, MA (reprint author), NIDA, IRP, NIH, Biomed Res Ctr, 251 Bayview Blvd,Suite 200 Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Department of Defense Counter Narcotics Program; National Institute for Drug Abuse (NIDA), National Institutes of Health (NIH), Department of Health and Human Services (DHHS) FX This work was funded by the Department of Defense Counter Narcotics Program and the Intramural Research Program of the National Institute for Drug Abuse (NIDA), National Institutes of Health (NIH), Department of Health and Human Services (DHHS). The assistance of the Forensic Toxicology Drug Testing Laboratory, Fort Meade, MD, and Randox Toxicology Corporation in the conduct of this study is greatly appreciated. We acknowledge the staff of the Chemistry and Drug Metabolism Section, NIDA, NIH, and the Graduate Partnership Program, NIH. NR 61 TC 10 Z9 10 U1 1 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1942-7603 EI 1942-7611 J9 DRUG TEST ANAL JI Drug Test. Anal. PD JUL-AUG PY 2014 VL 6 IS 7-8 SI SI BP 728 EP 738 DI 10.1002/dta.1633 PG 11 WC Biochemical Research Methods; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA AQ6YR UT WOS:000342960300014 PM 24659527 ER PT J AU Soto-Pantoja, DR Shih, HB Maxhimer, JB Cook, KL Ghosh, A Isenberg, JS Roberts, DD AF Soto-Pantoja, David R. Shih, Hubert B. Maxhimer, Justin B. Cook, Katherine L. Ghosh, Arunima Isenberg, Jeffrey S. Roberts, David D. TI Thrombospondin-1 and CD47 signaling regulate healing of thermal injury in mice SO MATRIX BIOLOGY LA English DT Article DE Thrombospondin-1; CD47; TGF-beta 1; Wound healing ID GROWTH-FACTOR-BETA; ISCHEMIA-REPERFUSION INJURY; TISSUE SURVIVAL; NITRIC-OXIDE; CELL RESPONSES; MESSENGER-RNA; WOUND REPAIR; TGF-BETA; ACTIVATION; SKIN AB More than 2.5 million Americans suffer from burn injuries annually, and burn management is a major public health problem. Treatments have been developed to manage wound injuries employing skin grafts, various dressings and topical and systemic agents. However, these often achieve limited degrees of success. We previously reported that targeting the interaction of thrombospondin-1 with its signaling receptor CD47 or deletion of the genes encoding either of these proteins in mice improves recovery from soft tissue ischemic injuries as well as tissue injuries caused by ionizing radiation. We now demonstrate that the absence of CD47 improves the rate of wound closure for a focal dermal second-degree thermal injury, whereas lack of thrombospondin-1 initially delays wound closure compared to healing in wild type mice. Doppler analysis of the wounded area showed increased blood flow in both CD47 and thrombospondin-1 null mice. Accelerated wound closure in the CD47 null mice was associated with increased fibrosis as demonstrated by a 4-fold increase in collagen fraction. Wound tissue of CD47 null mice showed increased thrombospondin-1 mRNA and protein expression and TGF-beta 1 mRNA levels. Activation of latent TGF-beta 1 was increased in thermally injured CD47-null tissue as assessed by phosphorylation of the TGF-beta 1 receptor-regulated transcription factors SMAD-2 and -3. Overall these results indicate that targeting CD47 may improve the speed of healing thermal injuries, but some level of CD47 expression may be required to limit the long term TGF-beta 1-dependent fibrosis of these wounds. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Soto-Pantoja, David R.; Shih, Hubert B.; Maxhimer, Justin B.; Ghosh, Arunima; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shih, Hubert B.] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20814 USA. [Isenberg, Jeffrey S.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Isenberg, Jeffrey S.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15213 USA. [Cook, Katherine L.] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20057 USA. [Cook, Katherine L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. RP Roberts, DD (reprint author), NIH, Bldg 10 Room 2A33,10 Ctr Dr MSC1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008; OI Roberts, David/0000-0002-2481-2981; Cook, Katherine/0000-0001-6241-0214 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Howard Hughes Medical Institute-NIH Research Scholars Program; DOD Breast Cancer Research Program Postdoctoral Fellowship [BC112023] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (D.D.R.), the Howard Hughes Medical Institute-NIH Research Scholars Program (H.B.S.), and by a DOD Breast Cancer Research Program Postdoctoral Fellowship BC112023 (K.L.C.). NR 37 TC 5 Z9 5 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X EI 1569-1802 J9 MATRIX BIOL JI Matrix Biol. PD JUL PY 2014 VL 37 BP 25 EP 34 DI 10.1016/j.matbio.2014.05.003 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AQ8LO UT WOS:000343077200003 PM 24840925 ER PT J AU Kaur, S Singh, SP Elkahloun, AG Wu, WW Abu-Asab, MS Roberts, DD AF Kaur, Sukhbir Singh, Satya P. Elkahloun, Abdel G. Wu, Weiwei Abu-Asab, Mones S. Roberts, David D. TI CD47-dependent immunomodulatory and angiogenic activities of extracellular vesicles produced by T cells SO MATRIX BIOLOGY LA English DT Article DE Thrombospondin-1; CD47; Extracellular vesicles; Intercellular communication ID PROTEIN CD47; PROTEOMIC ANALYSIS; ENDOTHELIAL-CELLS; DENDRITIC CELLS; EXOSOMES; THROMBOSPONDIN-1; ASSOCIATION; ACTIVATION; ECTOSOMES; ADHESION AB Intercellular communication is critical for integrating complex signals in multicellular eukaryotes. Vascular endothelial cells and T lymphocytes closely interact during the recirculation and trans-endothelial migration of T cells. In addition to direct cell-cell contact, we show that T cell derived extracellular vesicles can interact with endothelial cells and modulate their cellular functions. Thrombospondin-1 and its receptor CD47 are expressed on exosomes/ectosomes derived from T cells, and these extracellular vesicles are internalized and modulate signaling in both T cells and endothelial cells. Extracellular vesicles released from cells expressing or lacking CD47 differentially regulate activation of T cells induced by engaging the T cell receptor. Similarly, T cell-derived extracellular vesicles modulate endothelial cell responses to vascular endothelial growth factor and tube formation in a CD47-dependent manner. Uptake of T cell derived extracellular vesicles by recipient endothelial cells globally alters gene expression in a CD47-dependent manner. CD47 also regulates the mRNA content of extracellular vesicles in a manner consistent with some of the resulting alterations in target endothelial cell gene expression. Therefore, the thrombospondin-1 receptor CD47 directly or indirectly regulates intercellular communication mediated by the transfer of extracellular vesicles between vascular cells. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Kaur, Sukhbir; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20982 USA. [Singh, Satya P.] NIAID, Inflammat Biol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20982 USA. [Elkahloun, Abdel G.; Wu, Weiwei] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Abu-Asab, Mones S.] NEI, Histopathol Core, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NIH, Bldg 10 Room 2A33,10 Ctr Dr, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute [ZIA SC 009172]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases; Intramural Research Program of the National Human Genome Research Institute FX We thank Dr. Elise Kohn for sharing PKH26 and PKH67 dyes and Susan Garfield and Lim Langston for their help for confocal microscopy. We thank Dr. Michael L Pendrak for designing primers and making the CD47 siRNA construct. This work was supported by the Intramural Research Programs of the Center for Cancer Research, National Cancer Institute (ZIA SC 009172), National Institute of Allergy and Infectious Diseases, and National Human Genome Research Institute. NR 70 TC 7 Z9 7 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X EI 1569-1802 J9 MATRIX BIOL JI Matrix Biol. PD JUL PY 2014 VL 37 BP 49 EP 59 DI 10.1016/j.matbio.2014.05.007 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AQ8LO UT WOS:000343077200005 PM 24887393 ER PT J AU Wilson, WH Bromberg, JEC Stetler-Stevenson, M Steinberg, SM Martin-Martin, L Muniz, C Sancho, JM Caballero, MD Davidis, MA Brooimans, RA Sanchez-Gonzalez, B Salar, A Gonzalez-Barca, E Ribera, JM Shovlin, M Filie, A Dunleavy, K Mehrling, T Spina, M Orfao, A AF Wilson, Wyndham H. Bromberg, Jacoline E. C. Stetler-Stevenson, Maryalice Steinberg, Seth M. Martin-Martin, Lourdes Muniz, Carmen Manuel Sancho, Juan Dolores Caballero, Maria Davidis, Marjan A. Brooimans, Rik A. Sanchez-Gonzalez, Blanca Salar, Antonio Gonzalez-Barca, Eva Maria Ribera, Jose Shovlin, Margaret Filie, Armando Dunleavy, Kieron Mehrling, Thomas Spina, Michele Orfao, Alberto CA Spanish Grp Study CNS Dis NHL TI Detection and outcome of occult leptomeningeal disease in diffuse large B-cell lymphoma and Burkitt lymphoma SO HAEMATOLOGICA LA English DT Article ID NON-HODGKINS-LYMPHOMA; ACUTE LYMPHOBLASTIC-LEUKEMIA; DOSE-ADJUSTED EPOCH; FLOW-CYTOMETRY; RISK-FACTORS; ELDERLY-PATIENTS; RITUXIMAB ERA; CHEMOTHERAPY; GRADE; TRIAL AB The benefit of intrathecal therapy and systemic rituximab on the outcome of diffuse large B-cell lymphoma at risk of central nervous system disease is controversial. Furthermore, the effect of intrathecal treatment and rituximab in diffuse large B-cell and Burkitt lymphoma with occult leptomeningeal disease detected by flow cytometry at diagnosis is unknown. Untreated diffuse large B-cell (n=246) and Burkitt (n=80) lymphoma at clinical risk of central nervous system disease and having had pre-treatment cerebrospinal fluid were analyzed by flow cytometry and cytology. Spinal fluid involvement was detected by flow cytometry alone (occult) in 33 (13%) diffuse large B-cell and 9 (11%) Burkitt lymphoma patients, and detected by cytology in 11 (4.5%) and 5 (6%) patients, respectively. Diffuse large B-cell lymphoma with occult spinal fluid involvement had poorer survival (P=0.0001) and freedom from central nervous system relapse (P<0.0001) compared to negative cases. Burkitt lymphoma with occult spinal fluid involvement had an inferior freedom from central nervous system relapse (P=0.026) but not survival. The amount of intrathecal chemotherapy was quantitatively associated with survival in diffuse large B-cell lymphoma with (P=0.02) and without (P=0.001) occult spinal fluid involvement. However, progression of systemic disease and not control of central nervous system disease was the principal cause of treatment failure. In diffuse large B-cell lymphoma, systemic rituximab was associated with improved freedom from central nervous system relapse (P=0.003) but not with survival. Our results suggest that patients at risk of central nervous system disease should be evaluated by flow cytometry and that intrathecal prophylaxis/therapy is beneficial. C1 [Wilson, Wyndham H.; Stetler-Stevenson, Maryalice; Steinberg, Seth M.; Shovlin, Margaret; Filie, Armando; Dunleavy, Kieron] NCI, Lymphoid Malignancy Branch, Bethesda, MD 20892 USA. [Bromberg, Jacoline E. C.] Univ Med Ctr, Erasmus MC, Daniel den Hoed Canc Ctr, Dept Neurooncol, Rotterdam, Netherlands. [Martin-Martin, Lourdes; Muniz, Carmen; Dolores Caballero, Maria; Orfao, Alberto] Univ Hosp, Dept Med, IBSAL, Salamanca, Spain. [Martin-Martin, Lourdes; Muniz, Carmen; Dolores Caballero, Maria; Orfao, Alberto] Univ Hosp, Ctr Invest Canc IBMCC CSIC USAL, IBSAL, Salamanca, Spain. [Martin-Martin, Lourdes; Muniz, Carmen; Dolores Caballero, Maria; Orfao, Alberto] Univ Hosp, Dept Hematol, IBSAL, Salamanca, Spain. [Martin-Martin, Lourdes; Muniz, Carmen; Dolores Caballero, Maria; Orfao, Alberto] Univ Salamanca, E-37008 Salamanca, Spain. [Manuel Sancho, Juan; Maria Ribera, Jose] Univ Barcelona, Hosp German Trias & Puyol, Dept Hematol, E-08007 Barcelona, Spain. [Davidis, Marjan A.] Univ Med Ctr Rotterdam, Erasmus MC, Daniel den Hoed Canc Ctr, Dept Hematol, Rotterdam, Netherlands. [Brooimans, Rik A.] Univ Med Ctr Rotterdam, Erasmus MC, Daniel den Hoed Canc Ctr, Dept Med Immunol, Rotterdam, Netherlands. [Sanchez-Gonzalez, Blanca; Salar, Antonio] Hosp del Mar, Dept Hematol, Barcelona, Spain. [Gonzalez-Barca, Eva] Univ Barcelona, IDIBELL, Inst Catala Oncol, Dept Hematol,Hosp Duran & Reynals, E-08007 Barcelona, Spain. [Mehrling, Thomas] Mundipharma Int Ltd, Cambridge, England. [Spina, Michele] Natl Canc Inst, Div Med Oncol A, Aviano, Italy. RP Wilson, WH (reprint author), NCI, Lymphoid Malignancy Branch, Bethesda, MD 20892 USA. EM wilsonw@mail.nih.gov OI Salar, Antonio/0000-0002-4652-4825 FU RETICS-FEDER (Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Madrid, Spain) [RD06/0020/0035, RD12/0036/0048]; Mundipharma Pharmaceuticals, SL (Madrid, Spain) FX The work was partially supported by the following grants RD06/0020/0035 and RD12/0036/0048 from RETICS-FEDER (Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Madrid, Spain) and an unrestricted grant from Mundipharma Pharmaceuticals, SL (Madrid, Spain). NR 29 TC 22 Z9 22 U1 2 U2 7 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JUL 1 PY 2014 VL 99 IS 7 BP 1228 EP 1235 DI 10.3324/haematol.2013.101741 PG 8 WC Hematology SC Hematology GA AQ5FY UT WOS:000342833500027 PM 24727817 ER PT J AU Iantorno, M Campia, U Di Daniele, N Nistico, S Forleo, GB Cardillo, C Tesauro, M AF Iantorno, M. Campia, U. Di Daniele, N. Nistico, S. Forleo, G. B. Cardillo, C. Tesauro, M. TI GUT HORMONES AND ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH OBESITY AND DIABETES SO INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY LA English DT Letter DE gut hormones; obesity; diabetes; endothelial function ID METABOLIC SYNDROME; GHRELIN; GLP-1; HYPERINSULINEMIA; METAANALYSIS; OBESTATIN; SURGERY; WEIGHT; CELLS; NO AB Overweight and obesity are the fifth leading risk for global deaths and its prevalence has doubled since 1980. At least 2.8 million adults, worldwide, die each year as a result of being overweight or obese. The deleterious effects of obesity are tightly related to diabetes, as they are often clinically present in combination to confer increased cardiovascular mortality. Thus, patients with diabetes and obesity are known to develop accelerated atherosclerosis characterized by a dysfunctional endothelium and decreased nitric oxide bioavailability. Recent clinical studies support, indeed, the use of incretin-based antidiabetic therapies for vascular protection. Thus, attention has been focusing on gut hormones and their role, not only in the regulation of appetite but also in vascular health. Intervention directed at modulating these molecules has the potential to decrease mortality of patients with diabetes and obesity. This review will cover part of the ongoing research to understand the role of gut hormones on endothelial function and vascular health. C1 [Iantorno, M.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Campia, U.] MedStar Cardiovasc Res Network Washington, Washington, DC USA. [Di Daniele, N.; Forleo, G. B.; Tesauro, M.] Univ Roma Tor Vergata, Dept Syst Med, Rome, Italy. [Nistico, S.] Univ Catanzaro Magna Grecia, Dept Hlth Sci, Catanzaro, Italy. [Cardillo, C.] Catholic Univ, Rome, Italy. RP Nistico, S (reprint author), Univ Catanzaro, Dept Hlth Sci, I-88100 Germaneto, CZ, Italy. EM steven.nistico@gmail.com NR 32 TC 6 Z9 7 U1 0 U2 6 PU BIOLIFE SAS PI SILVA MARINA (TE) PA VIA S STEFANO 39 BIS, 64029 SILVA MARINA (TE), ITALY SN 0394-6320 J9 INT J IMMUNOPATH PH JI Int. J. Immunopathol. Pharmacol. PD JUL-SEP PY 2014 VL 27 IS 3 BP 433 EP 436 PG 4 WC Immunology; Pathology; Pharmacology & Pharmacy SC Immunology; Pathology; Pharmacology & Pharmacy GA AP9JW UT WOS:000342397100014 PM 25280035 ER PT J AU Nolting, S Giubellino, A Tayem, Y Young, K Lauseker, M Bullova, P Schovanek, J Anver, M Fliedner, S Korbonits, M Goke, B Vlotides, G Grossman, A Pacak, K AF Noelting, Svenja Giubellino, Alessio Tayem, Yasin Young, Karen Lauseker, Michael Bullova, Petra Schovanek, Jan Anver, Miriam Fliedner, Stephanie Korbonits, Marta Goeke, Burkhard Vlotides, George Grossman, Ashley Pacak, Karel TI Combination of 13-Cis Retinoic Acid and Lovastatin: Marked Antitumor Potential In Vivo in a Pheochromocytoma Allograft Model in Female Athymic Nude Mice SO ENDOCRINOLOGY LA English DT Article ID HMG-COA REDUCTASE; SQUAMOUS-CELL CARCINOMA; NEURO-BLASTOMA CELLS; 13-CIS-RETINOIC ACID; MEVALONATE PATHWAY; SIGNALING PATHWAYS; VITAMIN-E; CANCER; GROWTH; MOUSE AB Currently, there are no reliably effective therapeutic options for metastatic pheochromocytoma (PCC) and paraganglioma. Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggressive tumors. Therefore, we tested the approved and well-tolerated drugs lovastatin and 13-cis-retinoic acid (13cRA) in vitro in an aggressive PCC mouse cell line, mouse tumor tissue-derived (MTT) cells, and in vivo in a PCC allograft nude mouse model, in therapeutically relevant doses. Treatment was started 24 hours before sc tumor cell injection and continued for 30 more days. Tumor sizes were measured from outside by caliper and sizes of viable tumor mass by bioluminescence imaging. Lovastatin showed antiproliferative effects in vitro and led to significantly smaller tumor sizes in vivo compared with vehicle treatment. 13cRA promoted tumor cell growth in vitro and led to significantly larger viable tumor mass and significantly faster increase of viable tumor mass in vivo over time compared with vehicle, lovastatin, and combination treatment. However, when combined with lovastatin, 13cRA enhanced the antiproliferative effect of lovastatin in vivo. The combination-treated mice showed slowest tumor growth of all groups with significantly slower tumor growth compared with the vehicle-treated mice and significantly smaller tumorsizes. Moreover, the combination-treated group displayed the smallest size of viable tumor mass and the slowest increase inviable tumor mass overtime of all groups, with a significant difference compared with the vehicle-and 13cRA-treated group. The combination-treated tumors showed highest extent of necrosis, lowest median microvessel density and highest expression of alpha-smooth muscle actin. The combination of high microvessel density and low alpha-smooth muscle actin is a predictor of poor prognosis in other tumor entities. Therefore, this drug combination may be a well-tolerated novel therapeutic or preventiveoption for malignant PCC. C1 [Noelting, Svenja; Giubellino, Alessio; Tayem, Yasin; Bullova, Petra; Schovanek, Jan; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Noelting, Svenja; Young, Karen; Korbonits, Marta] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Dept Endocrinol, London EC1M 6BQ, England. [Noelting, Svenja; Goeke, Burkhard; Vlotides, George] Univ Munich, Univ Hosp, Dept Internal Med 2, D-81377 Munich, Germany. [Lauseker, Michael] Univ Munich, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany. [Bullova, Petra] Slovak Acad Sci, Inst Virol, Dept Mol Med, Bratislava 84505, Slovakia. [Schovanek, Jan] Palacky Univ, Fac Med & Dent, Dept Internal Med 3, Olomouc 77520, Czech Republic. [Anver, Miriam] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Fliedner, Stephanie] Univ Med Ctr Schleswig Holstein, Dept Med 1, D-23538 Lubeck, Germany. [Grossman, Ashley] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LE, England. RP Grossman, A (reprint author), Univ Oxford, Churchill Hosp, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LE, England. EM ashley.grossman@ocdem.ox.ac.uk; karel@mail.nih.gov OI Korbonits, Marta/0000-0002-4101-9432 FU National Cancer Institute, National Institutes of Health [HSN261200800001E]; German Research Foundation (Deutsche Forschungsgemeinschaft) FX This work was supported in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HSN261200800001E and in part by the German Research Foundation (Deutsche Forschungsgemeinschaft). NR 46 TC 6 Z9 6 U1 0 U2 5 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUL PY 2014 VL 155 IS 7 BP 2377 EP 2390 DI 10.1210/en.2014-1027 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8QI UT WOS:000342343400007 PM 24762141 ER PT J AU Taieb, D Timmers, HJLM Shulkin, BL Pacak, K AF Taieb, David Timmers, Henri J. L. M. Shulkin, Barry L. Pacak, Karel TI Renaissance of F-18-FDG Positron Emission Tomography in the Imaging of Pheochromocytoma/Paraganglioma Commentary SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID FUNCTIONAL-CHARACTERIZATION; PARAGANGLIOMA; PET; 2-DEOXY-2-FLUORO-D-GLUCOSE C1 [Taieb, David] Aix Marseille Univ, La Timone Univ Hosp, European Ctr Res Med Imaging, Dept Nucl Med, F-13005 Marseille, France. [Timmers, Henri J. L. M.] Radboud Univ Nijmegen, Med Ctr, Dept Med, Endocrinol Sect, NL-6500 HB Nijmegen, Netherlands. [Shulkin, Barry L.] St Jude Childrens Res Hosp, Div Diagnost Imaging, Memphis, TN 38105 USA. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Taieb, D (reprint author), Aix Marseille Univ, La Timone Univ Hosp, European Ctr Res Med Imaging, Dept Nucl Med, F-13005 Marseille, France. EM david.taieb@ap-hm.fr; karel@mail.nih.gov FU Intramural NIH HHS NR 10 TC 4 Z9 4 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2014 VL 99 IS 7 BP 2337 EP 2339 DI 10.1210/jc.2014-1048 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PM UT WOS:000342341000036 PM 24878044 ER PT J AU Chia, CW Odetunde, JO Kim, W Carlson, OD Ferrucci, L Egan, JM AF Chia, Chee W. Odetunde, Juliana O. Kim, Wook Carlson, Olga D. Ferrucci, Luigi Egan, Josephine M. TI GIP Contributes to Islet Trihormonal Abnormalities in Type 2 Diabetes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PANCREATIC-POLYPEPTIDE; INHIBITORY POLYPEPTIDE; GLUCOSE-PRODUCTION; GLUCAGON; MELLITUS; INSULIN; RELEASE; PEPTIDE; HYPERGLYCEMIA; EXENDIN-4 AB Context: Research and clinical treatments on type 2 diabetes mainly focus on insulin deficiency with little attention paid to other islet hormones. Objective: This study tested the hypothesis that glucose-dependent insulinotropic polypeptide (GIP) is involved in diabetes-associated multiislet hormone dysregulation. Design: This paper included a case-control study involving 92 community-based volunteers from the Baltimore Longitudinal Study of Aging (BLSA): 23 with type 2 diabetes on glucose-lowering agents, 25 with newly diagnosed drug-naive type 2 diabetes, 19 with prediabetes, and 25 with normal glucose tolerance; a separate intervention study with 13 non-BLSA volunteers with type 2 diabetes treated with diet alone, metformin, and/or metformin/sulfonylurea combination; a rodent study; and an in vitro cell line study. Interventions: An oral glucose tolerance test was performed in the BLSA participants. For the intervention study, saline (0.9% NaCl) or synthetic human GIP (20 ng . kg(-1) . min(-1)) was administered to type 2 diabetes subjects for 180 minutes together with a meal, and plasma samples were obtained at predetermined intervals for 360 minutes. A bolus of GIP or placebo was given to C57BL/6 mice. Main Outcome Measures: Plasma glucose, insulin, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and GIP were measured. Results: After an oral glucose tolerance test, glucose, glucagon, PP, GLP-1, and GIP levels were significantly elevated in type 2 diabetes groups, compared with normal and prediabetes groups. GIP infusion in type 2 diabetes subjects was associated with significantly elevated PP levels compared with placebo. The GIP bolus given to C57BL/6 mice was followed by increased PP levels. GIP receptors were found in both human and mouse PP cells. Conclusions: Up-regulation of GIP production may play an important role in multihormonal dysregulation in type 2 diabetes, most likely through interaction with GIP receptors on islets. C1 [Chia, Chee W.; Odetunde, Juliana O.; Carlson, Olga D.; Egan, Josephine M.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21225 USA. [Ferrucci, Luigi] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21225 USA. [Kim, Wook] Ajou Univ, Dept Mol Sci & Technol, Suwon 443749, South Korea. RP Chia, CW (reprint author), NIA, Intramural Res Program, 3001 South Hanover St,NM-533, Baltimore, MD 21225 USA. EM chiac@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging; Basic Science Research Program through the National Research Foundation of Korea - Ministry of Science, ICT, and Future [NRF-2012R1A1A1041352] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. W.K. is supported by Basic Science Research Program through the National Research Foundation of Korea supported by the Ministry of Science, ICT, and Future (Grant NRF-2012R1A1A1041352). NR 29 TC 10 Z9 10 U1 1 U2 4 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2014 VL 99 IS 7 BP 2477 EP 2485 DI 10.1210/jc.2013-3994 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PM UT WOS:000342341000055 PM 24712564 ER PT J AU Nilubol, N Boufraqech, M Zhang, L Kebebew, E AF Nilubol, Naris Boufraqech, Myriem Zhang, Lisa Kebebew, Electron TI Loss of CPSF2 Expression Is Associated with Increased Thyroid Cancer Cellular Invasion and Cancer Stem Cell Population, and More Aggressive Disease SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; BRAF V600E MUTATION; COLORECTAL-CANCER; ALTERNATIVE CLEAVAGE; BREAST-CANCER; CD44; CARCINOMA; POLYADENYLATION; MORTALITY; SURVIVAL AB Purpose: Identification of molecular factors that promote thyroid cancer progression have important clinical implications for therapy and prognostication in patients with papillary thyroid cancer (PTC). The aim of this study was to validate and determine the function of dysregulated genes that were associated increased mortality in patients with PTC. Experiemental Design: We selected the cleavage and polyadenylation specificity factor subunit 2 (CPSF2) gene from the top 5 significantly dysregulated genes associated with PTC-associated mortality from our previous study. We used 86 PTC samples enriched for aggressive disease (recurrence and mortality) by quantitative RT-PCR (qRT-PCR). In vitro functional studies of the validated gene were performed. Results: Decreased CPSF2 gene expression was associated with shorter disease-free survival (P = .03), large tumor size (T3 and T4) (P = .03), tumor recurrence (P < .01), and mortality (P < .01), independent of BRAF V600E mutation status. CPSF2 knockdown increased cellular invasion by 1.8-to 3.2-fold (P < .01) and increased markers of thyroid cancer stem cells (CD44 and CD133 expression). Immunohistochemistry showed an inverse correlation between CD44 protein expression in PTC samples and CPSF2 expression. Conclusion: Decreased CPSF2 expression is associated with increased cellular invasion and cancer stem cell population, and more aggressive disease in PTC. C1 [Nilubol, Naris; Boufraqech, Myriem; Zhang, Lisa; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Nilubol, N (reprint author), NCI, Endocrine Oncol Branch, Clin Res Ctr, 10 Ctr Dr,Room 3-5840, Bethesda, MD 20892 USA. EM niluboln@mail.nih.gov RI Boufraqech, Myriem/E-4823-2016 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health Intramural Research Program FX This study was supported by the Center for Cancer Research, National Cancer Institute, National Institutes of Health Intramural Research Program. NR 34 TC 5 Z9 6 U1 1 U2 4 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2014 VL 99 IS 7 BP E1173 EP E1182 DI 10.1210/jc.2013-4140 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PM UT WOS:000342341000003 PM 24654752 ER PT J AU Arnold, MA Ballester, LY Pack, SD Abdullaev, Z Merchant, M Tsokos, MG AF Arnold, Michael A. Ballester, Leomar Y. Pack, Svetlana D. Abdullaev, Ziedulla Merchant, Melinda Tsokos, Maria G. TI Primary Subcutaneous Spindle Cell Ewing Sarcoma with Strong S100 Expression and EWSR1-FLI1 Fusion: A Case Report SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Article DE Ewing sarcoma; spindle cell; S100; EWSR1-FLI1; RT-PCR; FISH ID TUMORS; FAMILY; SCHWANNOMA AB Ewing sarcoma is described classically as a small, round cell tumor of bone and soft tissue in children and young adults. Ewing sarcoma most often is characterized by a fusion of the Ewing sarcoma breakpoint region 1 (EWSR1) and the Friend leukemia virus integration 1 (FLI1) genes, forming an EWSR1-FLI1 fusion transcript. We report an exceptional case of primary subcutaneous Ewing sarcoma in a 16-year-old female composed entirely of spindle cells with focal fascicular growth and exhibiting strong, diffuse immunohistochemical reactivity for S100, unlike classic Ewing sarcoma. However, reverse transcription-polymerase chain reaction (RTPCR) analysis confirmed the presence of a rare variant of the EWSR1-FLI1 fusion transcript, featuring fusion of EWSR1 exon 10 to FLI1 exon 6. To our knowledge, the combined histologic, molecular, and clinical features have not been reported previously in Ewing sarcoma, and raise a broad differential diagnosis emphasizing the importance of molecular techniques in the diagnosis of this tumor. C1 [Arnold, Michael A.] Ohio State Univ, Coll Med, Dept Pathol & Lab Med, Columbus, OH 43210 USA. [Arnold, Michael A.] Nationwide Childrens Hosp, Columbus, OH USA. [Ballester, Leomar Y.; Pack, Svetlana D.; Abdullaev, Ziedulla] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Merchant, Melinda] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Tsokos, Maria G.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. RP Arnold, MA (reprint author), Ohio State Univ, Coll Med, Dept Pathol & Lab Med, Columbus, OH 43210 USA. EM Michael.Arnold@Nationwidechildrens.org OI Arnold, Michael/0000-0002-6921-3720 FU Intramural Research Program of the National Cancer Institute (NCI) FX This research was supported by the Intramural Research Program of the National Cancer Institute (NCI), and was performed at the Laboratory of Pathology, NCI, Bethesda, MD, USA. NR 22 TC 1 Z9 1 U1 0 U2 0 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 1093-5266 EI 1615-5742 J9 PEDIATR DEVEL PATHOL JI Pediatr. Dev. Pathol. PD JUL-AUG PY 2014 VL 17 IS 4 BP 302 EP 307 DI 10.2350/14-03-1454-CR.1 PG 6 WC Pathology; Pediatrics SC Pathology; Pediatrics GA AP9FD UT WOS:000342383300009 PM 24735198 ER PT J AU Bures, RM Mabry, PL Orleans, CT Esposito, L AF Bures, Regina M. Mabry, Patricia L. Orleans, C. Tracy Esposito, Layla TI Systems Science: A Tool for Understanding Obesity SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Bures, Regina M.; Mabry, Patricia L.; Esposito, Layla] NIH, Bethesda, MD 20892 USA. [Orleans, C. Tracy] Robert Wood Johnson Fdn, Princeton, NJ USA. RP Bures, RM (reprint author), NIH, Bethesda, MD 20892 USA. NR 0 TC 6 Z9 6 U1 1 U2 5 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2014 VL 104 IS 7 BP 1156 EP 1156 DI 10.2105/AJPH.2014.302082 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1EM UT WOS:000341809500024 PM 24832433 ER PT J AU Mabry, PL Bures, RM AF Mabry, Patricia L. Bures, Regina M. TI Systems Science for Obesity-Related Research Questions: An Introduction to the Theme Issue SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material ID PUBLIC-HEALTH C1 [Mabry, Patricia L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Bures, Regina M.] NIH, Populat Dynam Branch, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Mabry, PL (reprint author), NIH, Off Dis Prevent Off theDirector, 6100 Executive Blvd,Suite 2B03, Bethesda, MD 20892 USA. EM mabryp@od.nih.gov NR 22 TC 4 Z9 4 U1 0 U2 4 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2014 VL 104 IS 7 BP 1157 EP 1159 DI 10.2105/AJPH.2014.302083 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1EM UT WOS:000341809500025 PM 24832429 ER PT J AU Hall, KD Hammond, RA Rahmandad, H AF Hall, Kevin D. Hammond, Ross A. Rahmandad, Hazhir TI Dynamic Interplay Among Homeostatic, Hedonic, and Cognitive Feedback Circuits Regulating Body Weight SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID FOOD-INTAKE; ADOLESCENT GIRLS; ENERGY-INTAKE; NONOVERWEIGHT ADOLESCENTS; SOCIAL-ENVIRONMENT; MATHEMATICAL-MODEL; OBESITY RESEARCH; DECISION-MAKING; EATING BEHAVIOR; REWARD AB Obesity is associated with a prolonged imbalance between energy intake and expenditure, both of which are regulated by multiple feedback processes within and across individuals. These processes constitute 3 hierarchical control systems-homeostatic, hedonic, and cognitive-with extensive interaction among them. Understanding complex eating behavior requires consideration of all 3 systems and their interactions. Existing models of these processes are widely scattered, with relatively few attempts to integrate across mechanisms. We briefly review available empirical evidence and dynamic models, discussing challenges and potential for better integration. We conclude that developing richer models of dynamic interplay among systems should be a priority in the future study of obesity and that systems science modeling offers the potential to aid in this goal. C1 [Hall, Kevin D.] NIDDK, Bethesda, MD 20892 USA. [Hammond, Ross A.] Brookings Inst, Washington, DC 20036 USA. [Rahmandad, Hazhir] Virginia Tech, Dept Ind & Syst Engn, Falls Church, VA USA. RP Hall, KD (reprint author), NIDDK, 12A South Dr,Room 4007, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov RI Rahmandad, Hazhir/B-4474-2013 OI Rahmandad, Hazhir/0000-0002-2784-9042 FU National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases; National Collaborative on Childhood Obesity Research Envision Project from the Eunice Kennedy Shriver National Institute of Child Health and Human Development [1R01HD08023]; NIH's Office of Behavioral and Social Science Research [HHSN276201000004C] FX This research was supported (in part) by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (K. D. H.), National Collaborative on Childhood Obesity Research Envision Project through grant 1R01HD08023 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R. A. H.), and NIH's Office of Behavioral and Social Science Research contract HHSN276201000004C (H. R.). NR 97 TC 19 Z9 19 U1 5 U2 16 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2014 VL 104 IS 7 BP 1169 EP 1175 DI 10.2105/AJPH.2014.301931 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1EM UT WOS:000341809500028 PM 24832422 ER PT J AU Maglio, PP Sepulveda, MJ Mabry, PL AF Maglio, Paul P. Sepulveda, Martin-J. Mabry, Patricia L. TI Mainstreaming Modeling and Simulation to Accelerate Public Health Innovation SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID OBESITY; POLICY; COST; INTERVENTIONS; SMOKING; SCIENCE; DISEASE; TRENDS AB Dynamic modeling and simulation are systems science tools that examine behaviors and outcomes resulting from interactions among multiple system components over time. Although there are excellent examples of their application, they have not been adopted as mainstream tools in population health planning and policymaking. Impediments to their use include the legacy and ease of use of statistical approaches that produce estimates with confidence intervals, the difficulty of multidisciplinary collaboration for modeling and simulation, systems scientists' inability to communicate effectively the added value of the tools, and low funding for population health systems science. Proposed remedies include aggregation of diverse data sets, systems science training for public health and other health professionals, changing research incentives toward collaboration, and increased funding for population health systems science projects. C1 [Maglio, Paul P.] Univ Calif Merced, Sch Engn, Merced, CA 95343 USA. [Maglio, Paul P.] IBM Res, Almaden, CA USA. [Sepulveda, Martin-J.] IBM Res, Hlth Syst & Policy Res, Yorktown Hts, NY USA. [Mabry, Patricia L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP Maglio, PP (reprint author), Univ Calif Merced, Sch Engn, 5200 N Lake Rd, Merced, CA 95343 USA. EM pmaglio@ucmerced.edu NR 51 TC 8 Z9 8 U1 3 U2 8 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2014 VL 104 IS 7 BP 1181 EP 1186 DI 10.2105/AJPH.2014.301873 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1EM UT WOS:000341809500030 PM 24832426 ER PT J AU Fallah-Fini, S Rahmandad, H Huang, TTK Bures, RM Glass, TA AF Fallah-Fini, Saeideh Rahmandad, Hazhir Huang, Terry T. -K. Bures, Regina M. Glass, Thomas A. TI Modeling US Adult Obesity Trends: A System Dynamics Model for Estimating Energy Imbalance Gap SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID PUBLIC-HEALTH; PREVALENCE; SCIENCE; BALANCE AB Objectives. We present a system dynamics model that quantifies the energy imbalance gap responsible for the US adult obesity epidemic among gender and racial subpopulations. Methods. We divided the adult population into gender-race/ethnicity subpopulations and body mass index (BMI) classes. We defined transition rates between classes as a function of metabolic dynamics of individuals within each class. We estimated energy intake in each BMI class within the past 4 decades as a multiplication of the equilibrium energy intake of individuals in that class. Through calibration, we estimated the energy gap multiplier for each gender-race-BMI group by matching simulated BMI distributions for each subpopulation against national data with maximum likelihood estimation. Results. No subpopulation showed a negative or zero energy gap, suggesting that the obesity epidemic continues to worsen, albeit at a slower rate. In the past decade the epidemic has slowed for non-Hispanic Whites, is starting to slow for non-Hispanic Blacks, but continues to accelerate among Mexican Americans. Conclusions. The differential energy balance gap across subpopulations and over time suggests that interventions should be tailored to subpopulations' needs. C1 [Fallah-Fini, Saeideh] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Johns Hopkins Global Ctr Childhood Obes, Baltimore, MD USA. [Rahmandad, Hazhir] Virginia Tech, Ind & Syst Engn Dept, Falls Church, VA USA. [Huang, Terry T. -K.] Univ Nebraska Med Ctr, Coll Publ Hlth, Dept Hlth Promot Social & Behav Hlth, Omaha, NE USA. [Bures, Regina M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Glass, Thomas A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. RP Fallah-Fini, S (reprint author), Calif State & Polytech Univ, Ind & Mfg Engn Dept, 3801 W Temple Ave, Pomona, CA 91768 USA. EM sfallahfini@csupomona.edu RI Rahmandad, Hazhir/B-4474-2013; OI Rahmandad, Hazhir/0000-0002-2784-9042; Glass, Thomas/0000-0003-4399-612X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U54HD070725]; Office of Behavioral and Social Sciences Research (OBSSR); National Collaborative on Childhood Obesity Research Envision's Comparative Modeling Network program; National Institutes of Health OBSSR [HHSN276201000004C]; [R21-HL113680] FX The study is partially supported by grant U54HD070725 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). This grant is cofunded by the NICHD and the Office of Behavioral and Social Sciences Research (OBSSR). This study is also partially supported by R21-HL113680 and National Collaborative on Childhood Obesity Research Envision's Comparative Modeling Network program, and National Institutes of Health OBSSR contract HHSN276201000004C. NR 32 TC 19 Z9 19 U1 4 U2 16 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2014 VL 104 IS 7 BP 1230 EP 1239 DI 10.2105/AJPH.2014.301882 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1EM UT WOS:000341809500037 PM 24832405 ER PT J AU Whitehead, TP Metayer, C Ward, MH Colt, JS Gunier, RB Deziel, NC Rappaport, SM Buffler, PA AF Whitehead, Todd P. Metayer, Catherine Ward, Mary H. Colt, Joanne S. Gunier, Robert B. Deziel, Nicole C. Rappaport, Stephen M. Buffler, Patricia A. TI Persistent Organic Pollutants in Dust From Older Homes: Learning From Lead SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; CHILDRENS BLOOD LEAD; HAZARD CONTROL INTERVENTIONS; CONTAMINATED HOUSE-DUST; CONTROL GRANT PROGRAM; IN-UTERO EXPOSURE; POLYCHLORINATED-BIPHENYLS; NEURODEVELOPMENT; AGE; IQ AB Objectives. We aimed to (1) evaluate the relation between home age and concentrations of multiple chemical contaminants in settled dust and (2) discuss the feasibility of using lead hazard controls to reduce children's exposure to persistent organic pollutants. Methods. As part of the California Childhood Leukemia Study, from 2001 to 2007, we used a high-volume small surface sampler and household vacuum cleaners to collect dust samples from 583 homes and analyzed the samples for 94 chemicals with gas chromatography-mass spectrometry and inductively coupled plasma mass spectrometry. We evaluated relations between chemical concentrations in dust and home age with Spearman rank correlation coefficients. Results. Dust concentrations of lead, polychlorinated biphenyls, organochlorine insecticides, and polycyclic aromatic hydrocarbons were correlated with home age (rho > 0.2; P <.001), whereas concentrations of pyrethroid insecticides and polybrominated diphenyl ethers were not. Conclusions. Dust in older homes contains higher levels of multiple, persistent chemicals than does dust in newer homes. Further development of strategies to reduce chemical exposures for children living in older homes is warranted. C1 [Whitehead, Todd P.; Metayer, Catherine; Gunier, Robert B.; Rappaport, Stephen M.; Buffler, Patricia A.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Ward, Mary H.; Colt, Joanne S.; Deziel, Nicole C.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Whitehead, TP (reprint author), 1995 Univ Ave,Suite 460, Berkeley, CA 94704 USA. EM toddpwhitehead@berkeley.edu OI Gunier, Robert/0000-0001-5485-9919 FU National Institute of Environmental Health Sciences [R01ES009137, R01ES015899, P42ES0470518, P01ES018172]; National Cancer Institute (NCI), National Institutes of Health [7590-S-04, 7590-S-01]; NCI [N02-CP-11015]; Environmental Protection Agency [RD83451101] FX This work was supported in part by the National Institute of Environmental Health Sciences (grants R01ES009137, R01ES015899, P42ES0470518, P01ES018172); by the Intramural Research Program of the National Cancer Institute (NCI), National Institutes of Health (subcontracts 7590-S-04, 7590-S-01); by the NCI (contract N02-CP-11015); and by the Environmental Protection Agency (grant RD83451101). NR 48 TC 8 Z9 8 U1 3 U2 16 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2014 VL 104 IS 7 BP 1320 EP 1326 DI 10.2105/AJPH.2013.301835 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1EM UT WOS:000341809500050 PM 24832145 ER PT J AU Tabak, LA AF Tabak, Lawrence A. TI NATIONAL INSTITUTES OF HEALTH EFFORTS ON SEXUAL AND GENDER MINORITY HEALTH RESEARCH SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Letter C1 [Tabak, Lawrence A.] NIH, Bethesda, MD 20892 USA. RP Tabak, LA (reprint author), Bldg 1,Room 126,1 Ctr Dr, Bethesda, MD 20892 USA. EM Lawrence.tabak@nih.gov NR 1 TC 2 Z9 2 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2014 VL 104 IS 7 BP E7 EP E7 DI 10.2105/AJPH.2014.301973 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1EM UT WOS:000341809500006 PM 24832419 ER PT J AU Lee, SW Landers, KA Park, HS AF Lee, Sang Wook Landers, Katlin A. Park, Hyung-Soon TI Development of a Biomimetic Hand Exotendon Device (BiomHED) for Restoration of Functional Hand Movement Post-Stroke SO IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING LA English DT Article DE Biomimetic; exotendon; hand; orthosis; task-oriented training ID REHABILITATION FOLLOWING STROKE; DEFICITS FOLLOWING STROKE; UPPER EXTREMITY FUNCTION; ACTIVATION PATTERNS; EXTENSOR MECHANISM; TRUNK RESTRAINT; FINGER MUSCLES; PRECISION GRIP; MOTOR CONTROL; LOAD FORCE AB Significant functional impairment of the hand is common among stroke survivors and restoration of hand function should be prioritized during post-stroke rehabilitation. The goal of this study was to develop a novel biomimetic device to assist patients in producing complex hand movements with a limited number of actuators. The Biomimetic Hand Exoskeleton Device (BiomHED) is actuated by exotendons that mimic the geometry of the major tendons of the hand. Ten unimpaired subjects and four chronic stroke survivors participated in experiments that tested the efficacy of the system. The exotendons reproduced distinct spatial joint coordination patterns similar to their target muscle-tendon units for both subject groups. In stroke survivors, the exotendon-produced joint angular displacements were smaller, but not significantly different, than those of unimpaired subjects (p= 0.15-0.84) Even with limited use of the BiomHED, the kinematic workspace of the index finger increased by 63%-1014% in stroke survivors. The device improved the kinematics of the tip-pinch task in stroke survivors and resulted in a significant reduction in the fingertip-thumb tip distance (mm). This device is expected to enable effective "task-oriented" training of the hand post-stroke. C1 [Lee, Sang Wook; Landers, Katlin A.] Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. [Lee, Sang Wook] Natl Rehabil Hosp, Ctr Appl Biomech & Rehabil Res, Washington, DC 20010 USA. [Park, Hyung-Soon] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Lee, SW (reprint author), Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. EM leeb@cua.edu; katlin.landers@gmail.com; hyungspark@kaist.ac.kr RI Park, Hyung-Soon/B-3334-2010 OI Park, Hyung-Soon/0000-0003-4274-7420 FU National Institute of Health [1R03HD74870-01A1]; NIH intramural research program FX The work of S. W. Lee was supported by the National Institute of Health under Grant 1R03HD74870-01A1. The work of H.-S. Park was supported by the NIH intramural research program. H.-S. Park is corresponding author NR 70 TC 12 Z9 13 U1 3 U2 22 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1534-4320 EI 1558-0210 J9 IEEE T NEUR SYS REH JI IEEE Trans. Neural Syst. Rehabil. Eng. PD JUL PY 2014 VL 22 IS 4 BP 886 EP 898 DI 10.1109/TNSRE.2014.2298362 PG 13 WC Engineering, Biomedical; Rehabilitation SC Engineering; Rehabilitation GA AP4WK UT WOS:000342080000019 PM 24760924 ER PT J AU Cardone, G Moyer, AL Cheng, NQ Thompson, CD Dvoretzky, I Lowy, DR Schiller, JT Steven, AC Buck, CB Trus, BL AF Cardone, Giovanni Moyer, Adam L. Cheng, Naiqian Thompson, Cynthia D. Dvoretzky, Israel Lowy, Douglas R. Schiller, John T. Steven, Alasdair C. Buck, Christopher B. Trus, Benes L. TI Maturation of the Human Papillomavirus 16 Capsid SO MBIO LA English DT Article ID VIRUS-LIKE PARTICLES; MOLECULAR-DYNAMICS; CRYOELECTRON MICROSCOPY; BOVINE PAPILLOMAVIRUS; L1 PROTEIN; LIFE-CYCLE; L2; NEUTRALIZATION; STABILIZATION; MECHANISMS AB Papillomaviruses are a family of nonenveloped DNA viruses that infect the skin or mucosa of their vertebrate hosts. The viral life cycle is closely tied to the differentiation of infected keratinocytes. Papillomavirus virions are released into the environment through a process known as desquamation, in which keratinocytes lose structural integrity prior to being shed from the surface of the skin. During this process, virions are exposed to an increasingly oxidative environment, leading to their stabilization through the formation of disulfide cross-links between neighboring molecules of the major capsid protein, L1. We used time-lapse cryo-electron microscopy and image analysis to study the maturation of HPV16 capsids assembled in mammalian cells and exposed to an oxidizing environment after cell lysis. Initially, the virion is a loosely connected procapsid that, under in vitro conditions, condenses over several hours into the more familiar 60-nm-diameter papillomavirus capsid. In this process, the procapsid shrinks by similar to 5% in diameter, its pentameric capsomers change in structure (most markedly in the axial region), and the interaction surfaces between adjacent capsomers are consolidated. A C175S mutant that cannot achieve normal inter-L1 disulfide cross-links shows maturation-related shrinkage but does not achieve the fully condensed 60-nm form. Pseudoatomic modeling based on a 9-angstrom resolution reconstruction of fully mature capsids revealed C-terminal disulfide-stabilized "suspended bridges" that form intercapsomeric cross-links. The data suggest a model in which procapsids exist in a range of dynamic intermediates that can be locked into increasingly mature configurations by disulfide cross-linking, possibly through a Brownian ratchet mechanism. IMPORTANCE Human papillomaviruses (HPVs) cause nearly all cases of cervical cancer, a major fraction of cancers of the penis, vagina/vulva, anus, and tonsils, and genital and nongenital warts. HPV types associated with a high risk of cancer, such as HPV16, are generally transmitted via sexual contact. The nonenveloped virion of HPVs shows a high degree of stability, allowing the virus to persist in an infectious form in environmental fomites. In this study, we used cryo-electron microscopy to elucidate the structure of the HPV16 capsid at different stages of maturation. The fully mature capsid adopts a rigid, highly regular structure stabilized by intermolecular disulfide bonds. The availability of a pseudoatomic model of the fully mature HPV16 virion should help guide understanding of antibody responses elicited by HPV capsid-based vaccines. C1 [Cardone, Giovanni; Cheng, Naiqian; Steven, Alasdair C.] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Moyer, Adam L.; Thompson, Cynthia D.; Lowy, Douglas R.; Schiller, John T.; Buck, Christopher B.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Dvoretzky, Israel] Yale Univ, New Haven, CT USA. [Trus, Benes L.] NIH, Imaging Sci Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Trus, BL (reprint author), NIH, Imaging Sci Lab, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM trusb@mail.nih.gov OI Buck, Christopher/0000-0003-3165-8094 FU NIH; Center for Information Technology (CIT); National Cancer Institute's Center for Cancer Research; National Institute of Arthritis, Musculoskeletal and Skin Diseases; NIGMS [P41-GM103311] FX This research was supported in part by the Intramural Research Program of the NIH, the Center for Information Technology (CIT) the National Cancer Institute's Center for Cancer Research, and the National Institute of Arthritis, Musculoskeletal and Skin Diseases. Part of the molecular graphics and analyses were performed with the UCSF Chimera package. Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California San Francisco (supported by NIGMS P41-GM103311). NR 43 TC 11 Z9 12 U1 2 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2014 VL 5 IS 4 AR e01104-14 DI 10.1128/mBio.01104-14 PG 11 WC Microbiology SC Microbiology GA AO8FE UT WOS:000341588100011 PM 25096873 ER PT J AU de Wit, E Rasmussen, AL Feldmann, F Bushmaker, T Martellaro, C Haddock, E Okumura, A Proll, SC Chang, J Gardner, D Katze, MG Munster, VJ Feldmann, H AF de Wit, Emmie Rasmussen, Angela L. Feldmann, Friederike Bushmaker, Trenton Martellaro, Cynthia Haddock, Elaine Okumura, Atsushi Proll, Sean C. Chang, Jean Gardner, Don Katze, Michael G. Munster, Vincent J. Feldmann, Heinz TI Influenza Virus A/Anhui/1/2013 (H7N9) Replicates Efficiently in the Upper and Lower Respiratory Tracts of Cynomolgus Macaques SO MBIO LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; A VIRUS; H1N1 INFLUENZA; AIRBORNE TRANSMISSION; ENDOTHELIAL-CELLS; HUMAN INFECTIONS; FERRETS; MICE; SIMVASTATIN; MODEL AB In March 2013, three fatal human cases of infection with influenza A virus (H7N9) were reported in China. Since then, human cases have been accumulating. Given the public health importance of this virus, we performed a pathogenicity study of the H7N9 virus in the cynomolgus macaque model, focusing on clinical aspects of disease, radiographic, histological, and gene expression profile changes in the upper and lower respiratory tracts, and changes in systemic cytokine and chemokine profiles during infection. Cynomolgus macaques developed transient, mild to severe disease with radiographic evidence of pulmonary infiltration. Virus replicated in the upper as well as lower respiratory tract, with sustained replication in the upper respiratory tract until the end of the experiment at 6 days after inoculation. Virus shedding occurred mainly via the throat. Histopathological changes in the lungs were similar to those observed in humans, albeit less severe, with diffuse alveolar damage, infiltration of polymorphonuclear cells, formation of hyaline membranes, pneumocyte hyperplasia, and fibroproliferative changes. Analysis of gene expression profiles in lung lesions identified pathways involved in tissue damage during H7N9 infection as well as leads for development of therapeutics targeting host responses rather than virus replication. Overall, H7N9 infection was not as severe in cynomolgus macaques as in humans, supporting the possible role of underlying medical complications in disease severity as discussed for human H7N9 infection (H. N. Gao et al., N. Engl. J. Med. 368:2277-2285, 2013, doi:10.1056/NEJMoa1305584). IMPORTANCE Influenza A virus H7N9 emerged early in 2013, and human cases have continued to emerge since then. Although H7N9 virus-induced disease in humans is often very severe and even lethal, the majority of reported H7N9 cases occurred in older people and people with underlying medical conditions. To better understand the pathogenicity of this virus, healthy cynomolgus macaques were inoculated with influenza A virus H7N9. Cynomolgus macaques were used as a model because the receptor distribution for H7N9 virus in macaques was recently shown to be more similar to that in humans than that of other frequently used animal models. From comparison with previous studies, we conclude that the emerging H7N9 influenza virus was more pathogenic in cynomolgus macaques than seasonal influenza A viruses and most isolates of the pandemic H1N1 virus but less pathogenic than the 1918 Spanish influenza virus or highly pathogenic avian influenza (HPAI) H5N1 virus. C1 [de Wit, Emmie; Bushmaker, Trenton; Martellaro, Cynthia; Haddock, Elaine; Munster, Vincent J.; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. [Rasmussen, Angela L.; Okumura, Atsushi; Proll, Sean C.; Chang, Jean; Katze, Michael G.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Feldmann, Friederike; Gardner, Don] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH, Hamilton, MT USA. [Katze, Michael G.] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. EM vincent.munster@nih.gov; feldmannh@niaid.nih.gov RI Okumura, Atsushi/E-8012-2015 OI Okumura, Atsushi/0000-0002-7779-3059 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; NIH/NIAID [HHSN272200800060C, P51 OD010425 51, 8R24 OD011157] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; A. L. R., A.O., S. C. P., J.C., and M. G. K. were funded through NIH/NIAID contract number HHSN272200800060C, grant P51 OD010425 51, to the Washington Primate National Research Center, Division of Nonhuman Primate Systems Biology, and grant 8R24 OD011157, Development of a Primate Genomics Resource. NR 60 TC 4 Z9 4 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 JUL-AUG PY 2014 VL 5 IS 4 AR e01331-14 DI 10.1128/mBio.0133114 PG 12 WC Microbiology SC Microbiology GA AO8FE UT WOS:000341588100021 ER PT J AU Hayes, BM Dulebohn, DP Sarkar, A Tilly, K Bestor, A Ambroggio, X Rosa, PA AF Hayes, Beth M. Dulebohn, Daniel P. Sarkar, Amit Tilly, Kit Bestor, Aaron Ambroggio, Xavier Rosa, Patricia A. TI Regulatory Protein BBD18 of the Lyme Disease Spirochete: Essential Role during Tick Acquisition? (vol 5, e01017, 2014) SO MBIO LA English DT Correction C1 [Hayes, Beth M.; Dulebohn, Daniel P.; Sarkar, Amit; Tilly, Kit; Bestor, Aaron; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Ambroggio, Xavier] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Rosa, PA (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM prosa@niaid.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2014 VL 5 IS 4 AR e01608-14 DI 10.1128/mBio.01608-14 PG 1 WC Microbiology SC Microbiology GA AO8FE UT WOS:000341588100032 ER PT J AU Yan, ZP Bryant, KF Gregory, SM Angelova, M Dreyfus, DH Zhao, XZ Coen, DM Burke, TR Knipe, DM AF Yan, Zhipeng Bryant, Kevin F. Gregory, Sean M. Angelova, Magdalena Dreyfus, David H. Zhao, Xue Zhi Coen, Donald M. Burke, Terrence R., Jr. Knipe, David M. TI HIV Integrase Inhibitors Block Replication of Alpha-, Beta-, and Gammaherpesviruses SO MBIO LA English DT Article ID HERPES-SIMPLEX-VIRUS; DNA-BINDING-PROTEIN; VIRAL-DNA; NUCLEASE DOMAIN; IN-VITRO; INFECTION; TYPE-1; MUTANT; GENE; RECOMBINATION AB The catalytic site of the HIV integrase is contained within an RNase H-like fold, and numerous drugs have been developed that bind to this site and inhibit its activity. Herpes simplex virus (HSV) encodes two proteins with potential RNase H-like folds, the infected cell protein 8 (ICP8) DNA-binding protein, which is necessary for viral DNA replication and exhibits recombinase activity in vitro, and the viral terminase, which is essential for viral DNA cleavage and packaging. Therefore, we hypothesized that HIV integrase inhibitors might also inhibit HSV replication by targeting ICP8 and/or the terminase. To test this, we evaluated the effect of 118-D-24, a potent HIV integrase inhibitor, on HSV replication. We found that 118-D-24 inhibited HSV-1 replication in cell culture at submillimolar concentrations. To identify more potent inhibitors of HSV replication, we screened a panel of integrase inhibitors, and one compound with greater anti-HSV-1 activity, XZ45, was chosen for further analysis. XZ45 significantly inhibited HSV-1 and HSV-2 replication in different cell types, with 50% inhibitory concentrations that were approximately 1 mu M, but exhibited low cytotoxicity, with a 50% cytotoxic concentration greater than 500 mu M. XZ45 blocked HSV viral DNA replication and late gene expression. XZ45 also inhibited viral recombination in infected cells and ICP8 recombinase activity in vitro. Furthermore, XZ45 inhibited human cytomegalovirus replication and induction of Kaposi's sarcoma herpesvirus from latent infection. Our results argue that inhibitors of enzymes with RNase H-like folds may represent a general antiviral strategy, which is useful not only against HIV but also against herpesviruses. IMPORTANCE The herpesviruses cause considerable morbidity and mortality. Nucleoside analogs have served as effective antiviral agents against the herpesviruses, but resistance can arise through viral mutation. Second-line anti-herpes drugs have limitations in terms of pharmacokinetic properties and/or toxicity, so there is a great need for additional drugs for treatment of herpesviral infections. This study showed that the HIV integrase inhibitors also block herpesviral infection, raising the important potential of a new class of anti-herpes drugs and the prospect of drugs that combat both HIV and the herpesviruses. C1 [Yan, Zhipeng; Bryant, Kevin F.; Gregory, Sean M.; Angelova, Magdalena; Knipe, David M.] Harvard Univ, Dept Microbiol & Immunobiol, Sch Med, Boston, MA 02138 USA. [Dreyfus, David H.] Yale Univ, Sch Med, New Haven, CT USA. [Zhao, Xue Zhi; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Frederick Natl Lab Canc Res, Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Coen, Donald M.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Knipe, DM (reprint author), Harvard Univ, Dept Microbiol & Immunobiol, Sch Med, Boston, MA 02138 USA. EM david_knipe@hms.harvard.edu RI Zhao, Xue Zhi/N-9594-2014; Burke, Terrence/N-2601-2014; OI Zhao, Xue Zhi/0000-0003-1006-6364; Yan, Zhipeng/0000-0002-8463-1891 FU NIH [AI063106]; Harvard University Center for AIDS [P30 AI060354] FX This research was supported by NIH grant AI063106 and a Feasibility Project Award from the Harvard University Center for AIDS research grant (P30 AI060354) to D.M.K. NR 45 TC 7 Z9 7 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2014 VL 5 IS 4 AR e01318-14 DI 10.1128/mBio.01318-14 PG 8 WC Microbiology SC Microbiology GA AO8FE UT WOS:000341588100068 PM 24987091 ER PT J AU Zhang, C Xiao, B Jiang, YY Zhao, YH Li, ZK Gao, H Ling, Y Wei, J Li, SN Lu, MK Su, XZ Cui, HT Yuan, J AF Zhang, Cui Xiao, Bo Jiang, Yuanyuan Zhao, Yihua Li, Zhenkui Gao, Han Ling, Yuan Wei, Jun Li, Shaoneng Lu, Mingke Su, Xin-Zhuan Cui, Huiting Yuan, Jing TI Efficient Editing of Malaria Parasite Genome Using the CRISPR/Cas9 System SO MBIO LA English DT Article ID ZINC-FINGER NUCLEASES; CAS SYSTEM; PLASMODIUM; TRANSFECTION; SPECIFICITY; MUTAGENESIS; EFFECTORS AB Malaria parasites are unicellular organisms residing inside the red blood cells, and current methods for editing the parasite genes have been inefficient. The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats and Cas9 endonuclease-mediated genome editing) system is a new powerful technique for genome editing and has been widely employed to study gene function in various organisms. However, whether this technique can be applied to modify the genomes of malaria parasites has not been determined. In this paper, we demonstrated that Cas9 is able to introduce site-specific DNA double-strand breaks in the Plasmodium yoelii genome that can be repaired through homologous recombination. By supplying engineered homologous repair templates, we generated targeted deletion, reporter knock-in, and nucleotide replacement in multiple parasite genes, achieving up to 100% efficiency in gene deletion and 22 to 45% efficiencies in knock-in and allelic replacement. Our results establish methodologies for introducing desired modifications in the P. yoelii genome with high efficiency and accuracy, which will greatly improve our ability to study gene function of malaria parasites. IMPORTANCE Malaria, caused by infection of Plasmodium parasites, remains a world-wide public health burden. Although the genomes of many malaria parasites have been sequenced, we still do not know the functions of approximately half of the genes in the genomes. Studying gene function has become the focus of many studies; however, editing genes in malaria parasite genomes is still inefficient. Here we designed several efficient approaches, based on the CRISPR/Cas9 system, to introduce site-specific DNA double-strand breaks in the Plasmodium yoelii genome that can be repaired through homologous recombination. Using this system, we achieved high efficiencies in gene deletion, reporter tagging, and allelic replacement in multiple parasite genes. This technique for editing the malaria parasite genome will greatly facilitate our ability to elucidate gene function. C1 [Zhang, Cui; Xiao, Bo; Jiang, Yuanyuan; Zhao, Yihua; Li, Zhenkui; Gao, Han; Ling, Yuan; Wei, Jun; Li, Shaoneng; Lu, Mingke; Cui, Huiting; Yuan, Jing] Xiamen Univ, State Key Lab Cellular Stress Biol, Innovat Ctr Cell Biol, Sch Life Sci, Xiamen, Fujian, Peoples R China. [Su, Xin-Zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Cui, HT (reprint author), Xiamen Univ, State Key Lab Cellular Stress Biol, Innovat Ctr Cell Biol, Sch Life Sci, Xiamen, Fujian, Peoples R China. EM cuihuiting@xmu.edu.cn; yuanjing@xmu.edu.cn OI Su, Xinzhuan/0000-0003-3246-3248 FU China Thousand Youth Talents Plan; 863 National High Technology Research and Development Program of China [2014AA020530]; 973 National Key Basic Research Program of China [2014CB744501]; Fundamental Research Funds for the Central Universities of China [2013121033]; Special Research Fund for the Doctoral Program of Higher Education of China [20130121120023, 20130121120024]; 111 Project of the Ministration of Education of China [B06016]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by grants from China Thousand Youth Talents Plan, the 863 National High Technology Research and Development Program of China (2014AA020530), the 973 National Key Basic Research Program of China (2014CB744501), the Fundamental Research Funds for the Central Universities of China (2013121033), the Special Research Fund for the Doctoral Program of Higher Education of China (20130121120023 and 20130121120024), and the 111 Project of the Ministration of Education of China (B06016). This work was also partly supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 26 TC 14 Z9 16 U1 6 U2 24 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2014 VL 5 IS 4 AR e01414-14 DI 10.1128/mBio.01414-14 PG 9 WC Microbiology SC Microbiology GA AO8FE UT WOS:000341588100071 PM 24987097 ER PT J AU Sanchez, AM Rountree, W Berrong, M Garcia, A Schuetz, A Cox, J Frahm, N Manak, M Sarzotti-Kelsoe, M D'Souza, MP Denny, T Ferrari, G AF Sanchez, Ana M. Rountree, Wes Berrong, Mark Garcia, Ambrosia Schuetz, Alexandra Cox, Josephine Frahm, Nicole Manak, Mark Sarzotti-Kelsoe, Marcella D'Souza, M. Patricia Denny, Thomas Ferrari, Guido TI The External Quality Assurance Oversight Laboratory (EQAPOL) proficiency program for IFN-gamma enzyme-linked immunospot (IFN-gamma ELISpot) assay SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Review DE ELISpot; Standardization; Proficiency testing ID T-CELL RESPONSES; PEPTIDE VACCINE; PHASE-II; TRIALS; CANCER; HIV; INFECTIONS; GUIDELINES; CARCINOMA; PROTEIN AB The interferon-gamma enzyme-linked immunospot (IFN-gamma ELISpot) assay has been developed and used as an end-point assay in clinical trials for infectious diseases and cancer to detect the magnitude of antigen-specific immune responses. The ability to compare data generated by different laboratories across organizations is pivotal to understand the relative potency of different therapeutic and vaccine strategies. We developed an external proficiency program for the IFN-gamma ELISpot assay that evaluates laboratory performance based on five parameters: timeliness for data reporting; ability to handle cellular samples; detection of background (non-specific) responses; accuracy to consensus of the results; and precision of the measurements. Points are awarded for each criterion, and the sum of the points is used to determine a numeric and adjectival performance rating. Importantly, the evaluation of the accuracy to the consensus mean for the detection of antigen-specific responses using laboratory-specific procedures informs each laboratory and its sponsor on the degree of concordance of its results with those obtained by other laboratories. This study will ultimately provide the scientific community with information on how to organize and implement an external proficiency program to evaluate longitudinally the performance of the participating laboratories and, therefore, fulfill the requirements of the GCLP guidelines for laboratories performing end-point IFN-gamma ELISpot assay for clinical trials. (C) 2014 Elsevier B.V. All rights reserved. C1 [Sanchez, Ana M.; Rountree, Wes; Garcia, Ambrosia; Sarzotti-Kelsoe, Marcella; Denny, Thomas; Ferrari, Guido] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Berrong, Mark; Sarzotti-Kelsoe, Marcella; Ferrari, Guido] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Schuetz, Alexandra] USAMC AFRIMS, Dept Retrovirol, Bangkok, Thailand. [Cox, Josephine] Int AIDS Vaccine Initiat, New York, NY USA. [Frahm, Nicole] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Manak, Mark] Walter Reed Army Inst Res, Dept Diagnost & Monitoring, US Mil HIV Res Program MHRP, HJF, Silver Spring, MD USA. [Sarzotti-Kelsoe, Marcella] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. [Sarzotti-Kelsoe, Marcella; Ferrari, Guido] Duke Univ, Med Ctr, Duke Ctr AIDS Res, Durham, NC 27710 USA. [D'Souza, M. Patricia] NIAID, Vaccine Clin Res Branch, Div Aids, Bethesda, MD 20892 USA. [Denny, Thomas] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Denny, Thomas; Ferrari, Guido] Duke Univ, Med Ctr, Duke Global Hlth Inst, Durham, NC 27710 USA. RP Ferrari, G (reprint author), Duke Univ, Med Ctr, Dept Surg, POB 2926, Durham, NC 27710 USA. EM gflmp@duke.edu RI Ferrari, Guido/A-6088-2015 FU Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272201000045C] FX This project was funded in whole, or in part, by the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272201000045C entitled "External Quality Assurance Program Oversight Laboratory (EQAPOL)". NR 30 TC 6 Z9 7 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JUL PY 2014 VL 409 SI SI BP 31 EP 43 DI 10.1016/j.jim.2014.03.017 PG 13 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA AO7QW UT WOS:000341548700005 PM 24685833 ER PT J AU Richards, AJ Staats, J Enzor, J McKinnon, K Frelinger, J Denny, TN Weinhold, KJ Chan, C AF Richards, Adam J. Staats, Janet Enzor, Jennifer McKinnon, Katherine Frelinger, Jacob Denny, Thomas N. Weinhold, Kent J. Chan, Cliburn TI Setting objective thresholds for rare event detection in flow cytometry SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE ICS; Standardization; Reproducibility; Rare events; Positivity; Automated analysis ID QUALITY-ASSURANCE; IDENTIFICATION; GUIDELINE; ASSAYS AB The accurate identification of rare antigen-specific cytokine positive cells from peripheral blood mononuclear cells (PBMC) after antigenic stimulation in an intracellular staining (ICS) flow cytometry assay is challenging, as cytokine positive events may be fairly diffusely distributed and lack an obvious separation from the negative population. Traditionally, the approach by flow operators has been to manually set a positivity threshold to partition events into cytokine-positive and cytokine-negative. This approach suffers from subjectivity and inconsistency across different flow operators. The use of statistical clustering methods does not remove the need to find an objective threshold between between positive and negative events since consistent identification of rare event subsets is highly challenging for automated algorithms, especially when there is distributional overlap between the positive and negative events ("smear"). We present a new approach, based on the F-beta measure, that is similar to manual thresholding in providing a hard cutoff, but has the advantage of being determined objectively. The performance of this algorithm is compared with results obtained by expert visual gating. Several ICS data sets from the External Quality Assurance Program Oversight Laboratory (EQAPOL) proficiency program were used to make the comparisons. We first show that visually determined thresholds are difficult to reproduce and pose a problem when comparing results across operators or laboratories, as well as problems that occur with the use of commonly employed clustering algorithms. In contrast, a single parameterization for the F-beta method performs consistently across different centers, samples, and instruments because it optimizes the precision/recall tradeoff by using both negative and positive controls. (C) 2014 Elsevier B.V. All rights reserved. C1 [Richards, Adam J.; Chan, Cliburn] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. [Richards, Adam J.; Staats, Janet; Enzor, Jennifer; Weinhold, Kent J.; Chan, Cliburn] Duke Univ, Duke Ctr AIDS Res, Durham, NC USA. [Richards, Adam J.; Staats, Janet; Enzor, Jennifer; Denny, Thomas N.; Weinhold, Kent J.; Chan, Cliburn] Duke Univ, Duke External Qual Assurance Program, Oversight Lab, Durham, NC USA. [Staats, Janet; Enzor, Jennifer; Weinhold, Kent J.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [McKinnon, Katherine] NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Frelinger, Jacob] Duke Univ, Inst Genome Sci & Policy, Durham, NC 27706 USA. [Denny, Thomas N.] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. RP Richards, AJ (reprint author), French Natl Ctr Sci Res CNRS, CNRS Moulis, Stn Ecol Expt, F-09200 Moulis, France. EM adam.richards@ecoex-moulis.cnrs.fr FU NIH [RC1AI086032-01, 5P30-AI064518-05]; EQAPOL [HHSN272201000045C] FX This research was partially supported by NIH grants RC1AI086032-01 and 5P30-AI064518-05 (The Duke Center for AIDS Research), and the EQAPOL contract HHSN272201000045C. NR 27 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JUL PY 2014 VL 409 SI SI BP 54 EP 61 DI 10.1016/j.jim.2014.04.002 PG 8 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA AO7QW UT WOS:000341548700007 PM 24727143 ER PT J AU Lynch, HE Sanchez, AM D'Souza, MP Rountree, W Denny, TN Kalos, M Sempowski, GD AF Lynch, Heather E. Sanchez, Ana M. D'Souza, M. Patricia Rountree, Wes Denny, Thomas N. Kalos, Michael Sempowski, Gregory D. TI Development and implementation of a proficiency testing program for Luminex bead-based cytokine assays SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Review DE Luminex; Cytokines; Proficiency; GCLP; Multiplex AB Luminex bead array assays are widely used for rapid biomarker quantification due to the ability to measure up to 100 unique analytes in a single well of a 96-well plate. There has been, however, no comprehensive analysis of variables impacting assay performance, nor development of a standardized proficiency testing program for laboratories performing these assays. To meet this need, the NIH/NIAID and the Cancer Immunotherapy Consortium of the Cancer Research Institute collaborated to develop and implement a Luminex assay proficiency testing program as part of the NIH/NIAID-sponsored External Quality Assurance Program Oversight Laboratory (EQAPOL) at Duke University. The program currently monitors 25 domestic and international sites with two external proficiency panels per year. Each panel includes a de-identified commercial Luminex assay kit with standards to quantify human IFN gamma, TNF alpha, IL-6, IL-10 and IL-2, and a series of recombinant cytokine-spiked human serum samples. All aspects of panel development, testing and shipping are performed under GCLP by EQAPOL support teams. Following development testing, a comprehensive site proficiency scoring system comprised of timeliness, protocol adherence, accuracy and precision was implemented. The overall mean proficiency score across three rounds of testing has remained stable (EP3: 76%, EP4: 75%, EP5: 77%); however, a more detailed analysis of site reported results indicates a significant improvement of intra- (within) and inter- (between) site variation, suggesting that training and remediation for poor performing sites may be having a positive impact on proficiency. Through continued proficiency testing, identification of variables affecting Luminex assay outcomes will strengthen efforts to bring standardization to the field. (C) 2014 Elsevier B.V. All rights reserved. C1 [Lynch, Heather E.; Sanchez, Ana M.; Rountree, Wes; Denny, Thomas N.; Sempowski, Gregory D.] Duke Univ, Med Ctr, Dept Med, Duke Human Vaccine Inst, Durham, NC 27710 USA. [D'Souza, M. Patricia] NIAID, Div Aids, Bethesda, MD 20892 USA. [Kalos, Michael] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Kalos, Michael] Canc Res Inst, Canc Immunotherapy Consortium, Boston, MA USA. RP Sempowski, GD (reprint author), Duke Univ, Med Ctr, Human Vaccine Inst, 909 S La Salle St GHRB Room 1005, Durham, NC 27710 USA. EM gregory.sempowski@duke.edu FU Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272201000045C] FX This project was funded by the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract No. HHSN272201000045C entitled "External Quality Assurance Program Oversight Laboratory (EQAPOL)." NR 12 TC 10 Z9 10 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JUL PY 2014 VL 409 SI SI BP 62 EP 71 DI 10.1016/j.jim.2014.04.011 PG 10 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA AO7QW UT WOS:000341548700008 PM 24801479 ER PT J AU Sambor, A Garcia, A Berrong, M Pickeral, J Brown, S Rountree, W Sanchez, A Pollara, J Frahm, N Keinonen, S Kijak, GH Roederer, M Levine, G D'Souza, MP Jaimes, M Koup, R Denny, T Cox, J Ferrari, G AF Sambor, Anna Garcia, Ambrosia Berrong, Mark Pickeral, Joy Brown, Sara Rountree, Wes Sanchez, Ana Pollara, Justin Frahm, Nicole Keinonen, Sarah Kijak, Gustavo H. Roederer, Mario Levine, Gail D'Souza, M. Patricia Jaimes, Maria Koup, Richard Denny, Thomas Cox, Josephine Ferrari, Guido TI Establishment and maintenance of a PBMC repository for functional cellular studies in support of clinical vaccine trials SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Review DE Peripheral blood mononuclear cells; Cryopreservation; Repository ID BLOOD MONONUCLEAR-CELLS; POLYCHROMATIC FLOW-CYTOMETRY; ANTIBODY-RESPONSES; ELISPOT ASSAYS; OPTIMIZATION; HIV-1; INFECTION; IMMUNITY; DESIGN; PANEL AB A large repository of cryopreserved peripheral blood mononuclear cells (PBMCs) samples was created to provide laboratories testing the specimens from human immunodeficiency virus-1 (HIV-1) vaccine clinical trials the material for assay development, optimization, and validation. One hundred thirty-one PBMC samples were collected using leukapheresis procedure between 2007 and 2013 by the Comprehensive T cell Vaccine Immune Monitoring Consortium core repository. The donors included 83 human immunodeficiency virus-1 (HIV-1) seronegative and 32 HIV-1 seropositive subjects. The samples were extensively characterized for the ability of T cell subsets to respond to recall viral antigens including cytomegalovirus, Epstein-Barr virus, influenza virus, and HIV-1 using Interferon-gamma (IFN-gamma) enzyme linked immunospot (ELISpot) and IFN-gamma/interleukin 2 (IL-2) intracellular cytokine staining (ICS) assays. A subset of samples was evaluated over time to determine the integrity of the cryopreserved samples in relation to recovery, viability, and functionality. The principal results of our study demonstrate that viable and functional cells were consistently recovered from the cryopreserved samples. Therefore, we determined that this repository of large size cryopreserved cellular samples constitutes a unique resource for laboratories that are involved in optimization and validation of assays to evaluate T, B, and NI( cellular functions in the context of clinical trials. (C) 2014 Elsevier B.V. All rights reserved. C1 [Sambor, Anna; Levine, Gail] Fdn Natl Inst Hlth, Bethesda, MD USA. [Garcia, Ambrosia; Brown, Sara; Rountree, Wes; Sanchez, Ana; Keinonen, Sarah; Denny, Thomas; Ferrari, Guido] Duke Univ, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Garcia, Ambrosia; Berrong, Mark; Pickeral, Joy; Rountree, Wes; Sanchez, Ana; Pollara, Justin; Keinonen, Sarah; Denny, Thomas; Ferrari, Guido] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Frahm, Nicole] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Kijak, Gustavo H.] Walter Reed Army Inst Res, Viral Genet Sect, US Mil HIV Res Program, Henry M Jackson Fdn Adv Mil Med, Silver Spring, MD USA. [Roederer, Mario; Koup, Richard] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [D'Souza, M. Patricia] NIAD, Div Aids, NIH, Rockville, MD USA. [Jaimes, Maria] Becton Dickinson, San Jose, CA USA. [Cox, Josephine] Int AIDS Vaccine Initiat, New York, NY USA. RP Ferrari, G (reprint author), Duke Univ, Med Ctr, Dept Surg, POB 2926, Durham, NC 27710 USA. EM gflmp@duke.edu RI Ferrari, Guido/A-6088-2015 FU Bill & Melinda Gates Foundation [OPP1032325] FX This work was supported by a Collaboration for AIDS Vaccine Discovery (CAVD)/Comprehensive T Cell Vaccine Immune Monitoring Consortium (CTVIMC) grant from the Bill & Melinda Gates Foundation (Grant ID# OPP1032325). NR 31 TC 9 Z9 9 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JUL PY 2014 VL 409 SI SI BP 107 EP 116 DI 10.1016/j.jim.2014.04.005 PG 10 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA AO7QW UT WOS:000341548700013 PM 24787274 ER PT J AU Sarzotti-Kelsoe, M Bailer, RT Turk, E Lin, CL Bilska, M Greene, KM Gao, HM Todd, CA Ozaki, DA Seaman, MS Mascola, JR Montefiori, DC AF Sarzotti-Kelsoe, Marcella Bailer, Robert T. Turk, Ellen Lin, Chen-li Bilska, Miroslawa Greene, Kelli M. Gao, Hongmei Todd, Christopher A. Ozaki, Daniel A. Seaman, Michael S. Mascola, John R. Montefiori, David C. TI Optimization and validation of the TZM-bl assay for standardized assessments of neutralizing antibodies against HIV-1 SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Review DE Neutralizing antibody; Assay validation; HIV; TZM-bl cells; GCLP ID HUMAN-IMMUNODEFICIENCY-VIRUS; MONOCLONAL-ANTIBODIES; TYPE-1; INFECTION; CELLS; EFFICACY; PANEL; CCR5 AB The TZM-bl assay measures antibody-mediated neutralization of HIV-1 as a function of reductions in HIV-1 Tat-regulated firefly luciferase (Luc) reporter gene expression after a single round of infection with Env-pseudotyped viruses. This assay has become the main endpoint neutralization assay used for the assessment of pre-clinical and clinical trial samples by a growing number of laboratories worldwide. Here we present the results of the formal optimization and validation of the TZM-bl assay, performed in compliance with Good Clinical Laboratory Practice (GCLP) guidelines. The assay was evaluated for specificity, accuracy, precision, limits of detection and quantitation, linearity, range and robustness. The validated manual TZM-bl assay was also adapted, optimized and qualified to an automated 384-well format. (C) 2013 Elsevier B.V. All rights reserved. C1 [Sarzotti-Kelsoe, Marcella] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27705 USA. [Sarzotti-Kelsoe, Marcella; Bilska, Miroslawa; Greene, Kelli M.; Gao, Hongmei; Todd, Christopher A.; Ozaki, Daniel A.; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27705 USA. [Bailer, Robert T.; Turk, Ellen; Lin, Chen-li; Mascola, John R.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Seaman, Michael S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Sarzotti-Kelsoe, M (reprint author), Duke Univ, Med Ctr, 2812 Erwin Rd,Suite 301,Erwin Terrace 2, Durham, NC 27705 USA. EM marcella.sarzottikelsoe@dm.duke.edu FU Bill & Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery/Comprehensive Antibody Vaccine Immune Monitoring Consortium [38619, 1032144]; HIV Vaccine Trials Network [AI46705, AI068618]; NIH [AI30034, HHSN272200110016C]; Duke University Center for AIDS Research (CFAR), a NIH funded program, Flow Cytometry Core [5P30 AI064518] FX This study was supported in part by the Bill & Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery/Comprehensive Antibody Vaccine Immune Monitoring Consortium (Grant IDs: 38619 & 1032144), the HIV Vaccine Trials Network (AI46705 & AI068618), NIH (Contract IDs: AI30034 & HHSN272200110016C), and Duke University Center for AIDS Research (CFAR), a NIH funded program (Program ID: 5P30 AI064518), Flow Cytometry Core. The authors thank Monogram Bioscience, Inc. for performing the U87.CD4.CCR5 assays. NR 27 TC 42 Z9 42 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JUL PY 2014 VL 409 SI SI BP 131 EP 146 DI 10.1016/j.jim.2013.11.022 PG 16 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA AO7QW UT WOS:000341548700015 PM 24291345 ER PT J AU Rosen, CJ Taylor, CL AF Rosen, Clifford J. Taylor, Christine L. TI Vitamin D supplementation and fall risk SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Editorial Material ID METAANALYSIS; POPULATION C1 [Rosen, Clifford J.] Maine Med Res Inst, Scarborough, ME USA. [Taylor, Christine L.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Taylor, CL (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM TaylorCL3@od.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD JUL PY 2014 VL 2 IS 7 BP 532 EP 534 DI 10.1016/S2213-8587(14)70084-1 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP1AW UT WOS:000341799800005 PM 24768504 ER PT J AU Li, GW Zhang, P Gregg, EW Engelgau, MM Bennett, PH AF Li, Guangwei Zhang, Ping Gregg, Edward W. Engelgau, Michael M. Bennett, Peter H. TI Cardiovascular outcomes in the Da Qing Diabetes Prevention Study Reply SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Letter ID IMPAIRED GLUCOSE-TOLERANCE; FOLLOW-UP; PEOPLE C1 [Li, Guangwei] China Japan Friendship Hosp, Dept Endocrinol, Beijing 100029, Peoples R China. [Li, Guangwei] Natl Ctr Cardiol, Ctr Endocrinol & Cardiovasc Dis, Beijing, Peoples R China. [Li, Guangwei] Fuwai Hosp, Beijing, Peoples R China. [Zhang, Ping; Gregg, Edward W.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA 30333 USA. [Engelgau, Michael M.] Ctr Dis Control & Prevent, Ctr Global Hlth, Atlanta, GA 30333 USA. [Bennett, Peter H.] NIDDK, Clin Res Branch, Phoenix, AZ USA. RP Li, GW (reprint author), China Japan Friendship Hosp, Dept Endocrinol, Beijing 100029, Peoples R China. EM guangwei_li45@126.com FU Intramural CDC HHS [CC999999] NR 5 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD JUL PY 2014 VL 2 IS 7 BP 540 EP 540 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP1AW UT WOS:000341799800011 PM 24999258 ER PT J AU Morrisette-Thomas, V Cohen, AA Fulop, T Riesco, E Legault, V Li, Q Milot, E Dusseault-Belanger, F Ferrucci, L AF Morrisette-Thomas, Vincent Cohen, Alan A. Fueloep, Tamas Riesco, Eleonor Legault, Veronique Li, Qing Milot, Emmanuel Dusseault-Belanger, Francis Ferrucci, Luigi TI Inflamm-aging does not simply reflect increases in pro-inflammatory markers SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE Inflammation; Biomarker; Multivariate; Aging; Chronic disease ID PRINCIPAL COMPONENT ANALYSIS; CORONARY-ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; ALZHEIMERS-DISEASE; BODY-COMPOSITION; OLDER-ADULTS; CANCER-RISK; TNF-ALPHA; HEALTH; INTERLEUKIN-6 AB Many biodemographic studies use biomarkers of inflammation to understand or predict chronic disease and aging. Inflamm-aging, i.e. chronic low-grade inflammation during aging, is commonly characterized by pro-inflammatory biomarkers. However, most studies use just one marker at a time, sometimes leading to conflicting results due to complex interactions among the markers. A multidimensional approach allows a more robust interpretation of the various relationships between the markers. We applied principal component analysis (PCA) to 19 inflammatory biomarkers from the InCHIANTI study. We identified a clear, stable structure among the markers, with the first axis explaining inflammatory activation (both pro- and anti-inflammatory markers loaded strongly and positively) and the second axis innate immune response. The first but not the second axis was strongly correlated with age (r = 0.56, p < 0.0001, r = 0.08 p = 0.053), and both were strongly predictive of mortality (hazard ratios per PCA unit (95% CI): 1.33 (1.16-1.53) and 0.87 (0.76-0.98) respectively) and multiple chronic diseases, but in opposite directions. Both axes were more predictive than any individual markers for baseline chronic diseases and mortality. These results show that PCA can uncover a novel biological structure in the relationships among inflammatory markers, and that key axes of this structure play important roles in chronic disease. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Morrisette-Thomas, Vincent; Cohen, Alan A.; Legault, Veronique; Li, Qing; Milot, Emmanuel; Dusseault-Belanger, Francis] Univ Sherbrooke, Grp Rech PRIMUS, Dept Family Med, CHUS Fleurimont, Sherbrooke, PQ J1H 5N4, Canada. [Fueloep, Tamas] Univ Sherbrooke, Res Ctr Aging, Dept Med, CSSS IUGS, Sherbrooke, PQ J1H 4C4, Canada. [Riesco, Eleonor] Univ Sherbrooke, Res Ctr Aging, CSSS IUGS, Sherbrooke, PQ J1K 2R1, Canada. [Riesco, Eleonor] Univ Sherbrooke, Fac Phys Educ & Sport, Dept Kinanthropol, Sherbrooke, PQ J1K 2R1, Canada. [Ferrucci, Luigi] NIA, Translat Gerontol Branch, Longitudinal Studies Sect, NIH,MedStar Harbor Hosp, Baltimore, MD 21225 USA. RP Cohen, AA (reprint author), Univ Sherbrooke, Grp Rech PRIMUS, Dept Family Med, CHUS Fleurimont, 3001 12eAve North, Sherbrooke, PQ J1H 5N4, Canada. EM Alan.Cohen@USherbrooke.ca FU FRQ-S; CIHR [s 110789, 120305, 119485]; NSERC [402079-2011] FX Alan A. Cohen is a member of the FRQ-S-supported Centre de recherche sur he vieillissement and Centre de recherche clinique du CHUS and is a funded Research Scholar of the FRQ-S. This research was supported by CIHR grant #s 110789, 120305, 119485 and by NSERC Discovery Grant # 402079-2011. NR 35 TC 24 Z9 24 U1 3 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD JUL PY 2014 VL 139 BP 49 EP 57 DI 10.1016/j.mad.2014.06.005 PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA AP0IB UT WOS:000341743600006 PM 25011077 ER PT J AU Little, MP AF Little, Mark P. TI Oxford Textbook of Infectious Disease Control: A Geographical Analysis from Medieval Quarantine to Global Eradication SO JOURNAL OF HISTORICAL GEOGRAPHY LA English DT Book Review C1 [Little, Mark P.] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 1 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0305-7488 J9 J HIST GEOGR JI J. Hist. Geogr. PD JUL PY 2014 VL 45 BP 130 EP 131 DI 10.1016/j.jhg.2014.05.003 PG 2 WC Geography; History Of Social Sciences SC Geography; Social Sciences - Other Topics GA AO0FW UT WOS:000340985500024 ER PT J AU Petralia, RS Mattson, MP Yao, PJ AF Petralia, Ronald S. Mattson, Mark P. Yao, Pamela J. TI Aging and longevity in the simplest animals and the quest for immortality SO AGEING RESEARCH REVIEWS LA English DT Review DE Metazoa; Bilateria; Cnidaria; Planaria; Hydra; Neoblast ID CHOANOFLAGELLATE MONOSIGA-BREVICOLLIS; TRICHOPLAX-ADHAERENS PLACOZOA; MITOCHONDRIAL-DNA MUTATIONS; PROTEIN-FOLDING DISEASES; GERM-CELL SPECIFICATION; FRESH-WATER PLANARIANS; ORGANISMAL LIFE-SPAN; SOMATIC STEM-CELLS; ASEXUAL REPRODUCTION; OXIDATIVE STRESS AB Here we review the examples of great longevity and potential immortality in the earliest animal types and contrast and compare these to humans and other higher animals. We start by discussing aging in single-celled organisms such as yeast and ciliates, and the idea of the immortal cell clone. Then we describe how these cell clones could become organized into colonies of different cell types that lead to multicellular animal life. We survey aging and longevity in all of the basal metazoan groups including ctenophores (comb jellies), sponges, placozoans, cnidarians (hydras, jellyfish, corals and sea anemones) and myxozoans. Then we move to the simplest bilaterian animals (with a head, three body cell layers, and bilateral symmetry), the two phyla of flatworms. A key determinant of longevity and immortality in most of these simple animals is the large numbers of pluripotent stem cells that underlie the remarkable abilities of these animals to regenerate and rejuvenate themselves. Finally, we discuss briefly the evolution of the higher bilaterians and how longevity was reduced and immortality lost due to attainment of greater body complexity and cell cycle strategies that protect these complex organisms from developing tumors. We also briefly consider how the evolution of multiple aging-related mechanisms/pathways hinders our ability to understand and modify the aging process in higher organisms. Published by Elsevier B.V. C1 [Petralia, Ronald S.] NIDCD, Adv Imaging Core, NIH, Bethesda, MD 20892 USA. [Mattson, Mark P.; Yao, Pamela J.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Petralia, RS (reprint author), 35A Convent Dr,Room 1E614, Bethesda, MD 20892 USA. EM petralia@nidcd.nih.gov FU Intramural Research Program of NIDCD/NIH; Intramural Research Program of NIA/NIH FX Supported by the Intramural Research Programs of NIDCD/NIH and NIA/NIH. NR 193 TC 10 Z9 10 U1 20 U2 140 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 EI 1872-9649 J9 AGEING RES REV JI Ageing Res. Rev. PD JUL PY 2014 VL 16 BP 66 EP 82 DI 10.1016/j.arr.2014.05.003 PG 17 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA AO7NE UT WOS:000341539100005 PM 24910306 ER PT J AU Keadle, SK Lyden, K Staudenmayer, J Hickey, A Viskochil, R Braun, B Freedson, PS AF Keadle, Sarah Kozey Lyden, Kate Staudenmayer, John Hickey, Amanda Viskochil, Richard Braun, Barry Freedson, Patty S. TI The independent and combined effects of exercise training and reducing sedentary behavior on cardiometabolic risk factors SO APPLIED PHYSIOLOGY NUTRITION AND METABOLISM-PHYSIOLOGIE APPLIQUEE NUTRITION ET METABOLISME LA English DT Article DE sitting; training; cardiometabolic risk factors; insulin resistance ID LIPOPROTEIN-LIPASE ACTIVITY; PHYSICAL-ACTIVITY; INSULIN SENSITIVITY; ENERGY-EXPENDITURE; US ADULTS; CARDIOVASCULAR-DISEASE; PLASMA-LIPOPROTEINS; METABOLIC SYNDROME; GLUCOSE-TOLERANCE; UNITED-STATES AB This pilot study examined if the combination of exercise training and reducing sedentary time (ST) results in greater changes to health markers than either intervention alone. Fifty-seven overweight/obese participants (19 males/39 females) (mean +/- SD; age, 43.6 +/- 9.9 years; body mass index (BMI), 35.1 +/- 4.6 kg m(-2)) completed the 12-week study and were randomly assigned to (i) EX: exercise 5 days.week(-1) for 40 min.session(-1) at moderate intensity; (ii) rST: reduce ST and increase nonexercise physical activity; (iii) EX-rST: combination of EX and rST; and (iv) CON: maintain behavior. Fasting lipids, blood pressure (BP), peak oxygen uptake, BMI, and 2-h oral glucose tolerance tests were completed pre- and post-intervention. EX and EX-rST increased peak oxygen uptake by similar to 10% and decreased systolic BP (both p < 0.001). BMI decreased by -3.3% (95% confidence interval: -4.6% to -1.9%) for EX-rST and -2.2% (-3.5% to 0.0%) for EX. EX-rST significantly increased composite insulin-sensitivity index by 17.8% (2.8% to 32.8%) and decreased insulin area under the curve by 19.4% (-31.4% to -7.3%). No other groups improved in insulin action variables. rST group decreased ST by 7% (similar to 50 min.day(-1)); however, BP was the only health-related outcome that improved. EX and EX-rST improved peak oxygen uptake and BMI, providing further evidence that moderate-intensity exercise is beneficial. The within-group analysis provides preliminary evidence that exercising and reducing ST may result in improvements in metabolic biomarkers that are not seen with exercise alone, though between-group differences did not reach statistical significance. Future studies, with larger samples, should examine health-related outcomes resulting from greater reductions in ST over longer intervention periods. C1 [Keadle, Sarah Kozey; Lyden, Kate; Hickey, Amanda; Viskochil, Richard; Braun, Barry; Freedson, Patty S.] Univ Massachusetts, Dept Kinesiol, Amherst, MA 01003 USA. [Staudenmayer, John] Univ Massachusetts, Dept Math, Amherst, MA 01003 USA. [Staudenmayer, John] Univ Massachusetts, Dept Stat, Amherst, MA 01003 USA. RP Keadle, SK (reprint author), NCI, 9609 Med Ctr Dr 6E-318, Bethesda, MD 20892 USA. EM Sarah.keadle@nih.gov OI Keadle, Sarah/0000-0002-9569-9306 FU National Institutes of Health [NIH RC1HL099557]; National Cancer Institute through the Cancer Prevention Fellowship Program FX The authors thank the study participants and the dedicated graduate and undergraduate research assistants and trainers. We also thank Carolyn Kuzontkoski and Anna Kenseth for their assistance with data collection. This study was funded by a National Institutes of Health grant (NIH RC1HL099557). Sarah Kozey Keadle is supported by the National Cancer Institute through the Cancer Prevention Fellowship Program. NR 48 TC 12 Z9 12 U1 3 U2 15 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 65 AURIGA DR, SUITE 203, OTTAWA, ON K2E 7W6, CANADA SN 1715-5312 EI 1715-5320 J9 APPL PHYSIOL NUTR ME JI Appl. Physiol. Nutr. Metab. PD JUL PY 2014 VL 39 IS 7 BP 770 EP 780 DI 10.1139/apnm-2013-0379 PG 11 WC Nutrition & Dietetics; Physiology; Sport Sciences SC Nutrition & Dietetics; Physiology; Sport Sciences GA AO7GE UT WOS:000341519700004 ER PT J AU Madka, V Mohammed, A Li, Q Zhang, YT Patlolla, JMR Biddick, L Lightfoot, S Wu, XR Steele, V Kopelovich, L Rao, CV AF Madka, Venkateshwar Mohammed, Altaf Li, Qian Zhang, Yuting Patlolla, Jagan M. R. Biddick, Laura Lightfoot, Stan Wu, Xue-Ru Steele, Vernon Kopelovich, Levy Rao, Chinthalapally V. TI Chemoprevention of Urothelial Cell Carcinoma Growth and Invasion by the Dual COX-LOX Inhibitor Licofelone in UPII-SV40T Transgenic Mice SO CANCER PREVENTION RESEARCH LA English DT Article ID BLADDER-CANCER; 5-LIPOXYGENASE PATHWAY; ARACHIDONIC-ACID; EXPRESSION; CELECOXIB; COLON; TUMORIGENESIS; MODEL; VEGF; OVEREXPRESSION AB Epidemiologic and clinical data suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. We determined the chemopreventive efficacy of licofelone, a dual COX-lipoxygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm licofelone for 34 weeks. At 40 weeks of age, all mice were euthanized, and urinary bladders were collected to determine urothelial tumor weights and to evaluate histopathology. Results showed that bladders of the transgenic mice fed control diet weighed 3 to 5-fold more than did those of the wild-type mice due to urothelial tumor growth. However, treatment of transgenic mice with licofelone led to a significant, dose-dependent inhibition of the urothelial tumor growth (by 68.6%-80.2%, P < 0.0001 in males; by 36.9%-55.3%, P < 0.0001 in females) compared with the control group. The licofelone diet led to the development of significantly fewer invasive tumors in these transgenic mice. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 50%; P < 0.01) and female mice (41%-44%; P < 0.003). Urothelial tumors of the licofelone-fed mice showed an increase in apoptosis (p53, p21, Bax, and caspase3) with a decrease in proliferation, inflammation, and angiogenesis markers (proliferating cell nuclear antigen, COX-2, 5-LOX, prostaglandin E synthase 1, FLAP, and VEGF). These results suggest that licofelone can serve as potential chemopreventive for bladder TCC. (C)2014 AACR. C1 [Madka, Venkateshwar; Mohammed, Altaf; Li, Qian; Zhang, Yuting; Patlolla, Jagan M. R.; Biddick, Laura; Lightfoot, Stan; Rao, Chinthalapally V.] Univ Oklahoma Hlth Sci Ctr, PCS Oklahoma Canc Ctr, Ctr Canc Prevent & Drug Dev,Dept Med,Hem Onc Sect, Oklahoma City, OK USA. [Wu, Xue-Ru] NYU, Med Ctr, Dept Urol, New York, NY 10016 USA. [Steele, Vernon; Kopelovich, Levy] NCI, Div Canc Prevent, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), Oklahoma Univ Hlth Sci Ctr, 975 NE 10th St,BRC 1203, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu FU NIH/NCI [NCI-CN53300] FX This study was funded by NIH/NCI (NCI-CN53300). NR 45 TC 10 Z9 10 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUL PY 2014 VL 7 IS 7 BP 708 EP 716 DI 10.1158/1940-6207.CAPR-14-0087 PG 9 WC Oncology SC Oncology GA AO9TM UT WOS:000341700200009 PM 24795386 ER PT J AU Mattison, JA Wang, MY Bernier, M Zhang, J Park, SS Maudsley, S An, SS Santhanam, L Martin, B Faulkner, S Morrell, C Baur, JA Peshkin, L Sosnowska, D Csiszar, A Herbert, RL Tilmont, EM Ungvari, Z Pearson, KJ Lakatta, EG de Cabo, R AF Mattison, Julie A. Wang, Mingyi Bernier, Michel Zhang, Jing Park, Sung-Soo Maudsley, Stuart An, Steven S. Santhanam, Lakshmi Martin, Bronwen Faulkner, Shakeela Morrell, Christopher Baur, Joseph A. Peshkin, Leonid Sosnowska, Danuta Csiszar, Anna Herbert, Richard L. Tilmont, Edward M. Ungvari, Zoltan Pearson, Kevin J. Lakatta, Edward G. de Cabo, Rafael TI Resveratrol Prevents High Fat/Sucrose Diet-Induced Central Arterial Wall Inflammation and Stiffening in Nonhuman Primates SO CELL METABOLISM LA English DT Article ID SMOOTH-MUSCLE-CELLS; PULSE-WAVE VELOCITY; VASCULAR OXIDATIVE STRESS; MACACA-MULATTA; SUGAR DIET; AGE; ATHEROSCLEROSIS; CALCIFICATION; HYPERTENSION; INCREASES AB Central arterial wall stiffening, driven by a chronic inflammatory milieu, accompanies arterial diseases, the leading cause of cardiovascular (CV) morbidity and mortality in Western society. An increase in central arterial wall stiffening, measured as an increase in aortic pulse wave velocity (PWV), is a major risk factor for clinical CV disease events. However, no specific therapies to reduce PWV are presently available. In rhesus monkeys, a 2 year diet high in fat and sucrose (HFS) increases not only body weight and cholesterol, but also induces prominent central arterial wall stiffening and increases PWV and inflammation. The observed loss of endothelial cell integrity, lipid and macrophage infiltration, and calcification of the arterial wall were driven by genomic and proteomic signatures of oxidative stress and inflammation. Resveratrol prevented the HFS-induced arterial wall inflammation and the accompanying increase in PWV. Dietary resveratrol may hold promise as a therapy to ameliorate increases in PWV. C1 [Mattison, Julie A.; Bernier, Michel; Faulkner, Shakeela; Tilmont, Edward M.; de Cabo, Rafael] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wang, Mingyi; Zhang, Jing; Morrell, Christopher; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Park, Sung-Soo; Maudsley, Stuart] NIA, Lab Neurosci, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Martin, Bronwen] NIA, Lab Clin Invest, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [An, Steven S.] Johns Hopkins Bloomberg Sch Publ Hlth, Program Resp Biol & Lung Dis, Baltimore, MD 21205 USA. [Santhanam, Lakshmi] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Morrell, Christopher] Loyola Univ Maryland, Dept Math & Stat, Baltimore, MD 21210 USA. [Baur, Joseph A.] Univ Penn, Perelman Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. [Baur, Joseph A.] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Peshkin, Leonid] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Sosnowska, Danuta; Csiszar, Anna; Ungvari, Zoltan] Univ Oklahoma, Dept Geriatr Med, Reynolds Oklahoma Ctr Aging, BRC 1303, Oklahoma City, OK 73104 USA. [Herbert, Richard L.] NIAID, NIH Anim Ctr, Dickerson, MD 20842 USA. [Pearson, Kevin J.] Univ Kentucky, Dept Pharmacol & Nutr Sci, Lexington, KY 40536 USA. RP de Cabo, R (reprint author), NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Suite 100,251 Bayview Blvd, Baltimore, MD 21224 USA. EM decabora@mail.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Bernier, Michel/0000-0002-5948-368X; , rafael/0000-0003-2830-5693 FU Intramural Research Program of the NIH, National Institute on Aging; Office of Dietary Supplements, NIH; National Heart, Lung, and Blood Institute [HL107361]; NIH/National Center for Complementary and Alternative Medicine (NCCAM) [AT006526] FX We thank the animal care staff and technicians at the National Institute of Health Animal Center (NIHAC), in particular Joe Travis, as well as William Woods III, Elin Lehrmann, Yongqing Zhang, and Kevin G. Becker for microarray analysis. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging, and the Office of Dietary Supplements, NIH. S.S.A. was the recipient of a National Heart, Lung, and Blood Institute grant HL107361. J.A.B. is a New Scholar of the Ellison Medical Foundation. Z.U. was supported by NIH/National Center for Complementary and Alternative Medicine (NCCAM) (AT006526). The resveratrol used in this study was a generous gift from DSM Nutritional Products (resVida). NR 32 TC 46 Z9 46 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD JUL 1 PY 2014 VL 20 IS 1 BP 183 EP 190 DI 10.1016/j.cmet.2014.04.018 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AO5QZ UT WOS:000341401300019 PM 24882067 ER PT J AU Kotch, JB Smith, J Margolis, B Black, MM English, D Thompson, R Lee, LC Taneja, G Bangdiwala, SI AF Kotch, Jonathan B. Smith, Jamie Margolis, Benyamin Black, Maureen M. English, Diana Thompson, Richard Lee, Li-Ching Taneja, Gitanjali Bangdiwala, Shrikant I. TI Does Social Capital Protect Against the Adverse Behavioural Outcomes of Child Neglect? SO CHILD ABUSE REVIEW LA English DT Article DE child neglect; social capital; collective efficacy; caregiver depression ID ADOLESCENT SUBSTANCE USE; MATERNAL DEPRESSION; COLLECTIVE EFFICACY; YOUNG-CHILDREN; MALTREATMENT; RISK; ABUSE; AGGRESSION; FAMILIES; HEALTH AB LONGSCAN was a longitudinal study of the risks and consequences of child abuse and neglect conducted between 1992 and 2012 among five sites across the US. Interviews with mothers of at-risk children began when the children were four years of age, and mothers and children from age six to age 18 years were interviewed every other year. Maltreatment reports were obtained from departments of social services, and subjects' self-reported abuse was obtained at age 12. Generalised estimating equations were used to investigate the impact of informal social control, social cohesion and trust (SCT), and caregiver depression at ages 12, 14 and 16 years on externalising behaviours, smoking and alcohol use among 18-year olds who had been neglected prior to age 12. In models controlling for child age and gender, maltreatment types other than neglect, maternal education and study site, SCT significantly reduced the impact of caregiver depression on externalising behaviour and alcohol use among the neglected children at age 18. This moderating effect was not seen among non-neglected 18-year-old children. Copyright (C) 2014 John Wiley & Sons, Ltd. C1 [Kotch, Jonathan B.] Univ N Carolina, Dept Maternal & Child Hlth, Chapel Hill, NC 27599 USA. [Smith, Jamie] Univ N Carolina, Injury Prevent Res Ctr, Chapel Hill, NC 27599 USA. [Margolis, Benyamin] US Dept HHS, Maternal & Child Hlth Bur, Hlth Resources & Serv Adm, Rockville, MD USA. [Black, Maureen M.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [English, Diana] Univ Washington, Sch Social Work, Seattle, WA 98195 USA. [Thompson, Richard] Juvenile Protect Assoc, Chicago, IL USA. [Lee, Li-Ching] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Taneja, Gitanjali] NICHHD, NIH, Bethesda, MD 20892 USA. [Bangdiwala, Shrikant I.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. RP Kotch, JB (reprint author), Univ N Carolina, Dept Maternal & Child Hlth, CB 7445,Rosenau Hall, Chapel Hill, NC 27599 USA. EM Jonathan_kotch@unc.edu NR 58 TC 4 Z9 4 U1 7 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-9136 EI 1099-0852 J9 CHILD ABUSE REV JI Child Abus. Rev. PD JUL-AUG PY 2014 VL 23 IS 4 SI SI BP 246 EP 261 DI 10.1002/car.2345 PG 16 WC Family Studies; Social Work SC Family Studies; Social Work GA AO7CI UT WOS:000341509200003 ER PT J AU Aravind, L Burroughs, AM Zhang, DP Iyer, LM AF Aravind, L. Burroughs, A. Maxwell Zhang, Dapeng Iyer, Lakshminarayan M. TI Protein and DNA Modifications: Evolutionary Imprints of Bacterial Biochemical Diversification and Geochemistry on the Provenance of Eukaryotic Epigenetics SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID DOMAIN-CONTAINING PROTEINS; COMPARATIVE GENOMICS; HISTONE H3; STRUCTURAL BASIS; DAMAGE RESPONSE; POSTTRANSLATIONAL MODIFICATIONS; NONHISTONE PROTEINS; NATURAL-HISTORY; GIARDIA-LAMBLIA; VIRULENCE GENES AB Epigenetic information, which plays a major role in eukaryotic biology, is transmitted by covalent modifications of nuclear proteins (e. g., histones) and DNA, along with poorly understood processes involving cytoplasmic/secreted proteins and RNAs. The origin of eukaryotes was accompanied by emergence of a highly developed biochemical apparatus for encoding, resetting, and reading covalent epigenetic marks in proteins such as histones and tubulins. The provenance of this apparatus remained unclear until recently. Developments in comparative genomics show that key components of eukaryotic epigenetics emerged as part of the extensive biochemical innovation of secondary metabolism and intergenomic/interorganismal conflict systems in prokaryotes, particularly bacteria. These supplied not only enzymatic components for encoding and removing epigenetic modifications, but also readers of some of these marks. Diversification of these prokaryotic systems and subsequently eukaryotic epigenetics appear to have been considerably influenced by the great oxygenation event in the Earth's history. C1 [Aravind, L.; Burroughs, A. Maxwell; Zhang, Dapeng; Iyer, Lakshminarayan M.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU National Library of Medicine, National Institutes of Health FX Work by the authors is supported by the intramural funds of the National Library of Medicine, National Institutes of Health. NR 163 TC 5 Z9 5 U1 1 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD JUL PY 2014 VL 6 IS 7 AR a016063 DI 10.1101/cshperspect.a016063 PG 22 WC Cell Biology SC Cell Biology GA AO8BB UT WOS:000341576100002 PM 24984775 ER PT J AU Yaniv, Y Ahmet, I Liu, J Lyashkov, AE Guiriba, TR Okamoto, Y Ziman, BD Lakatta, EG AF Yaniv, Yael Ahmet, Ismayil Liu, Jie Lyashkov, Alexey E. Guiriba, Toni-Rose Okamoto, Yosuke Ziman, Bruce D. Lakatta, Edward G. TI Synchronization of sinoatrial node pacemaker cell clocks and its autonomic modulation impart complexity to heart beating intervals SO HEART RHYTHM LA English DT Article DE Autonomic neural impulse; chaotic processes; Fractal-like behavior; Heart rate variability; sinoatrial node pacemaker cell ID POWER-LAW BEHAVIOR; RATE-VARIABILITY; DYNAMICS; ENTRAINMENT; MECHANISM; SIGNALS; MODEL AB BACKGROUND A reduction of complexity of heart beating interval variability that is associated with an increased morbidity and mortality in cardiovascular disease states is thought to derive from the balance of sympathetic and parasympathetic neural impulses to the heart. However, rhythmic clocklike behavior intrinsic to pacemaker cells in the sinoatrial node (SAN) drives their beating, even in the absence of autonomic neural input. OBJECTIVE To test how this rhythmic clocklike behavior intrinsic to pacemaker cells interacts with autonomic impulses to the heart beating interval variability in vivo. METHODS We analyzed beating interval variability in time and frequency domains and by fractal and entropy analyses: (1) in vivo, when the brain input to the SAN is intact; (2) during autonomic denervation in vivo; (3) in isolated SAN tissue (ie, in which the autonomic neural input is completely absent); (4) in single pacemaker cells isolated from the SAN; and (5) after autonomic receptor stimulation of these cells. RESULTS Spontaneous beating intervals of pacemaker cells residing in the isolated SAN tissue exhibit fractal-like behavior and have lower approximate entropy compared with those in the intact heart. Isolation of pacemaker cells from SAN tissue, however, leads to a loss in the beating interval order and fractal-like behavior. beta-Adrenergic receptor stimulation of isolated pacemaker cells increases intrinsic clock synchronization, decreases their action potential period, and increases system complexity. CONCLUSIONS Both the average beating interval in vivo and beating interval complexity are conferred by the combined effects of clock periodicity intrinsic to pacemaker cells and their response to autonomic neural input. C1 [Yaniv, Yael; Ahmet, Ismayil; Liu, Jie; Guiriba, Toni-Rose; Okamoto, Yosuke; Ziman, Bruce D.; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Biomed Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Yaniv, Yael] Technion Israel Inst Technol, Biomed Engn Fac, IL-32000 Haifa, Israel. [Liu, Jie] Univ Sydney, Cardiovasc Physiol Lab, Sch Med Sci, Sydney, NSW 2006, Australia. [Lyashkov, Alexey E.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. RP Yaniv, Y (reprint author), Technion Israel Inst Technol, Biomed Engn Fac, IL-32000 Haifa, Israel. EM yaely@bm.technion.ac.il; lakattae@grc.nia.nih.gov RI Yaniv, Yael/B-3311-2015 OI Yaniv, Yael/0000-0002-5183-6284 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work was supported partially by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 25 TC 13 Z9 13 U1 2 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD JUL PY 2014 VL 11 IS 7 BP 1210 EP 1219 DI 10.1016/j.hrthm.2014.03.049 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO6CK UT WOS:000341435900020 PM 24713624 ER PT J AU Li, WQ Ma, JL Zhang, L Brown, LM Li, JY Shen, L Pan, KF Liu, WD Hu, YR Han, ZX Crystal-Mansour, S Pee, D Blot, WJ Fraumeni, JF You, WC Gail, MH AF Li, Wen-Qing Ma, Jun-Ling Zhang, Lian Brown, Linda M. Li, Ji-You Shen, Lin Pan, Kai-Feng Liu, Wei-Dong Hu, Yuanreng Han, Zhong-Xiang Crystal-Mansour, Susan Pee, David Blot, William J. Fraumeni, Joseph F., Jr. You, Wei-Cheng Gail, Mitchell H. TI Effects of Helicobacter pylori Treatment on Gastric Cancer Incidence and Mortality in Subgroups SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; HIGH-RISK; FACTORIAL TRIAL; LESIONS; ERADICATION; POPULATION; REDUCE; CHINA AB Among 2258 Helicobacter pylori-seropositive subjects randomly assigned to receive one-time H. pylori treatment with amoxicillin-omeprazole or its placebo, we evaluated the 15-year effect of treatment on gastric cancer incidence and mortality in subgroups defined by age, baseline gastric histopathology, and post-treatment infection status. We used conditional logistic and Cox regressions for covariable adjustments in incidence and mortality analyses, respectively. Treatment was associated with a statistically significant decrease in gastric cancer incidence (odds ratio = 0.36; 95% confidence interval [CI] = 0.17 to 0.79) and mortality (hazard ratio = 0.26; 95% CI = 0.09 to 0.79) at ages 55 years and older and a statistically significant decrease in incidence among those with intestinal metaplasia or dysplasia at baseline (odds ratio = 0.56; 95% CI = 0.34 to 0.91). Treatment benefits for incidence and mortality among those with and without post-treatment infection were similar. Thus H. pylori treatment can benefit older members and those with advanced baseline histopathology, and benefits are present even with post-treatment infection, suggesting treatment can benefit an entire population, not just the young or those with mild histopathology. C1 [Li, Wen-Qing; Fraumeni, Joseph F., Jr.; Gail, Mitchell H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Li, Wen-Qing; Ma, Jun-Ling; Zhang, Lian; Li, Ji-You; Shen, Lin; Pan, Kai-Feng; You, Wei-Cheng] Peking Univ, Canc Hosp & Inst, Dept Canc Epidemiol, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100871, Peoples R China. [Brown, Linda M.] RTI Int, Rockville, MD USA. [Liu, Wei-Dong; Han, Zhong-Xiang] Linqu Cty Publ Hlth Bur, Linqu, Shandong, Peoples R China. [Crystal-Mansour, Susan] WESTAT Corp, Rockville, MD 20850 USA. [Pee, David] Informat Management Serv Inc, Rockville, MD USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Blot, William J.] Vanderbilt Univ, Dept Med Epidemiol, Nashville, TN 37235 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 7E138, Rockville, MD 20890 USA. EM weichengyou@yahoo.com; gailm@mail.nih.gov RI Li, Wenqing/N-2293-2014 OI Li, Wenqing/0000-0002-1283-4091 FU National Institutes of Health, National Cancer Institute; National Cancer Institute [NO2-CP-71103, NO2-CP-21169]; National Basic Research Program of China (973 program) [2004CB518702, 2010CB529303] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and, in part, by National Cancer Institute contracts NO2-CP-71103 and NO2-CP-21169. National Cancer Institute contracts also supported work at Westat and at Information Management Services. Additional support was from the National Basic Research Program of China (973 program: 2004CB518702 and 2010CB529303). NR 16 TC 2 Z9 2 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JUL PY 2014 VL 106 IS 7 AR dju0116 DI 10.1093/jnci/dju116 PG 4 WC Oncology SC Oncology GA AO8WX UT WOS:000341637400004 ER PT J AU Reeve, BB Mitchell, SA Dueck, AC Basch, E Cella, D Reilly, CM Minasian, LM Denicoff, AM O'Mara, AM Fisch, MJ Chauhan, C Aaronson, NK Coens, C Bruner, DW AF Reeve, Bryce B. Mitchell, Sandra A. Dueck, Amylou C. Basch, Ethan Cella, David Reilly, Carolyn Miller Minasian, Lori M. Denicoff, Andrea M. O'Mara, Ann M. Fisch, Michael J. Chauhan, Cynthia Aaronson, Neil K. Coens, Corneel Bruner, Deborah Watkins TI Recommended Patient-Reported Core Set of Symptoms to Measure in Adult Cancer Treatment Trials SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID QUALITY-OF-LIFE; CLINICAL-TRIALS; MULTIPLE SYMPTOMS; PALLIATIVE CARE; NECK-CANCER; EUROPEAN-ORGANIZATION; OUTCOME MEASURES; PROSTATE-CANCER; BREAST-CANCER; ONCOLOGY AB Background The National Cancer Institute's Symptom Management and Health-Related Quality of Life Steering Committee held a clinical trials planning meeting (September 2011) to identify a core symptom set to be assessed across oncology trials for the purposes of better understanding treatment efficacy and toxicity and to facilitate cross-study comparisons. We report the results of an evidence-synthesis and consensus-building effort that culminated in recommendations for core symptoms to be measured in adult cancer clinical trials that include a patient-reported outcome (PRO). Methods We used a data-driven, consensus-building process. A panel of experts, including patient representatives, conducted a systematic review of the literature (2001-2011) and analyzed six large datasets. Results were reviewed at a multistakeholder meeting, and a final set was derived emphasizing symptom prevalence across diverse cancer populations, impact on health outcomes and quality of life, and attribution to either disease or anticancer treatment. Results We recommend that a core set of 12 symptoms-specifically fatigue, insomnia, pain, anorexia (appetite loss), dyspnea, cognitive problems, anxiety (includes worry), nausea, depression (includes sadness), sensory neuropathy, constipation, and diarrhea-be considered for inclusion in clinical trials where a PRO is measured. Inclusion of symptoms and other patient-reported endpoints should be well justified, hypothesis driven, and meaningful to patients. Conclusions This core set will promote consistent assessment of common and clinically relevant disease-and treatment-related symptoms across cancer trials. As such, it provides a foundation to support data harmonization and continued efforts to enhance measurement of patient-centered outcomes in cancer clinical trials and observational studies. C1 [Reeve, Bryce B.; Basch, Ethan] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Mitchell, Sandra A.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Minasian, Lori M.; O'Mara, Ann M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Denicoff, Andrea M.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Dueck, Amylou C.] Mayo Clin, Div Hlth Sci Res, Scottsdale, AZ USA. [Cella, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Reilly, Carolyn Miller; Bruner, Deborah Watkins] Emory Univ, Nell Hodgson Woodruff Sch Nursing, Atlanta, GA 30322 USA. [Fisch, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Gen Oncol, Houston, TX 77030 USA. [Chauhan, Cynthia] Mayo Clin Breast SPORE, Rochester, MN USA. [Aaronson, Neil K.] Netherlands Canc Inst, Dept Psychol Res, Amsterdam, Netherlands. [Coens, Corneel] European Org Res Treatment Canc, Qual Life Dept, Brussels, Belgium. RP Reeve, BB (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, 1101-D McGavran Greenberg Bldg,135 Dauer Dr,CB 74, Chapel Hill, NC 27599 USA. EM bbreeve@email.unc.edu OI Reilly, Carolyn/0000-0003-1641-1747 NR 65 TC 49 Z9 49 U1 5 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JUL PY 2014 VL 106 IS 7 AR dju129 DI 10.1093/jnci/dju129 PG 8 WC Oncology SC Oncology GA AO8WX UT WOS:000341637400009 ER PT J AU Woditschka, S Evans, L Duchnowska, R Reed, LT Palmieri, D Qian, YZ Badve, S Sledge, G Gril, B Aladjem, MI Fu, HQ Flores, NM Gokmen-Polar, Y Biernat, W Szutowicz-Zielinska, E Mandat, T Trojanowski, T Och, W Czartoryska-Arlukowicz, B Jassem, J Mitchell, JB Steeg, PS AF Woditschka, Stephan Evans, Lynda Duchnowska, Renata Reed, L. Tiffany Palmieri, Diane Qian, Yongzhen Badve, Sunil Sledge, George, Jr. Gril, Brunilde Aladjem, Mirit I. Fu, Haiqing Flores, Natasha M. Goekmen-Polar, Yesim Biernat, Wojciech Szutowicz-Zielinska, Ewa Mandat, Tomasz Trojanowski, Tomasz Och, Waldemar Czartoryska-Arlukowicz, Bogumila Jassem, Jacek Mitchell, James B. Steeg, Patricia S. TI DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NERVOUS-SYSTEM METASTASES; HOMOLOGOUS RECOMBINATION; IN-VIVO; CHROMOSOME BREAKS; LIGASE ACTIVITY; BRCA1; RAD51; BARD1; REPLICATION; CELLS AB Background Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood. Methods Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis-specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group). Results Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression. Conclusions BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species-mediated genotoxic stress in the metastatic brain. C1 [Woditschka, Stephan; Evans, Lynda; Reed, L. Tiffany; Palmieri, Diane; Gril, Brunilde; Flores, Natasha M.; Steeg, Patricia S.] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Aladjem, Mirit I.; Fu, Haiqing] NCI, DNA Replicat Grp, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Mitchell, James B.] NCI, Tumor Biol Sect, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Duchnowska, Renata] Mil Inst Med, Dept Oncol, Warsaw, Poland. [Qian, Yongzhen] Frederick Natl Lab, Lab Anim Sci Program, Frederick, MD USA. [Badve, Sunil] Indiana Univ Sch Med, Dept Pathol, Indianapolis, IN 46202 USA. [Badve, Sunil] Indiana Univ Sch Med, Dept Lab Med, Indianapolis, IN 46202 USA. [Sledge, George, Jr.; Goekmen-Polar, Yesim] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Biernat, Wojciech] Med Univ Gdansk, Dept Pathol, Gdansk, Poland. [Szutowicz-Zielinska, Ewa; Jassem, Jacek] Med Univ Gdansk, Dept Radiotherapy & Oncol, Gdansk, Poland. [Mandat, Tomasz] Maria Sklodowska Curie Mem Canc Ctr, Dept Neurosurg, Warsaw, Poland. [Mandat, Tomasz] Inst Oncol, Warsaw, Poland. [Trojanowski, Tomasz] Med Univ Lublin, Dept Neurosurg, Lublin, Poland. [Trojanowski, Tomasz] Med Univ Lublin, Childrens Neurosurg Clin, Lublin, Poland. [Och, Waldemar] Interior Affairs Hosp, Dept Neurosurg, Olsztyn, Poland. [Czartoryska-Arlukowicz, Bogumila] Bialystok Oncol Ctr, Dept Clin Oncol, Bialystok, Poland. RP Woditschka, S (reprint author), NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM woditschkas@mail.nih.gov; steegp@mail.nih.gov RI Palmieri, Diane/B-4258-2015; Aladjem, Mirit/G-2169-2010; OI Aladjem, Mirit/0000-0002-1875-3110; Gokmen-Polar, Yesim/0000-0001-9927-4893 FU National Cancer Institute; US Department of Defense Breast Cancer Research Program [W81 XWH-062-0033]; Medical University of Gdansk, Poland [ST-51] FX This work was supported by the intramural research program of the National Cancer Institute and by the US Department of Defense Breast Cancer Research Program grant No. W81 XWH-062-0033 and by intramural grant of the Medical University of Gdansk, Poland grant No. ST-51. NR 55 TC 6 Z9 6 U1 1 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JUL PY 2014 VL 106 IS 7 AR dju145 DI 10.1093/jnci/dju145 PG 13 WC Oncology SC Oncology GA AO8WX UT WOS:000341637400015 ER PT J AU Choi, AD Joly, JM Chen, MY Weigold, WG AF Choi, Andrew D. Joly, Joanna M. Chen, Marcus Y. Weigold, Wm. Guy TI Physiologic evaluation of ischemia using cardiac CT: Current status of CT myocardial perfusion and CT fractional flow reserve SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Article DE Cardiac computed tomography; Computed tomography perfusion; Coronary artery disease; Fractional flow reserve; Ischemia ID CORONARY-ARTERY-DISEASE; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; DUAL-SOURCE CT; DIAGNOSTIC PERFORMANCE; DISCOVER-FLOW; STRESS; MULTICENTER; STENOSIS; ACCURACY; CORE320 AB Cardiac CT, specifically coronary CT angiography (CTA), is an established technology which detects anatomically significant coronary artery disease with a high sensitivity and negative predictive value compared with invasive coronary angiography. However, the limited ability of CTA to determine the physiologic significance of intermediate coronary stenoses remains a shortcoming compared with other noninvasive methods such as single-photon emission CT, stress echocardiography, and stress cardiac magnetic resonance. Two methods have been investigated recently: (1) myocardial CT perfusion and (2) fractional flow reserve (FFR) computed from CT (FFRCT). Improving diagnostic accuracy by combining the anatomic aspects of coronary CTA with a physiologic assessment via CT perfusion or FFRCT may reduce the need for additional testing to evaluate for ischemia, reduce downstream costs and risks associated with an invasive procedure, and lead to improved patient outcomes. Given a rapidly expanding body of research in this field, this comparative review summarizes the present literature while contrasting the benefits, limitations, and future directions in myocardial CT perfusion and FFRCT imaging. Published by Elsevier Inc. on behalf of Society of Cardiovascular Computed Tomography. C1 [Choi, Andrew D.; Joly, Joanna M.; Weigold, Wm. Guy] MedStar Washington Hosp Ctr, MedStar Heart Inst, Div Cardiol, Washington, DC 20010 USA. [Choi, Andrew D.; Joly, Joanna M.] Medstar Georgetown Univ Hosp, Div Cardiol, Washington, DC USA. [Choi, Andrew D.; Chen, Marcus Y.] NHLBI, Cardiovasc & Pulm Branch, Adv Cardiovasc Imaging Lab, NIH, Bethesda, MD 20892 USA. RP Choi, AD (reprint author), MedStar Washington Hosp Ctr, MedStar Heart Inst, Div Cardiol, 110 Irving St NW, Washington, DC 20010 USA. EM Andrew.D.Choi@gunet.georgetown.edu NR 37 TC 6 Z9 6 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD JUL-AUG PY 2014 VL 8 IS 4 BP 272 EP 281 DI 10.1016/j.jcct.2014.06.006 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AO4ZS UT WOS:000341350500003 PM 25151919 ER PT J AU Chow, CC Hall, KD AF Chow, Carson C. Hall, Kevin D. TI Short and long-term energy intake patterns and their implications for human body weight regulation SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Energy balance; Food intake; Energy intake; Body weight regulation; Feedback control; Mathematical model ID FAT-FREE MASS; FOOD-INTAKE; EXPENDITURE; OBESITY; MECHANISMS; MODEL; PREDICTION; BEHAVIOR; BALANCE; ADULTS AB Adults consume millions of kilocalories over the course of a few years, but the typical weight gain amounts to only a few thousand kilocalories of stored energy. Furthermore, food intake is highly variable from day to day and yet body weight is remarkably stable. These facts have been used as evidence to support the hypothesis that human body weight is regulated by active control of food intake operating on both short and long time scales. Here, we demonstrate that active control of human food intake on short time scales is not required for body weight stability and that the current evidence for long term control of food intake is equivocal. To provide more data on this issue, we emphasize the urgent need for developing new methods for accurately measuring energy intake changes over long time scales. We propose that repeated body weight measurements can be used along with mathematical modeling to calculate long-term changes in energy intake and thereby quantify adherence to a diet intervention and provide dynamic feedback to individuals that seek to control their body weight. Published by Elsevier Inc. C1 [Chow, Carson C.; Hall, Kevin D.] NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), NIDDK, 12A South Dr,Room 4007, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes & Digestive & Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes & Digestive & Kidney Diseases. NR 38 TC 5 Z9 5 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD JUL PY 2014 VL 134 SI SI BP 60 EP 65 DI 10.1016/j.physbeh.2014.02.044 PG 6 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA AO6QF UT WOS:000341475900010 PM 24582679 ER PT J AU Little, MP Kwon, D Doi, K Simon, SL Preston, DL Doody, MM Lee, T Miller, JS Kampa, DM Bhatti, P Tucker, JD Linet, MS Sigurdson, AJ AF Little, Mark P. Kwon, Deukwoo Doi, Kazataka Simon, Steven L. Preston, Dale L. Doody, Michele M. Lee, Terrence Miller, Jeremy S. Kampa, Diane M. Bhatti, Parveen Tucker, James D. Linet, Martha S. Sigurdson, Alice J. TI Association of Chromosome Translocation Rate with Low Dose Occupational Radiation Exposures in US Radiologic Technologists SO RADIATION RESEARCH LA English DT Article ID ATOMIC-BOMB SURVIVORS; X-RAY EXAMINATIONS; IONIZING-RADIATION; CANCER-RISK; INCREASED FREQUENCY; MEASUREMENT ERROR; PERIPHERAL-BLOOD; UNITED-STATES; ABERRATIONS; WORKERS AB Chromosome translocations are a well-recognized biological marker of radiation exposure and cancer risk. However, there is uncertainty about the lowest dose at which excess translocations can be detected, and whether there is temporal decay of induced translocations in radiation-exposed populations. Dosimetric uncertainties can substantially alter the shape of dose-response relationships; although regression-calibration methods have been used in some datasets, these have not been applied in radio-occupational studies, where there are also complex patterns of shared and unshared errors that these methods do not account for. In this article we evaluated the relationship between estimated occupational ionizing radiation doses and chromosome translocation rates using fluorescent in situ hybridization in 238 U. S. radiologic technologists selected from a large cohort. Estimated cumulative red bone marrow doses (mean 29.3 mGy, range 0-135.7 mGy) were based on available badge-dose measurement data and on questionnaire-reported work history factors. Dosimetric assessment uncertainties were evaluated using regression calibration, Bayesian and Monte Carlo maximum likelihood methods, taking account of shared and unshared error and adjusted for overdispersion. There was a significant dose response for estimated occupational radiation exposure, adjusted for questionnaire-based personal diagnostic radiation, age, sex and study group (5.7 translocations per 100 whole genome cell equivalents per Gy, 95% CI 0.2, 11.3, P = 0.0440). A significant increasing trend with dose continued to be observed for individuals with estimated doses,100 mGy. For combined estimated occupational and personal-diagnostic-medical radiation exposures, there was a borderline-significant modifying effect of age (P = 0.0704), but little evidence (P > 0.5) of temporal decay of induced translocations. The three methods of analysis to adjust for dose uncertainty gave similar results. In summary, chromosome translocation dose-response slopes were detectable down to <100 mGy and were compatible with those observed in other radiation-exposed populations. However, there are substantial uncertainties in both occupational and other (personal-diagnostic-medical) doses that may be imperfectly taken into account in our analysis. (C) 2014 by Radiation Research Society C1 [Little, Mark P.; Doi, Kazataka; Simon, Steven L.; Doody, Michele M.; Lee, Terrence; Linet, Martha S.; Sigurdson, Alice J.] NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [Kwon, Deukwoo] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Preston, Dale L.] Hirosoft Int, Eureka, CA 95501 USA. [Miller, Jeremy S.] Informat Management Serv Inc, Silver Spring, MD 20904 USA. [Kampa, Diane M.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN 55409 USA. [Bhatti, Parveen] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98109 USA. [Tucker, James D.] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. RP Little, MP (reprint author), NCI, Room 7E546,9609 Med Ctr Dr,MSC 9778, Bethesda, MD 20892 USA. EM mark.little@nih.gov OI Little, Mark/0000-0003-0980-7567 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute, Division of Cancer Epidemiology and Genetics FX The authors are grateful for the detailed and helpful comments of Professor Jan Tawn, of the Associated Editor and the three referees. This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. The authors would also like to thank Chris McClure of Research Triangle Institute, Inc. (Research Triangle Park, NC), and Alison Iwan of the University of Minnesota, who organized the in-home phlebotomy, as well as all the participating radiologic technologists in the USRT Study. NR 67 TC 9 Z9 9 U1 2 U2 9 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 EI 1938-5404 J9 RADIAT RES JI Radiat. Res. PD JUL PY 2014 VL 182 IS 1 BP 1 EP 17 DI 10.1667/RR13413.1 PG 17 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA AO4LE UT WOS:000341308700002 PM 24932535 ER PT J AU Figg, WD Chau, CH Price, DK Till, C Goodman, PJ Cho, Y Varella-Garcia, M Reichardt, JKV Tangen, CM Leach, RJ van Bokhoven, A Thompson, IM Lucia, MS AF Figg, William D. Chau, Cindy H. Price, Douglas K. Till, Cathee Goodman, Phyllis J. Cho, Yonggon Varella-Garcia, Marileila Reichardt, Juergen K. V. Tangen, Catherine M. Leach, Robin J. van Bokhoven, Adrie Thompson, Ian M. Lucia, M. Scott TI Androgen Receptor CAG Repeat Length and TMPRSS2:ETS Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial SO UROLOGY LA English DT Article ID GENETIC-VARIATION; FUSION; CELLS AB OBJECTIVE To investigate the association between the length of the polymorphic trinucleotide CAG microsatellite repeats in exon 1 of the AR gene and the risk of prostate cancer containing TMPRSS2:ETS fusion genes. METHODS This nested case-control study came from subjects enrolled in the Prostate Cancer Prevention Trial and included 195 biopsy-proven prostate cancer cases with a known TMPRSS2: ETS status and 1344 matched controls. RESULTS There was no association between the CAG repeat length and the risk of TMPRSS2:ETS-positive (odds ratio, 0.97; 95% confidence interval, 0.91-1.04) or TMPRSS2: ETS-negative prostate cancer (odds ratio, 1.04; 95% confidence interval, 0.97-1.11) and in patients with low-or high-grade disease. CONCLUSION Our findings suggested that AR CAG repeats are not associated with TMPRSS2: ETS formation in prostate cancer. (C) 2014. Published by Elsevier Inc. C1 [Figg, William D.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98104 USA. Chonbuk Natl Univ, Sch Med, Jeonju, South Korea. Univ Colorado Denver, Sch Med, Dept Pathol, Aurora, CO USA. James Cook Univ, Sch Pharm & Mol Sci, Townsville, Qld 4811, Australia. Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. RP Figg, WD (reprint author), NCI, Genitourinary Malignancies Branch, Ctr Canc Res, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM figgw@helix.nih.gov RI Figg Sr, William/M-2411-2016; Cho, Yong Gon/Q-9924-2016; OI Cho, Yong Gon/0000-0003-3011-6875; Reichardt, Juergen/0000-0001-6458-2773 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research [ZO1 BC010453]; Biology of the Prostate Cancer Prevention Trial [P01 CA108964]; University of Colorado Cancer Center [P30 CA046934]; Cancer Therapy and Research Center [P30 CA054174]; Public Health Service Grant from the National Cancer Institute, Division of Cancer Prevention [CA37429] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (ZO1 BC010453); The Biology of the Prostate Cancer Prevention Trial (P01 CA108964); the University of Colorado Cancer Center Support Grant (P30 CA046934); the Cancer Therapy and Research Center Support Grant (P30 CA054174); and Public Health Service Grant (CA37429) from the National Cancer Institute, Division of Cancer Prevention. NR 16 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD JUL PY 2014 VL 84 IS 1 BP 127 EP 131 DI 10.1016/j.urology.2014.03.015 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA AO5EE UT WOS:000341364900030 PM 24824408 ER PT J AU Marschall, J Mermel, LA Fakih, M Hadaway, L Kallen, A O'Grady, NP Pettis, AM Rupp, ME Sandora, T Maragakis, LL Yokoe, DS AF Marschall, Jonas Mermel, Leonard A. Fakih, Mohamad Hadaway, Lynn Kallen, Alexander O'Grady, Naomi P. Pettis, Ann Marie Rupp, Mark E. Sandora, Thomas Maragakis, Lisa L. Yokoe, Deborah S. TI Strategies to Prevent Central Line-Associated Bloodstream Infections in Acute Care Hospitals: 2014 Update SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID CENTRAL VENOUS CATHETERS; RANDOMIZED-CONTROLLED-TRIAL; CRITICALLY-ILL PATIENTS; NEONATAL INTENSIVE-CARE; OF-THE-LITERATURE; STERILE BARRIER PRECAUTIONS; DOUBLE-BLIND TRIAL; NEEDLELESS INTRAVASCULAR CONNECTOR; ANTIMICROBIAL-COATED CATHETERS; PULMONARY-ARTERY CATHETERS C1 [Marschall, Jonas] Washington Univ, Sch Med, St Louis, MO USA. [Marschall, Jonas] Univ Hosp Bern, CH-3010 Bern, Switzerland. [Marschall, Jonas] Univ Bern, Bern, Switzerland. [Mermel, Leonard A.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Mermel, Leonard A.] Rhode Isl Hosp, Providence, RI 02903 USA. [Fakih, Mohamad] St John Hosp & Med Ctr, Detroit, MI USA. [Fakih, Mohamad] Wayne State Univ, Sch Med, Detroit, MI USA. [Hadaway, Lynn] Lynn Hadaway Associates Inc, Milner, GA USA. [Kallen, Alexander] Ctr Dis Control & Prevent, Atlanta, GA USA. [O'Grady, Naomi P.] NIH, Bethesda, MD 20892 USA. [Pettis, Ann Marie] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Rupp, Mark E.] Univ Nebraska Med Ctr, Omaha, NE USA. [Sandora, Thomas] Boston Childrens Hosp, Boston, MA USA. [Sandora, Thomas; Yokoe, Deborah S.] Harvard Univ, Sch Med, Boston, MA USA. [Maragakis, Lisa L.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Yokoe, Deborah S.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Mermel, LA (reprint author), Rhode Isl Hosp, Div Infect Dis, 593 Eddy St, Providence, RI 02903 USA. EM lmermel@lifespan.org FU Bard FX J.M. reports receiving a speaker honorarium from Gilead Sciences Switzerland. L. A. M. reports serving as an advisor/consultant for ICU Medical, Fresenius Medical Care, Bard Access Systems, Marvao Medical Devices, CareFusion, 3M Healthcare, Catheter Connections, Semprus Biosciences, and Sharklet Technologies. L. H. reports serving as an advisor/consultant for B Braun Medical, BD Medical, Excelsior Medical, Ivera Medical, Access Scientific, 3M, and Baxter Healthcare. A. M. P. reports receiving speaking fees from Bard and serving as a speaker and author for Covidien. M. E. R reports serving as an advisor/consultant for 3M, Ariste, Semprus, and Sharklet Technologies and receiving honoraria from Baxter and CareFusion. All other authors report no relevant conflicts of interest. NR 248 TC 0 Z9 0 U1 4 U2 12 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD JUL PY 2014 VL 35 IS 7 BP 753 EP 771 DI 10.1086/676533 PG 19 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AJ5OV UT WOS:000337735400001 ER PT J AU Daunhauer, LA Fidler, DJ Hahn, L Will, E Lee, NR Hepburn, S AF Daunhauer, Lisa A. Fidler, Deborah J. Hahn, Laura Will, Elizabeth Lee, Nancy Raitano Hepburn, Susan TI Profiles of Everyday Executive Functioning in Young Children With Down Syndrome SO AJIDD-AMERICAN JOURNAL ON INTELLECTUAL AND DEVELOPMENTAL DISABILITIES LA English DT Article DE executive function; cognition; Down syndrome; trisomy 21 ID BEHAVIOR RATING INVENTORY; CONFIRMATORY FACTOR-ANALYSIS; PREFRONTAL CORTEX; PRESCHOOL-CHILDREN; EFFORTFUL CONTROL; UNITED-STATES; FRAGILE-X; MEMORY; DISORDERS; AUTISM AB We investigated executive functioning (EF) in children with Down syndrome (DS; n = 25) and typically developing (TD) children matched for mental age (MA; n = 23) using the Behavior Rating Inventory of Executive Function-Preschool. We sought to (1) compare children with DS to a developmentally matched control group, and (2) to characterize the EF profile of children with DS. Across teacher and parent reports, significant deficits in working memory and planning were observed in the DS group. Parents, but not teachers, of children with DS also reported difficulties in inhibitory control relative to the comparison group. Results extend earlier findings regarding EF impairments in children with DS. The complementary role inhibitory control may play in this profile is discussed. C1 [Daunhauer, Lisa A.; Fidler, Deborah J.; Will, Elizabeth] Colorado State Univ, Ft Collins, CO 80523 USA. [Hahn, Laura] Univ Kansas, Lawrence, KS 66045 USA. [Lee, Nancy Raitano] NIMH, Bethesda, MD USA. [Hepburn, Susan] Univ Colorado, Sch Med, Boulder, CO 80309 USA. RP Daunhauer, LA (reprint author), Colorado State Univ, Room 447,Behav Sci Bldg, Ft Collins, CO 80523 USA. EM Lisa.Daunhauer@colostate.edu RI Lee, Nancy/M-7492-2016 OI Lee, Nancy/0000-0002-6663-0713 FU NCATS NIH HHS [UL1 TR001082]; NCRR NIH HHS [UL1 RR025780]; NICHD NIH HHS [L30 HD048361, U19 HD035468] NR 67 TC 10 Z9 10 U1 2 U2 15 PU AMER ASSOC INTELLECTUAL DEVELOPMENTAL DISABILITIES PI WASHINGTON PA 444 N CAPITOL ST, NW STE 846, WASHINGTON, DC 20001-1512 USA SN 1944-7515 EI 1944-7558 J9 AJIDD-AM J INTELLECT JI AJIDD-Am. J. Intellect. Dev. Disabil. PD JUL PY 2014 VL 119 IS 4 BP 303 EP 318 DI 10.1352/1944-7558-119.4.303 PG 16 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA AO3XP UT WOS:000341270900002 PM 25007296 ER PT J AU Mellion, ML Silbermann, E Gilchrist, JM Machan, JT Leggio, L de la Monte, S AF Mellion, Michelle L. Silbermann, Elizabeth Gilchrist, James M. Machan, Jason T. Leggio, Lorenzo de la Monte, Suzanne TI Small-Fiber Degeneration in Alcohol-Related Peripheral Neuropathy SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Peripheral Neuropathy; Alcohol; Nerve; Small Fiber ID STIMULATED PHOSPHOINOSITIDE METABOLISM; GROWTH-FACTOR RESISTANCE; SKIN BIOPSY; TRANSKETOLASE ACTIVITY; LIVER-DISEASE; THIAMINE; ETHANOL; NERVE; POLYNEUROPATHY; INSULIN AB Background: Alcohol-related peripheral neuropathy (ALN) is generally characterized as an axonal large-fiber polyneuropathy caused by thiamine deficiency. We hypothesized, based on clinical observations, that ALN is associated with a small-fiber polyneuropathy that can be diagnosed with skin biopsy in heavy alcohol drinking subjects with normal thiamine status. Methods: Eighteen individuals (9 heavy alcohol drinking subjects and 9 healthy control subjects) were assessed for the potential utility of skin biopsies in detecting ALN-associated small nerve fiber degeneration. Heavy drinking was defined as greater than 4 drinks/d and 5 drinks/d in women and men, respectively, as determined by the Timeline Follow-Back and lifetime drinking history. All subjects underwent neurological examination, nerve conduction studies, and skin biopsies to quantify end nerve fiber densities (ENFD). Other causes of neuropathy were excluded and thiamine status was assessed. Results: Average ENFD were significantly decreased at the calf in the alcohol group as compared with control group (p < 0.0001). Histological sections demonstrated striking attrition and architectural simplification of intraepidermal nerve fibers in the heavy alcohol drinking subjects. There were no significant intergroup differences with respect to clinical assessments of neuropathy or thiamine status. Conclusions: ALN is associated with a small-fiber neuropathy that can be detected with skin biopsy in heavy alcohol drinking individuals with normal thiamine status. Skin biopsy is a useful, minimally invasive biomarker that could extend studies to understand the effect of alcohol on the peripheral nerves and to evaluate potential therapeutic agents in larger clinical trials. C1 [Mellion, Michelle L.; de la Monte, Suzanne] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Dept Neurol, Providence, RI 02905 USA. [Silbermann, Elizabeth] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Dept Med, Providence, RI 02905 USA. [Gilchrist, James M.] SIU Sch Med, Dept Neurol, Springfield, IL USA. [Machan, Jason T.] Brown Univ, Alpert Med Sch, Lifespan Biostat Core, Dept Orthopaed, Providence, RI 02905 USA. [Machan, Jason T.] Brown Univ, Alpert Med Sch, Lifespan Biostat Core, Dept Surg, Providence, RI 02905 USA. [Leggio, Lorenzo] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Leggio, Lorenzo] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Leggio, Lorenzo] Brown Univ, Dept Behav & Social Sci, Providence, RI 02905 USA. [de la Monte, Suzanne] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Dept Pathol Neuropathol, Providence, RI 02905 USA. [de la Monte, Suzanne] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Dept Neurosurg, Providence, RI 02905 USA. [de la Monte, Suzanne] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Dept Med, Providence, RI 02905 USA. RP Mellion, ML (reprint author), Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Dept Neurol, 2 Dudley St,Suite 555, Providence, RI 02905 USA. EM mmellionmd@gmail.com RI Leggio, Lorenzo/M-2972-2016; Machan, Jason/D-3897-2013 OI Machan, Jason/0000-0003-2048-4914 FU NIAAA NIH HHS [R01 AA012908, R37 AA011431, K24 AA016126]; NIGMS NIH HHS [P20 GM104937] NR 39 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUL PY 2014 VL 38 IS 7 BP 1965 EP 1972 DI 10.1111/acer.12470 PG 8 WC Substance Abuse SC Substance Abuse GA AN4ZC UT WOS:000340597600019 PM 24961481 ER PT J AU Kim, JH Martins, SS Shmulewitz, D Santaella, J Wall, MM Keyes, KM Eaton, NR Krueger, R Grant, BF Hasin, DS AF Kim, June H. Martins, Silvia S. Shmulewitz, Dvora Santaella, Julian Wall, Melanie M. Keyes, Katherine M. Eaton, Nicholas R. Krueger, Robert Grant, Bridget F. Hasin, Deborah S. TI Childhood Maltreatment, Stressful Life Events, and Alcohol Craving in Adult Drinkers SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol Craving; Stressful Life Events; Childhood Maltreatment; Stress Sensitivity ID NATIONAL EPIDEMIOLOGIC SURVEY; GENERAL-POPULATION SAMPLE; PSYCHIATRIC DIAGNOSTIC MODULES; SUBSTANCE USE DISORDERS; IV AUDADIS-IV; DSM-IV; UNITED-STATES; FAMILY-HISTORY; RISK-FACTORS; DEPENDENT INDIVIDUALS AB Background: Little is known about the relationship between stressful life events and alcohol craving in the general population, and whether a history of childhood maltreatment sensitizes individuals to crave alcohol after adult stressors. Methods: Participants were 22,147 past-year drinkers from Wave 2 (2004 to 2005) of the National Epidemiologic Survey on Alcohol and Related Conditions. A structured, face-to-face interview assessed past-year stressful life events, alcohol craving, and history of childhood maltreatment. Logistic regression was used to generate adjusted odds ratios (aOR) to evaluate the relationship between stressful life events and craving, adjusting for demographic characteristics and parental history of alcoholism. Interaction between stressful life events and childhood maltreatment was also assessed. Results: Compared to participants with no stressful life events, those with >= 3 events had increased odds of moderate alcohol craving (aOR = 3.15 [95% CI = 2.30 to 4.33]) and severe craving (aOR = 8.47 [95% CI = 4.78 to 15.01]). Stressful life events and childhood maltreatment interacted in predicting severe craving (p = 0.017); those with = 3 events were at higher risk of craving if they had been exposed to childhood maltreatment. Conclusions: A direct relationship between stressful life events and risk of alcohol craving was observed. Further, history of childhood maltreatment increased the salience of stressful life events in adulthood. Future studies should examine the role of psychiatric comorbidity in more complex models of stress sensitization and alcohol craving. C1 [Kim, June H.; Martins, Silvia S.; Santaella, Julian; Wall, Melanie M.; Keyes, Katherine M.; Hasin, Deborah S.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Shmulewitz, Dvora; Wall, Melanie M.; Hasin, Deborah S.] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Shmulewitz, Dvora; Wall, Melanie M.; Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Eaton, Nicholas R.] SUNY Stony Brook, Dept Psychol, New York, NY USA. [Krueger, Robert] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Grant, Bridget F.] NIAAA, Div Intramural Clin & Biol Res, Rockville, MD 20852 USA. RP Hasin, DS (reprint author), Columbia Univ, 1051 Riverside Dr 123, New York, NY 10032 USA. EM dsh2@columbia.edu RI Martins, Silvia/C-9405-2014 FU NIAAA NIH HHS [K01 AA021511, K05 AA014223, K05AA014223, U01 AA018111, U01AA018111]; NICHD NIH HHS [1R01HD060072, R01 HD060072]; NIDA NIH HHS [T32 DA031099, T32DA031099-01A1] NR 55 TC 8 Z9 8 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUL PY 2014 VL 38 IS 7 BP 2048 EP 2055 DI 10.1111/acer.12473 PG 8 WC Substance Abuse SC Substance Abuse GA AN4ZC UT WOS:000340597600029 PM 24961735 ER PT J AU Barry, LC Thorpe, RJ Penninx, BWJH Yaffe, K Wakefield, D Ayonayon, HN Satterfield, S Newman, AB Simonsick, EM AF Barry, Lisa C. Thorpe, Roland J., Jr. Penninx, Brenda W. J. H. Yaffe, Kristine Wakefield, Dorothy Ayonayon, Hilsa N. Satterfield, Suzanne Newman, Anne B. Simonsick, Eleanor M. TI Race-related Differences in Depression Onset and Recovery in Older Persons Over Time: The Health, Aging, and Body Composition Study SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Aging; depression; depressive symptoms; race differences; epidemiology; prospective studies ID LATE-LIFE DEPRESSION; AFRICAN-AMERICANS; UNITED-STATES; ELDERLY POPULATION; NATIONAL-SURVEY; CARE PATIENTS; SERVICE USE; FOLLOW-UP; ADULTS; SYMPTOMS AB Objectives: To evaluate race-related differences in depression onset and recovery in older persons, overall and by sex, and examine race-related differences in mortality according to depression. Design: Prospective cohort study. Setting: General community in pre-designated zip code areas in Memphis, Tennessee, and Pittsburgh, Pennsylvania. Participants: 3,075 persons aged 70-79 years at baseline in the Health, Aging, and Body Composition study. Measurements: Depression was assessed at eight time points over 10 years using the 10-item Center for Epidemiologic Studies-Depression scale; patients were categorized as nondepressed (score less than 8) or depressed (score of 8 or higher). We created variables for transitions across each 18-month time interval, namely, from nondepressed or depressed to nondepressed, depressed, or death, and determined the association between race and the average likelihood of these transitions over time. Results: A higher percentage of blacks than whites were depressed at nearly all time points. Adjusting for demographics, common chronic conditions, and body mass index, blacks had a higher likelihood of experiencing depression onset than whites (odds ratio [OR]: 1.22; 95% confidence interval [CI]: 1.03-1.43); among men, blacks were more likely to experience depression onset than whites (OR: 1.44; 95% CI: 1.24-2.89). Blacks also had a higher likelihood of transitioning from nondepressed to death (OR: 1.79; 95% CI: 1.30-2.46). Overall and in sex-stratified analyses, race was not associated with recovery from depression or with the transition from depression to death. Conclusion: Our findings highlight race differences in depression in older persons and encourage further research on the course of depression in older black patients. C1 [Barry, Lisa C.; Wakefield, Dorothy] Univ Connecticut, Ctr Aging, Farmington, CT 06030 USA. [Thorpe, Roland J., Jr.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Penninx, Brenda W. J. H.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Barry, LC (reprint author), Univ Connecticut, Ctr Aging, 263 Farmington Ave, Farmington, CT 06030 USA. EM LiBarry@uchc.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA at the National Institutes of Health research [R01-AG028050, K01-AG-031324]; National Institute of Nursing [R01-NR012459]; National Institute of Mental Health [R01-MH086498] FX This work was supported in part by the Intramural Research Program of the National Institute on Aging (NIA) contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; the NIA at the National Institutes of Health research grants R01-AG028050 and K01-AG-031324 (to LCB); the National Institute of Nursing research grant R01-NR012459; and National Institute of Mental Health research grant R01-MH086498. NR 48 TC 7 Z9 7 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD JUL PY 2014 VL 22 IS 7 BP 682 EP 691 DI 10.1016/j.jagp.2013.09.001 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AN9ZX UT WOS:000340969600006 PM 24125816 ER PT J AU Cid, J Lozano, M Klein, HG Flegel, WA AF Cid, Joan Lozano, Miguel Klein, Harvey G. Flegel, Willy A. TI Matching for the D antigen in haematopoietic progenitor cell transplantation: definition and clinical outcomes SO BLOOD TRANSFUSION LA English DT Review DE transplantation; mismatching; incompatibility; D antigen; haematopoietic progenitor cell ID BONE-MARROW-TRANSPLANTATION; D ALLOIMMUNIZATION; D ALLOANTIBODIES; BLOOD; RECIPIENT; DONOR; HEMOLYSIS; FREQUENCY; ANTIBODY; DISEASES C1 [Cid, Joan; Lozano, Miguel] Hosp Clin Barcelona, Dept Haemotherapy & Haemostasis, IDIBAPS, Barcelona, Spain. [Cid, Joan; Klein, Harvey G.; Flegel, Willy A.] NTH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Flegel, WA (reprint author), NTH, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM bill.flegel@nih.gov RI Cid, Joan/F-7778-2016; OI Cid, Joan/0000-0001-5445-4508; Lozano, Miguel/0000-0003-2593-833X FU Sociedad Espanola de Transfusion Sanguinea y Terapia Celular; Intramural Research Program of the NIH Clinical Center FX This research was facilitated by a sabbatical leave and supported by a research grant from the "Sociedad Espanola de Transfusion Sanguinea y Terapia Celular" for Joan Cid and by the Intramural Research Program of the NIH Clinical Center. NR 24 TC 5 Z9 5 U1 0 U2 1 PU SIMITI SERVIZI SRL PI MILAN PA VIA DESIDERIO 21, MILAN, 20131, ITALY SN 1723-2007 J9 BLOOD TRANSFUS-ITALY JI Blood Transf. PD JUL PY 2014 VL 12 IS 3 BP 301 EP 306 DI 10.2450/2014.0238-13 PG 6 WC Hematology SC Hematology GA AO1KF UT WOS:000341070300006 PM 24887231 ER PT J AU Bornstein, MH Hahn, CS Putnick, DL Suwalsky, JTD AF Bornstein, Marc H. Hahn, Chun-Shin Putnick, Diane L. Suwalsky, Joan T. D. TI Stability of Core Language Skill from Early Childhood to Adolescence: A Latent Variable Approach SO CHILD DEVELOPMENT LA English DT Article ID FIT INDEXES; MEASUREMENT INVARIANCE; ACADEMIC-ACHIEVEMENT; UNITED-STATES; CHILDREN; RESPONSIVENESS; ATTENTION; CASCADES; INFANTS; MOTHER AB This four-wave prospective longitudinal study evaluated stability of language in 324 children from early childhood to adolescence. Structural equation modeling supported loadings of multiple age-appropriate multi-source measures of child language on single-factor core language skills at 20 months and 4, 10, and 14 years. Large stability coefficients (standardized indirect effect = .46) were obtained between language latent variables from early childhood to adolescence even when accounting for child nonverbal intelligence and social competence and maternal verbal intelligence, education, speech, and social desirability. Stability coefficients were similar for girls and boys. Stability of core language skill was stronger from 4 to 10 to 14 years than from 20 months to 4 years, so early intervention to improve lagging language is recommended. C1 [Bornstein, Marc H.; Hahn, Chun-Shin; Putnick, Diane L.; Suwalsky, Joan T. D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, US PHS, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Born-stein@nih.gov OI Putnick, Diane/0000-0002-6323-749X FU Intramural NIH HHS [ZIA HD001119-27] NR 44 TC 10 Z9 10 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-3920 EI 1467-8624 J9 CHILD DEV JI Child Dev. PD JUL-AUG PY 2014 VL 85 IS 4 BP 1346 EP 1356 DI 10.1111/cdev.12192 PG 11 WC Psychology, Educational; Psychology, Developmental SC Psychology GA AN5BG UT WOS:000340603400002 PM 25165797 ER PT J AU Maul, RW Gearhart, PJ AF Maul, Robert W. Gearhart, Patricia J. TI Refining the Neuberger model: Uracil processing by activated B cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Editorial Material DE Class switch recombination; DNA repair; SMUG1; Somatic hypermutation; UNG ID CLASS SWITCH RECOMBINATION; CYTIDINE DEAMINASE AID; DNA-POLYMERASE-ETA; SOMATIC HYPERMUTATION; IMMUNOGLOBULIN GENES; MISMATCH-REPAIR; ANTIBODY DIVERSIFICATION; UNG-DEFICIENT; MUTATION; REGIONS AB During the immune response, B cells undergo a programed mutagenic cascade to promote increased affinity and expanded antibody function. The two processes, somatic hypermutation (SHM) and class switch recombination (CSR), are initiated by the protein activation-induced deaminase (AID), which converts cytosine to uracil in the immunoglobulin loci. The presence of uracil in DNA promotes DNA mutagenesis though a subset of DNA repair proteins. Two distinct mechanisms have been proposed to control uracil processing. The first is through base removal by uracil DNA glycosylase (UNG), and the second is through detection by the mismatch repair (MMR) complex MSH2/6. In a study published in this issue of European Journal of Immunology, Dingler et al. [Eur. J. Immunol. 2014. 44: 1925-1935] examine uracil processing in B cells in the absence of UNG and SMUG1 glycosylases. Similar to UNG, SMUG1 is an uracil glycosylase which can remove the uracil base. While Smug1(-/-)mice show no clear deficiency in SHM or CSR, Ung(-/-)Smug(1-/-)mice display exacerbated phenotypes, suggesting a back-up role for SMUG1 in antibody diversity. This new information expands the model of uracil processing in B cells and raises several interesting questions about the dynamic relationship between base excision repair and MMR. C1 [Maul, Robert W.; Gearhart, Patricia J.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. RP Maul, RW (reprint author), NIA, Lab Mol Biol & Immunol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM maulrw@mail.nih.gov OI Maul, Robert/0000-0002-6958-8514 FU Intramural Research program of the NIH, National Institute on Aging FX This work was supported entirely by the Intramural Research program of the NIH, National Institute on Aging. We gratefully thank Lisa Russell and Kim Zanotti for insightful comments. NR 28 TC 5 Z9 5 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2014 VL 44 IS 7 BP 1913 EP 1916 DI 10.1002/eji.201444813 PG 4 WC Immunology SC Immunology GA AN4UP UT WOS:000340584300005 PM 24920531 ER PT J AU Metenou, S Coulibaly, YI Sturdevant, D Dolo, H Diallo, AA Soumaoro, L Coulibaly, ME Kanakabandi, K Porcella, SF Klion, AD Nutman, TB AF Metenou, Simon Coulibaly, Yaya I. Sturdevant, Daniel Dolo, Housseini Diallo, Abdallah A. Soumaoro, Lamine Coulibaly, Michel E. Kanakabandi, Kishore Porcella, Stephen F. Klion, Amy D. Nutman, Thomas B. TI Highly heterogeneous, activated, and short-lived regulatory T cells during chronic filarial infection SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Chronic infection; Foxp3; Regulatory molecules; Regulatory T (Treg) cells ID HUMAN LYMPHATIC FILARIASIS; ANTIGEN-PRESENTING CELLS; GROWTH-FACTOR-BETA; TGF-BETA; BRUGIA-MALAYI; MYASTHENIA-GRAVIS; CHEMOKINE CXCL16; IMMUNE-RESPONSES; ORAL TOLERANCE; IN-VIVO AB The mechanisms underlying the increase in the numbers of regulatory T (Treg) cells in chronic infection settings remain unclear. Here we have delineated the phenotype and transcriptional profiles of Treg cells from 18 filarial-infected (Fil(+)) and 19 filarial-uninfected (Fil(-)) subjects. We found that the frequencies of Foxp3(+) Treg cells expressing CTLA-4, GITR, LAG-3, and IL-10 were significantly higher in Fil(+) subjects compared with that in Fil(-) subjects. Foxp3-expressing Treg-cell populations in Fil(+) subjects were also more heterogeneous and had higher expression of IL-10, CCL-4, IL-29, CTLA-4, and TGF-beta than Fil(-) subjects, each of these cytokines having been implicated in immune suppression. Moreover, Foxp3-expressing Treg cells from Fil(+) subjects had markedly upregulated expression of activation-induced apoptotic genes with concomitant downregulation of those involved in cell survival. To determine whether the expression of apoptotic genes was due to Treg-cell activation, we found that the expression of CTLA-4, CDk8, RAD50, TNFRSF1A, FOXO3, and RHOA were significantly upregulated in stimulated cells compared with unstimulated cells. Taken together, our results suggest that in patent filarial infection, the expanded Treg-cell populations are heterogeneous, short-lived, activated, and express higher levels of molecules known to modulate immune responsiveness, suggesting that filarial infection is associated with high Treg-cell turnover. C1 [Metenou, Simon; Klion, Amy D.; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Coulibaly, Yaya I.; Dolo, Housseini; Diallo, Abdallah A.; Soumaoro, Lamine; Coulibaly, Michel E.] Univ Bamako, Fac Med Pharm & Dent, Bamako, Mali. [Sturdevant, Daniel; Kanakabandi, Kishore; Porcella, Stephen F.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Metenou, S (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr,Room B1-05, Bethesda, MD 20892 USA. EM metenous@niaid.nih.gov OI Klion, Amy/0000-0002-4986-5326 FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work 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 83 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2014 VL 44 IS 7 BP 2036 EP 2047 DI 10.1002/eji.201444452 PG 12 WC Immunology SC Immunology GA AN4UP UT WOS:000340584300019 PM 24737144 ER PT J AU Kitano, M Maker, AV Lanier, BJ Danforth, DN Kammula, US AF Kitano, Mio Maker, Ajay V. Lanier, Brock J. Danforth, David N. Kammula, Udai S. TI Appendicitis Secondary to Metastatic Melanoma Review of the National Institutes of Health Experience SO JAMA SURGERY LA English DT Review ID MALIGNANT-MELANOMA; GASTROINTESTINAL-TRACT; SURGERY; REGRESSION; MANAGEMENT AB IMPORTANCE Malignant melanoma has an unusual propensity to metastasize to the small bowel; however, malignant melanoma with metastatic spread to the appendix presenting as acute appendicitis has rarely been reported. We describe cases of melanoma of the appendix presenting with appendicitis and review our institutional experience with this entity. OBSERVATIONS Medical records were reviewed in patients with melanoma at the National Cancer Institute between January 1,1953, and December 31, 2010, who underwent appendectomy. Of 5822 cases of melanoma treated at the National Institutes of Health, appendectomies were performed on 31 patients, 2 of whom had acute appendicitis secondary to malignant obstruction and presented with symptoms of vague abdominal pain. Both patients had been heavily pretreated for metastatic melanoma and had multiple sites of intraperitoneal and extraperitoneal disease. On exploratory laparotomy, both patients showed clinical evidence of acute appendicitis, and an appendectomy was performed. Both patients recovered fully from the operation and proceeded to further systemic therapy. CONCLUSIONS AND RELEVANCE Although rare, the diagnosis of appendicitis should be considered in patients with melanoma and acute abdominal pain. Timely surgical intervention may allow palliation and the ability to pursue subsequent systemic treatment. C1 [Kitano, Mio] Albert Einstein Coll Med, Dept Surg, Bronx, NY 10467 USA. [Maker, Ajay V.] Univ Illinois, Dept Surg, Div Surg Oncol, Chicago, IL 60680 USA. [Lanier, Brock J.] Georgetown Univ, Sch Med, Dept Surg, Washington, DC USA. [Danforth, David N.; Kammula, Udai S.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Kitano, M (reprint author), Albert Einstein Coll Med, Dept Surg, 3400 Bainbridge Ave,MAP4, Bronx, NY 10467 USA. EM mkitano@montefiore.org NR 23 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD JUL PY 2014 VL 149 IS 7 BP 735 EP 738 DI 10.1001/jamasurg.2013.4067 PG 4 WC Surgery SC Surgery GA AN8DV UT WOS:000340833800022 PM 24871401 ER PT J AU Little, MP AF Little, Mark P. TI Atlas of Epidemic Britain: A Twentieth-Century Picture SO JOURNAL OF HISTORICAL GEOGRAPHY LA English DT Book Review C1 [Little, Mark P.] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0305-7488 J9 J HIST GEOGR JI J. Hist. Geogr. PD JUL PY 2014 VL 45 BP 130 EP 130 DI 10.1016/j.jhg.2014.05.004 PG 1 WC Geography; History Of Social Sciences SC Geography; Social Sciences - Other Topics GA AO0FW UT WOS:000340985500023 ER PT J AU Cox, JM Heitmann, RJ Hailstorks, T Armstrong, AY AF Cox, Jeris M. Heitmann, Ryan J. Hailstorks, Tiffany Armstrong, Alicia Y. TI MRI Evidence of Embryo Implantation Onto the Fibromuscular Uterine Septum SO JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY LA English DT Editorial Material ID ANOMALIES; WOMEN C1 [Cox, Jeris M.; Heitmann, Ryan J.; Armstrong, Alicia Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Hailstorks, Tiffany] Howard Univ, Sch Med, Dept Obstet & Gynecol, Washington, DC 20059 USA. RP Cox, JM (reprint author), NICHD, Program Reprod & Adult Endocrinol, NIH, 10 CRC,1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM Jeris.Cox@nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1553-4650 EI 1553-4669 J9 J MINIM INVAS GYN JI J. Mimim. Invasive Gynecol. PD JUL-AUG PY 2014 VL 21 IS 4 BP 535 EP 536 DI 10.1016/j.jmig.2013.12.092 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AN6ED UT WOS:000340686800007 PM 24374247 ER PT J AU Gadermann, AM Heeringa, SG Stein, MB Ursano, RJ Colpe, LJ Fullerton, CS Gilman, SE Gruber, MJ Nock, MK Rosellini, AJ Sampson, NA Schoenbaum, M Zaslavsky, AM Kessler, RC AF Gadermann, Anne M. Heeringa, Steven G. Stein, Murray B. Ursano, Robert J. Colpe, Lisa J. Fullerton, Carol S. Gilman, Stephen E. Gruber, Michael J. Nock, Matthew K. Rosellini, Anthony J. Sampson, Nancy A. Schoenbaum, Michael Zaslavsky, Alan M. Kessler, Ronald C. CA Army STARRS Collaborators TI Classifying US Army Military Occupational Specialties Using the Occupational Information Network SO MILITARY MEDICINE LA English DT Article ID O-ASTERISK-NET; EXPLORATORY FACTOR-ANALYSIS; WORK; JOB; ATTRIBUTES; SUICIDE; HEALTH; RISK; ASSOCIATIONS; DISPARITIES AB Objectives: To derive job condition scales for future studies of the effects of job conditions on soldier health and job functioning across Army Military Occupation Specialties (MOSs) and Areas of Concentration (AOCs) using Department of Labor (DoL) Occupational Information Network (O*NET) ratings. Methods: A consolidated administrative dataset was created for the "Army Study to Assess Risk and Resilience in Servicemembers" (Army STARRS) containing all soldiers on active duty between 2004 and 2009. A crosswalk between civilian occupations and MOS/AOCs (created by DoL and the Defense Manpower Data Center) was augmented to assign scores on all 246 O*NET dimensions to each soldier in the dataset. Principal components analysis was used to summarize these dimensions. Results: Three correlated components explained the majority of O*NET dimension variance: "physical demands" (20.9% of variance), "interpersonal complexity" (17.5%), and "substantive complexity" (15.0%). Although broadly consistent with civilian studies, several discrepancies were found with civilian results reflecting potentially important differences in the structure of job conditions in the Army versus the civilian labor force. Conclusions: Principal components scores for these scales provide a parsimonious characterization of key job conditions that can be used in future studies of the effects of MOS/AOC job conditions on diverse outcomes. C1 [Gadermann, Anne M.] Univ British Columbia, St Pauls Hosp, Ctr Hlth Evaluat & Outcome Sci, Vancouver, BC V6Z IY6, Canada. [Heeringa, Steven G.] Univ Michigan, Inst Social Res, Ann Arbor, MI 48104 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Stein, Murray B.] VA San Diego Hlthcare Syst, San Diego, CA 92161 USA. [Ursano, Robert J.; Fullerton, Carol S.] Uniformed Serv Univ Hlth Sci, Ctr Study Traumat Stress, Sch Med, Dept Psychiat, Bethesda, MD 20814 USA. [Colpe, Lisa J.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gruber, Michael J.; Rosellini, Anthony J.; Sampson, Nancy A.; Zaslavsky, Alan M.; Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Schoenbaum, Michael] NIMH, Off Sci Policy Planning and Commun, Bethesda, MD 20892 USA. RP Gadermann, AM (reprint author), Univ British Columbia, St Pauls Hosp, Ctr Hlth Evaluat & Outcome Sci, 620B-1081 Burrard St, Vancouver, BC V6Z IY6, Canada. RI Gilman, Stephen/E-7632-2010 OI Gilman, Stephen/0000-0002-8331-6419 FU Department of the Army; U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) [U01MH087981] FX Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). NR 43 TC 1 Z9 1 U1 2 U2 4 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD JUL PY 2014 VL 179 IS 7 BP 752 EP 761 DI 10.7205/MILMED-D-13-00446 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AN7UN UT WOS:000340806600011 PM 25003860 ER PT J AU Kitahara, CM Flint, AJ de Gonzalez, AB Bernstein, L Brotzman, M MacInnis, RJ Moore, SC Robien, K Rosenberg, PS Singh, PN Weiderpass, E Adami, HO Anton-Culver, H Ballard-Barbash, R Buring, JE Freedman, DM Fraser, GE Freeman, LEB Gapstur, SM Gaziano, JM Giles, GG Hakansson, N Hoppin, JA Hu, FB Koenig, K Linet, MS Park, Y Patel, AV Purdue, MP Schairer, C Sesso, HD Visvanathan, K White, E Wolk, A Zeleniuch-Jacquotte, A Hartge, P AF Kitahara, Cari M. Flint, Alan J. de Gonzalez, Amy Berrington Bernstein, Leslie Brotzman, Michelle MacInnis, Robert J. Moore, Steven C. Robien, Kim Rosenberg, Philip S. Singh, Pramil N. Weiderpass, Elisabete Adami, Hans Olov Anton-Culver, Hoda Ballard-Barbash, Rachel Buring, Julie E. Freedman, D. Michal Fraser, Gary E. Freeman, Laura E. Beane Gapstur, Susan M. Gaziano, John Michael Giles, Graham G. Hakansson, Niclas Hoppin, Jane A. Hu, Frank B. Koenig, Karen Linet, Martha S. Park, Yikyung Patel, Alpa V. Purdue, Mark P. Schairer, Catherine Sesso, Howard D. Visvanathan, Kala White, Emily Wolk, Alicja Zeleniuch-Jacquotte, Anne Hartge, Patricia TI Association between Class III Obesity (BMI of 40-59 kg/m(2)) and Mortality: A Pooled Analysis of 20 Prospective Studies SO PLOS MEDICINE LA English DT Article ID BODY-MASS INDEX; CARDIOVASCULAR RISK-FACTORS; BASE-LINE CHARACTERISTICS; MORBID-OBESITY; BREAST-CANCER; WEIGHT-LOSS; PHYSICAL-ACTIVITY; UNITED-STATES; PREDICTING MORTALITY; RANDOMIZED-TRIAL AB Background: The prevalence of class III obesity (body mass index [BMI]>= 40 kg/m(2)) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity. Methods and Findings: In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex-and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m(2)) compared with those classified as normal weight (BMI 18.5-24.9 kg/m(2)). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (19762009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m(2) was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report. Conclusions: Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. C1 [Kitahara, Cari M.; de Gonzalez, Amy Berrington; Moore, Steven C.; Rosenberg, Philip S.; Freedman, D. Michal; Freeman, Laura E. Beane; Linet, Martha S.; Park, Yikyung; Purdue, Mark P.; Schairer, Catherine; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Flint, Alan J.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Flint, Alan J.; Adami, Hans Olov; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Brotzman, Michelle] WESTAT Corp, Rockville, MD 20850 USA. [MacInnis, Robert J.; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [MacInnis, Robert J.; Giles, Graham G.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Robien, Kim] George Washington Univ, Dept Epidemiol & Biostat, Sch Publ Hlth & Hlth Serv, Washington, DC USA. [Singh, Pramil N.] Loma Linda Univ, Sch Publ Hlth, Ctr Hlth Res, Loma Linda, CA 92350 USA. [Weiderpass, Elisabete; Adami, Hans Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Ballard-Barbash, Rachel] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Buring, Julie E.; Gaziano, John Michael; Sesso, Howard D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.; Gaziano, John Michael; Sesso, Howard D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Aging, Boston, MA 02115 USA. [Fraser, Gary E.] Loma Linda Univ, Sch Publ Hlth, Dept Epidemiol Biostat & Populat Med, Loma Linda, CA 92350 USA. [Gapstur, Susan M.; Patel, Alpa V.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Gaziano, John Michael] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Hakansson, Niclas; Wolk, Alicja] Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, Stockholm, Sweden. [Hoppin, Jane A.] NIEHS, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Koenig, Karen; Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA. [Koenig, Karen; Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Inst Canc, New York, NY USA. [Visvanathan, Kala] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [White, Emily] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Kitahara, CM (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM kitaharac@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015; Purdue, Mark/C-9228-2016; Moore, Steven/D-8760-2016; Weiderpass, Elisabete/M-4029-2016; Kitahara, Cari/R-8267-2016; OI Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Park, Yikyung/0000-0002-6281-489X; Beane Freeman, Laura/0000-0003-1294-4124; Purdue, Mark/0000-0003-1177-3108; Moore, Steven/0000-0002-8169-1661; Weiderpass, Elisabete/0000-0003-2237-0128; MacInnis, Robert/0000-0002-1627-5047 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. Certain data were provided by the Vital Statistics Administration, Maryland Department of Health and Mental Hygiene, Baltimore, Maryland. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 48 Z9 48 U1 2 U2 33 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD JUL PY 2014 VL 11 IS 7 AR e1001673 DI 10.1371/journal.pmed.1001673 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA AN5FZ UT WOS:000340617400006 PM 25003901 ER PT J AU Costa-da-Silva, AL Marinotti, O Ribeiro, JMC Silva, MCP Lopes, AR Barros, MS Sa-Nunes, A Kojin, BB Carvalho, E Suesdek, L Silva-Neto, MAC James, AA Capurro, ML AF Costa-da-Silva, Andre L. Marinotti, Osvaldo Ribeiro, Jose M. C. Silva, Maria C. P. Lopes, Adriana R. Barros, Michele S. Sa-Nunes, Anderson Kojin, Bianca B. Carvalho, Eneas Suesdek, Lincoln Silva-Neto, Mario Alberto C. James, Anthony A. Capurro, Margareth L. TI Transcriptome Sequencing and Developmental Regulation of Gene Expression in Anopheles aquasalis SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID NEOTROPICAL MALARIA VECTOR; AEDES-AEGYPTI MOSQUITOS; BLOOD MEAL; PROTEIN PHOSPHATASE; TRYPSIN GENES; GAMBIAE; DATABASE; INFECTION; DIGESTION; MIDGUT AB Background: Anopheles aquasalis is a major malaria vector in coastal areas of South and Central America where it breeds preferentially in brackish water. This species is very susceptible to Plasmodium vivax and it has been already incriminated as responsible vector in malaria outbreaks. There has been no high-throughput investigation into the sequencing of An. aquasalis genes, transcripts and proteins despite its epidemiological relevance. Here we describe the sequencing, assembly and annotation of the An. aquasalis transcriptome. Methodology/Principal Findings: A total of 419 thousand cDNA sequence reads, encompassing 164 million nucleotides, were assembled in 7544 contigs of >= 2 sequences, and 1999 singletons. The majority of the An. aquasalis transcripts encode proteins with their closest counterparts in another neotropical malaria vector, An. darlingi. Several analyses in different protein databases were used to annotate and predict the putative functions of the deduced An. aquasalis proteins. Larval and adult-specific transcripts were represented by 121 and 424 contig sequences, respectively. Fifty-one transcripts were only detected in blood-fed females. The data also reveal a list of transcripts up-or down-regulated in adult females after a blood meal. Transcripts associated with immunity, signaling networks and blood feeding and digestion are discussed. Conclusions/Significance: This study represents the first large-scale effort to sequence the transcriptome of An. aquasalis. It provides valuable information that will facilitate studies on the biology of this species and may lead to novel strategies to reduce malaria transmission on the South American continent. The An. aquasalis transcriptome is accessible at http://exon.niaid.nih.gov/transcriptome/An_aquasalis/Anaquexcel.xlsx. C1 [Costa-da-Silva, Andre L.; Silva, Maria C. P.; Suesdek, Lincoln; Capurro, Margareth L.] Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, Lab Mosquitos Geneticamente Modificados, BR-05508 Sao Paulo, Brazil. [Costa-da-Silva, Andre L.; Sa-Nunes, Anderson; Silva-Neto, Mario Alberto C.; Capurro, Margareth L.] INCT EM, Inst Nacl Ciencia & Tecnol Entomol Mol, Rio De Janeiro, Brazil. [Marinotti, Osvaldo; Kojin, Bianca B.; James, Anthony A.] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA. [Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Lopes, Adriana R.] Inst Butantan, Lab Bioquim & Biofis, Sao Paulo, Brazil. [Barros, Michele S.; Sa-Nunes, Anderson] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, Lab Imunol Expt, BR-05508 Sao Paulo, Brazil. [Carvalho, Eneas] Inst Butantan, Ctr Biotechnol, Sao Paulo, Brazil. [Suesdek, Lincoln] Inst Butantan, Parasitol Lab, Sao Paulo, Brazil. [Silva-Neto, Mario Alberto C.] Univ Fed Rio de Janeiro, Lab Sinalizacao Celular, Inst Bioquim Med, Rio De Janeiro, Brazil. [James, Anthony A.] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. RP Costa-da-Silva, AL (reprint author), Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, Lab Mosquitos Geneticamente Modificados, BR-05508 Sao Paulo, Brazil. EM mcapurro@icb.usp.br RI Costa-da-Silva, Andre/F-7874-2012; Silva, maria/I-4060-2014; Sa-Nunes, Anderson/D-8667-2012; Capurro, Margareth/F-8679-2012; Ribeiro, Jose/J-7011-2015; Lopes, Adriana/I-9551-2014; OI Costa-da-Silva, Andre/0000-0002-7615-7376; Sa-Nunes, Anderson/0000-0002-1859-4973; Capurro, Margareth/0000-0002-7480-2116; Lopes, Adriana/0000-0002-9741-2110; Marinotti, Osvaldo/0000-0002-7173-7160; Ribeiro, Jose/0000-0002-9107-0818 FU Brazilian Malaria Network (MCT/CNPq/MS/SCTIE/DECIT/PRONEX) [555648/2009-5]; Sao Paulo Research Foundation (FAPESP) [2009/53637-0]; Research Network on Bioactive Molecules from Arthropod Vectors (NAP-MOBIARVE, University of Sao Paulo); NIH NIAID [AI29746]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This work was funded by grants from Brazilian Malaria Network (MCT/CNPq/MS/SCTIE/DECIT/PRONEX 555648/2009-5), grant # 2009/53637-0 from Sao Paulo Research Foundation (FAPESP) and from Research Network on Bioactive Molecules from Arthropod Vectors (NAP-MOBIARVE, University of Sao Paulo). OM and AAJ were supported in part by a grant from the NIH NIAID (AI29746). JMCR was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. Because JMCR is a government employee and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U. S. subject to a government use license. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 97 TC 5 Z9 5 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2014 VL 8 IS 7 AR e3005 DI 10.1371/journal.pntd.0003005 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AN4IQ UT WOS:000340551500051 PM 25033462 ER PT J AU Garamszegi, S Yen, JY Honko, AN Geisbert, JB Rubins, KH Geisbert, TW Xia, Y Hensley, LE Connor, JH AF Garamszegi, Sara Yen, Judy Y. Honko, Anna N. Geisbert, Joan B. Rubins, Kathleen H. Geisbert, Thomas W. Xia, Yu Hensley, Lisa E. Connor, John H. TI Transcriptional Correlates of Disease Outcome in Anticoagulant-Treated Non-Human Primates Infected with Ebolavirus SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID BINDING-PROTEIN-BETA; HEMORRHAGIC-FEVER; VIRUS INFECTION; HEPATITIS-C; MARBURG VIRUSES; GENE-EXPRESSION; DENDRITIC CELLS; MICROARRAY DATA; POSTEXPOSURE TREATMENT; CYNOMOLGUS MACAQUES AB Ebola virus (EBOV) infection in humans and non-human primates (NHPs) is highly lethal, and there is limited understanding of the mechanisms associated with pathogenesis and survival. Here, we describe a transcriptomic analysis of NHPs that survived lethal EBOV infection, compared to NHPs that did not survive. It has been previously demonstrated that anticoagulant therapeutics increase the survival rate in EBOV-infected NHPs, and that the characteristic transcriptional profile of immune response changes in anticoagulant-treated NHPs. In order to identify transcriptional signatures that correlate with survival following EBOV infection, we compared the mRNA expression profile in peripheral blood mononuclear cells from EBOV-infected NHPs that received anticoagulant treatment, to those that did not receive treatment. We identified a small set of 20 genes that are highly confident predictors and can accurately distinguish between surviving and non-surviving animals. In addition, we identified a larger predictive signature of 238 genes that correlated with disease outcome and treatment; this latter signature was associated with a variety of host responses, such as the inflammatory response, T cell death, and inhibition of viral replication. Notably, among survival-associated genes were subsets of genes that are transcriptionally regulated by (1) CCAAT/enhancer-binding protein alpha, (2) tumor protein 53, and (3) megakaryoblastic leukemia 1 and myocardin-like protein 2. These pathways merit further investigation as potential transcriptional signatures of host immune response to EBOV infection. C1 [Garamszegi, Sara; Xia, Yu; Connor, John H.] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Yen, Judy Y.; Connor, John H.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02215 USA. [Yen, Judy Y.; Connor, John H.] Boston Univ, Natl Emerging Infect Dis Labs, Boston, MA 02215 USA. [Honko, Anna N.] US Army Med Res Inst Infect Dis, Frederick, MD USA. [Geisbert, Joan B.; Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Rubins, Kathleen H.] Natl Aeronaut & Space Adm, Houston, TX USA. [Xia, Yu] McGill Univ, Dept Bioengn, Montreal, PQ, Canada. [Hensley, Lisa E.] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD USA. RP Garamszegi, S (reprint author), Boston Univ, Bioinformat Program, Boston, MA 02215 USA. EM jhconnor@bu.edu OI Connor, John/0000-0002-8867-7256; Xia, Yu/0000-0002-5596-5518; Honko, Anna/0000-0001-9165-148X FU National Science Foundation (NSF) Integrative Graduate Education and Research Traineeship [DGE-0654108]; NSF Graduate Research Fellowship [DGE-0741448]; Pharmaceutical Research and Manufacturers of America Foundation; Joint Science and Technology Office for Chemical and Biological Defense; Defense Threat Reduction Agency [JSTO-CBD 4.0021.08.RD.B]; USAMRIID [19595, 188261]; JSTO-CBD FX SG was supported by a fellowship from the National Science Foundation (NSF) Integrative Graduate Education and Research Traineeship (DGE-0654108) and an NSF Graduate Research Fellowship (DGE-0741448). YX was supported by a Research Starter Grant in Informatics from the Pharmaceutical Research and Manufacturers of America Foundation. Funding for experimental animal studies was provided by the Joint Science and Technology Office for Chemical and Biological Defense and the Defense Threat Reduction Agency (JSTO-CBD 4.0021.08.RD.B). This work was conducted at USAMRIID under project numbers 19595 and 188261 supported by JSTO-CBD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 83 TC 7 Z9 7 U1 0 U2 24 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2014 VL 8 IS 7 AR e3061 DI 10.1371/journal.pntd.0003061 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AN4IQ UT WOS:000340551500076 PM 25079789 ER PT J AU Minnick, MF Anderson, BE Lima, A Battisti, JM Lawyer, PG Birtles, RJ AF Minnick, Michael F. Anderson, Burt E. Lima, Amorce Battisti, James M. Lawyer, Phillip G. Birtles, Richard J. TI Oroya Fever and Verruga Peruana: Bartonelloses Unique to South America SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Review ID OUTER-MEMBRANE PROTEINS; FLIES DIPTERA PSYCHODIDAE; REAL-TIME PCR; PHLEBOTOMUS-PAPATASI DIPTERA; HUMAN-IMMUNODEFICIENCY-VIRUS; ZAMORA-CHINCHIPE PROVINCE; ENDOTHELIAL GROWTH-FACTOR; SCRATCH DISEASE PATIENTS; CITRATE SYNTHASE GENE; HOST-CELL INTERACTION AB Bartonella bacilliformis is the bacterial agent of Carrion's disease and is presumed to be transmitted between humans by phlebotomine sand flies. Carrion's disease is endemic to high-altitude valleys of the South American Andes, and the first reported outbreak (1871) resulted in over 4,000 casualties. Since then, numerous outbreaks have been documented in endemic regions, and over the last two decades, outbreaks have occurred at atypical elevations, strongly suggesting that the area of endemicity is expanding. Approximately 1.7 million South Americans are estimated to be at risk in an area covering roughly 145,000 km(2) of Ecuador, Colombia, and Peru. Although disease manifestations vary, two disparate syndromes can occur independently or sequentially. The first, Oroya fever, occurs approximately 60 days following the bite of an infected sand fly, in which infection of nearly all erythrocytes results in an acute hemolytic anemia with attendant symptoms of fever, jaundice, and myalgia. This phase of Carrion's disease often includes secondary infections and is fatal in up to 88% of patients without antimicrobial intervention. The second syndrome, referred to as verruga peruana, describes the endothelialcell-derived, blood-filled tumors that develop on the surface of the skin. Verrugae are rarely fatal, but can bleed and scar the patient. Moreover, these persistently infected humans provide a reservoir for infecting sand flies and thus maintaining B. bacilliformis in nature. Here, we discuss the current state of knowledge regarding this life-threatening, neglected bacterial pathogen and review its host-cell parasitism, molecular pathogenesis, phylogeny, sand fly vectors, diagnostics, and prospects for control. C1 [Minnick, Michael F.; Battisti, James M.] Univ Montana, Div Biol Sci, Missoula, MT 59812 USA. [Anderson, Burt E.; Lima, Amorce] Univ S Florida, Morsani Coll Med, Dept Mol Med, Tampa, FL USA. [Lawyer, Phillip G.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Birtles, Richard J.] Univ Salford, Sch Environm & Life Sci, Salford M5 4WT, Lancs, England. RP Minnick, MF (reprint author), Univ Montana, Div Biol Sci, Missoula, MT 59812 USA. EM mike.minnick@mso.umt.edu FU NIH [R21 AI095804] FX MFM is supported by NIH grant R21 AI095804. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 218 TC 13 Z9 14 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2014 VL 8 IS 7 AR e2919 DI 10.1371/journal.pntd.0002919 PG 19 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AN4IQ UT WOS:000340551500012 PM 25032975 ER PT J AU Okamoto, KW Robert, MA Gould, F Lloyd, AL AF Okamoto, Kenichi W. Robert, Michael A. Gould, Fred Lloyd, Alun L. TI Feasible Introgression of an Anti-pathogen Transgene into an Urban Mosquito Population without Using Gene-Drive SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID AEDES-AEGYPTI POPULATION; GENETICALLY-MODIFIED INSECTS; DENGUE-VIRUS TRANSMISSION; VECTOR MOSQUITOS; MALARIA CONTROL; BORNE DISEASES; STERILE MALES; PEST-CONTROL; WOLBACHIA; RELEASE AB Background: Introgressing anti-pathogen constructs into wild vector populations could reduce disease transmission. It is generally assumed that such introgression would require linking an anti-pathogen gene with a selfish genetic element or similar technologies. Yet none of the proposed transgenic anti-pathogen gene-drive mechanisms are likely to be implemented as public health measures in the near future. Thus, much attention now focuses instead on transgenic strategies aimed at mosquito population suppression, an approach generally perceived to be practical. By contrast, aiming to replace vector competent mosquito populations with vector incompetent populations by releasing mosquitoes carrying a single anti-pathogen gene without a gene-drive mechanism is widely considered impractical. Methodology/Principal Findings: Here we use Skeeter Buster, a previously published stochastic, spatially explicit model of Aedes aegypti to investigate whether a number of approaches for releasing mosquitoes with only an anti-pathogen construct would be efficient and effective in the tropical city of Iquitos, Peru. To assess the performance of such releases using realistic release numbers, we compare the transient and long-term effects of this strategy with two other genetic control strategies that have been developed in Ae. aegypti: release of a strain with female-specific lethality, and a strain with both female-specific lethality and an anti-pathogen gene. We find that releasing mosquitoes carrying only an anti-pathogen construct can substantially decrease vector competence of a natural population, even at release ratios well below that required for the two currently feasible alternatives that rely on population reduction. Finally, although current genetic control strategies based on population reduction are compromised by immigration of wild-type mosquitoes, releasing mosquitoes carrying only an anti-pathogen gene is considerably more robust to such immigration. Conclusions/Significance: Contrary to the widely held view that transgenic control programs aimed at population replacement require linking an anti-pathogen gene to selfish genetic elements, we find releasing mosquitoes in numbers much smaller than those considered necessary for transgenic population reduction can result in comparatively rapid and robust population replacement. In light of this non-intuitive result, directing efforts to improve rearing capacity and logistical support for implementing releases, and reducing the fitness costs of existing recombinant technologies, may provide a viable, alternative route to introgressing anti-pathogen transgenes under field conditions. C1 [Okamoto, Kenichi W.; Gould, Fred] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Robert, Michael A.; Lloyd, Alun L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Robert, Michael A.; Lloyd, Alun L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. [Robert, Michael A.] Univ New Mexico, Dept Biol, Albuquerque, NM 87131 USA. [Robert, Michael A.] Univ New Mexico, Dept Math & Stat, Albuquerque, NM 87131 USA. [Gould, Fred; Lloyd, Alun L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Okamoto, KW (reprint author), N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. EM kenichi_okamoto@ncsu.edu FU National Institutes of Health (NIH) grant [R01AI091980-01A1]; Foundation for the NIH through the Bill and Melinda Gates Foundation Grand Challenges in Global Health initiative; University of PretoriaNorth Carolina State University Strategic Collaboration Seed Grant FX This work is funded in part by National Institutes of Health (NIH) grant R01AI091980-01A1, a grant to the Regents of the University of California from the Foundation for the NIH through the Bill and Melinda Gates Foundation Grand Challenges in Global Health initiative, and in part by a University of PretoriaNorth Carolina State University Strategic Collaboration Seed Grant (to ALL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 10 Z9 11 U1 4 U2 24 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2014 VL 8 IS 7 AR e2827 DI 10.1371/journal.pntd.0002827 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AN4IQ UT WOS:000340551500001 PM 24992213 ER PT J AU Stoddard, ST Wearing, HJ Reiner, RC Morrison, AC Astete, H Vilcarromero, S Alvarez, C Ramal-Asayag, C Sihuincha, M Rocha, C Halsey, ES Scott, TW Kochel, TJ Forshey, BM AF Stoddard, Steven T. Wearing, Helen J. Reiner, Robert C., Jr. Morrison, Amy C. Astete, Helvio Vilcarromero, Stalin Alvarez, Carlos Ramal-Asayag, Cesar Sihuincha, Moises Rocha, Claudio Halsey, Eric S. Scott, Thomas W. Kochel, Tadeusz J. Forshey, Brett M. TI Long-Term and Seasonal Dynamics of Dengue in Iquitos, Peru SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID AEDES-AEGYPTI DIPTERA; VIRUS TRANSMISSION; TEMPERATURE-FLUCTUATIONS; HEMORRHAGIC-FEVER; CLIMATE VARIABILITY; GLOBAL DISTRIBUTION; SOUTH-AMERICA; PUERTO-RICO; EPIDEMICS; THAILAND AB Introduction: Long-term disease surveillance data provide a basis for studying drivers of pathogen transmission dynamics. Dengue is a mosquito-borne disease caused by four distinct, but related, viruses (DENV-1-4) that potentially affect over half the world's population. Dengue incidence varies seasonally and on longer time scales, presumably driven by the interaction of climate and host susceptibility. Precise understanding of dengue dynamics is constrained, however, by the relative paucity of laboratory-confirmed longitudinal data. Methods: We studied 10 years (2000-2010) of laboratory-confirmed, clinic-based surveillance data collected in Iquitos, Peru. We characterized inter and intra-annual patterns of dengue dynamics on a weekly time scale using wavelet analysis. We explored the relationships of case counts to climatic variables with cross-correlation maps on annual and trimester bases. Findings: Transmission was dominated by single serotypes, first DENV-3 (2001-2007) then DENV-4 (2008-2010). After 2003, incidence fluctuated inter-annually with outbreaks usually occurring between October and April. We detected a strong positive autocorrelation in case counts at a lag of similar to 70 weeks, indicating a shift in the timing of peak incidence year-to-year. All climatic variables showed modest seasonality and correlated weakly with the number of reported dengue cases across a range of time lags. Cases were reduced after citywide insecticide fumigation if conducted early in the transmission season. Conclusions: Dengue case counts peaked seasonally despite limited intra-annual variation in climate conditions. Contrary to expectations for this mosquito-borne disease, no climatic variable considered exhibited a strong relationship with transmission. Vector control operations did, however, appear to have a significant impact on transmission some years. Our results indicate that a complicated interplay of factors underlie DENV transmission in contexts such as Iquitos. C1 [Stoddard, Steven T.; Reiner, Robert C., Jr.; Morrison, Amy C.; Scott, Thomas W.] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. [Stoddard, Steven T.; Reiner, Robert C., Jr.; Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Wearing, Helen J.] Univ New Mexico, Albuquerque, NM 87131 USA. [Morrison, Amy C.; Astete, Helvio; Vilcarromero, Stalin; Rocha, Claudio; Halsey, Eric S.; Forshey, Brett M.] US Naval Med Res Unit 6, Lima, Peru. [Alvarez, Carlos] Loreto Reg Hlth Dept, Iquitos, Peru. [Ramal-Asayag, Cesar] Hosp Reg Iquitos, Iquitos, Peru. [Sihuincha, Moises] Hosp Apoyo Iquitos, Iquitos, Peru. [Kochel, Tadeusz J.] US Naval Med Res Ctr, Silver Spring, MD USA. RP Stoddard, ST (reprint author), Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA. EM ststoddard@gmail.com OI Vilcarromero, Stalin/0000-0002-9097-0638 FU Armed Forces Health Surveillance Center Global Emerging Infections Systems Research Program [847705.82000.25GB.B0016]; NIH/NIGMS Models of Infectious Disease Agent Study (MIDAS) program [U01-GM097661-01] FX This study was supported by the Armed Forces Health Surveillance Center Global Emerging Infections Systems Research Program (847705.82000.25GB.B0016). HJW was partially supported by a grant from the NIH/NIGMS Models of Infectious Disease Agent Study (MIDAS) program, U01-GM097661-01. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Ministries of Health of Peru or Department of the Navy, Department of Defense, or the U. S. Government. 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 4 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2014 VL 8 IS 7 AR e3003 DI 10.1371/journal.pntd.0003003 PG 15 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AN4IQ UT WOS:000340551500049 PM 25033412 ER PT J AU Georgopoulos, PG Brinkerhoff, CJ Isukapalli, S Dellarco, M Landrigan, PJ Lioy, PJ AF Georgopoulos, Panos G. Brinkerhoff, Christopher J. Isukapalli, Sastry Dellarco, Michael Landrigan, Philip J. Lioy, Paul J. TI A Tiered Framework for Risk-Relevant Characterization and Ranking of Chemical Exposures: Applications to the National Children's Study (NCS) SO RISK ANALYSIS LA English DT Article DE Birth outcomes; Exposure Information System (EXIS); Modeling Environment for Total Risk studies (MENTOR); Prioritization and Ranking of Toxic Exposures with GIS Extension (PRoTEGE); risk-relevant exposure indices (EIs); Tiered Exposure Ranking (TiER) framework ID BIOLOGICAL-SYSTEMS; DOSE ASSESSMENT; UNCERTAINTY; INDEXES AB A challenge for large-scale environmental health investigations such as the National Children's Study (NCS), is characterizing exposures to multiple, co-occurring chemical agents with varying spatiotemporal concentrations and consequences modulated by biochemical, physiological, behavioral, socioeconomic, and environmental factors. Such investigations can benefit from systematic retrieval, analysis, and integration of diverse extant information on both contaminant patterns and exposure-relevant factors. This requires development, evaluation, and deployment of informatics methods that support flexible access and analysis of multiattribute data across multiple spatiotemporal scales. Anew "Tiered Exposure Ranking" (TiER) framework, developed to support various aspects of risk-relevant exposure characterization, is described here, with examples demonstrating its application to the NCS. TiER utilizes advances in informatics computational methods, extant database content and availability, and integrative environmental/exposure/biological modeling to support both "discovery-driven" and "hypothesis-driven" analyses. "Tier 1" applications focus on "exposomic" pattern recognition for extracting information from multidimensional data sets, whereas second and higher tier applications utilize mechanistic models to develop risk-relevant exposure metrics for populations and individuals. In this article, "tier 1" applications of TiER explore identification of potentially causative associations among risk factors, for prioritizing further studies, by considering publicly available demographic/socioeconomic, behavioral, and environmental data in relation to two health endpoints (preterm birth and low birth weight). A "tier 2" application develops estimates of pollutant mixture inhalation exposure indices for NCS counties, formulated to support risk characterization for these endpoints. Applications of TiER demonstrate the feasibility of developing risk-relevant exposure characterizations for pollutants using extant environmental and demographic/socioeconomic data. C1 [Georgopoulos, Panos G.; Brinkerhoff, Christopher J.; Isukapalli, Sastry; Lioy, Paul J.] Rutgers State Univ, EOHSI, Piscataway, NJ 08854 USA. [Dellarco, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NICHD, Bethesda, MD USA. [Landrigan, Philip J.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP Georgopoulos, PG (reprint author), Rutgers State Univ, EOHSI, 170 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM panosg@ccl.rutgers.edu FU National Children's Study Queens Vanguard Center - Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [0258-325-4609]; NIEHS-sponsored Center for Environmental Exposures and Disease (CEED) at EOHSI [NIEHS P30ES005022] FX Support for this work has been provided by the National Children's Study Queens Vanguard Center, funded in whole or in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, under Contract 0258-325-4609. Further support was provided by the NIEHS-sponsored Center for Environmental Exposures and Disease (CEED) at EOHSI, under Grant NIEHS P30ES005022. Appreciation is extended to Linda Everett of EOHSI for editorial, formatting, and graphics assistance. NR 36 TC 4 Z9 4 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0272-4332 EI 1539-6924 J9 RISK ANAL JI Risk Anal. PD JUL PY 2014 VL 34 IS 7 BP 1299 EP 1316 DI 10.1111/risa.12165 PG 18 WC Public, Environmental & Occupational Health; Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Public, Environmental & Occupational Health; Mathematics; Mathematical Methods In Social Sciences GA AN4PU UT WOS:000340570900012 PM 24467550 ER PT J AU Wang, D Cortes-Puch, I Sun, JF Solomon, SB Kanias, T Remy, KE Feng, J Alimchandani, M Quezado, M Helms, C Perlegas, A Gladwin, MT Kim-Shapiro, DB Klein, HG Natanson, C AF Wang, Dong Cortes-Puch, Irene Sun, Junfeng Solomon, Steven B. Kanias, Tamir Remy, Kenneth E. Feng, Jing Alimchandani, Meghna Quezado, Martha Helms, Christine Perlegas, Andreas Gladwin, Mark T. Kim-Shapiro, Daniel B. Klein, Harvey G. Natanson, Charles TI Transfusion of older stored blood worsens outcomes in canines depending on the presence and severity of pneumonia SO TRANSFUSION LA English DT Article ID CELL-FREE HEMOGLOBIN; TRANSFERRIN-BOUND IRON; STAPHYLOCOCCUS-AUREUS; NITRIC-OXIDE; SEPTIC SHOCK; HEMODIALYSIS-PATIENTS; PLASMA HEMOGLOBIN; STORAGE LESION; IN-VIVO; INFLAMMATION AB BACKGROUND: In experimental pneumonia we found that transfused older blood increased mortality and lung injury that was associated with increased in vivo hemolysis and elevated plasma cell-free hemoglobin (CFH), non-transferrin-bound iron (NTBI), and plasma labile iron (PLI) levels. In this study, we additionally analyze identically treated animals that received lower or higher bacterial doses. STUDY DESIGN AND METHODS: Two-year-old purpose-bred beagles (n = 48) challenged intrabronchially with Staphylococcus aureus (0 [n = 8], 1.0 x 10(9) [n = 8], 1.25 x 10(9) [n = 24], and >= 1.5 x 10(9) [n = 8] colony-forming units/kg) were exchange transfused with either 7- or 42-day-old canine universal donor blood (80 mL/kg in four divided doses). RESULTS: The greater increases in CFH with older blood over days after exchange proved relatively independent of bacterial dose. The lesser increases in CFH observed with fresher blood were bacterial dose dependent potentially related to bacterial hemolysins. Without bacterial challenge, levels of CFH, NTBI, and PLI were significantly higher with older versus fresher blood transfusion but there was no significant measurable injury. With higher-dose bacterial challenge, the elevated NTBI and PLI levels declined more rapidly and to a greater extent after transfusion with older versus fresher blood, and older blood was associated with significantly worse shock, lung injury, and mortality. CONCLUSION: The augmented in vivo hemolysis of transfused older red blood cells (RBCs) appears to result in excess plasma CFH and iron release, which requires the presence of established infection to worsen outcome. These data suggest that transfused older RBCs increase the risks from infection in septic subjects. C1 [Wang, Dong; Cortes-Puch, Irene; Sun, Junfeng; Solomon, Steven B.; Remy, Kenneth E.; Feng, Jing; Natanson, Charles] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Klein, Harvey G.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Kanias, Tamir; Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Alimchandani, Meghna; Quezado, Martha] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Helms, Christine; Perlegas, Andreas; Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Helms, Christine; Perlegas, Andreas; Kim-Shapiro, Daniel B.] Wake Forest Univ, Translat Sci Ctr, Winston Salem, NC 27109 USA. [Gladwin, Mark T.] Univ Pittsburgh, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. RP Natanson, C (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM cnatanson@cc.nih.gov RI Kanias, Tamir/K-2384-2016; OI Kanias, Tamir/0000-0001-6558-0913; Remy, Kenneth/0000-0001-5222-9884 FU U.S. government FX We thank Juli Maltagliati and Kelly Byrne for assistance in producing the manuscript. The study was performed as part of U.S. government-funded research; however, opinions expressed are not necessarily those of the NIH. NR 52 TC 15 Z9 15 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUL PY 2014 VL 54 IS 7 BP 1712 EP 1724 DI 10.1111/trf.12607 PG 13 WC Hematology SC Hematology GA AN4ZZ UT WOS:000340600100006 PM 24588210 ER PT J AU Anliker, M von Zabern, I Hochsmann, B Kyrieleis, H Dohna-Schwake, C Flegel, WA Schrezenmeier, H Weinstock, C AF Anliker, Markus von Zabern, Inge Hoechsmann, Britta Kyrieleis, Henriette Dohna-Schwake, Christian Flegel, Willy A. Schrezenmeier, Hubert Weinstock, Christof TI A new blood group antigen is defined by anti-CD59, detected in a CD59-deficient patient SO TRANSFUSION LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; MEMBRANE-ATTACK COMPLEX; CD59 DEFICIENCY; PROTEIN AB BACKGROUND: CD59 is a cell surface glycoprotein of approximately 20 kDa limiting the lytic activity of the terminal complement complex C5b-9. Although CD59 is known as a red blood cell (RBC) antigen defined by monoclonal antibodies, it so far has not been identified as a blood group antigen, since the description of a human alloantibody was missing. In this study we show the presence of an anti-CD59 in a patient affected by a homozygous CD59 deficiency. STUDY DESIGN AND METHODS: RBC CD59 and CD55 were determined by flow cytometry or by the column agglutination technique using monoclonal antisera. Commercially available His-tagged recombinant soluble CD59 protein was used to inhibit anti-CD59. RESULTS: Seven cases of an isolated CD59 deficiency due to three distinct null alleles of the CD59 gene have been published so far. Recently we described the CD59-null allele c.146delA in a young child of heterozygous parents. Her plasma contained an alloantibody directed against the high-prevalence RBC antigen CD59. The antibody specificity was identified using soluble recombinant human CD59 protein, which blocked the reactivity of the patient's antibody and of monoclonal anti-CD59 but not of monoclonal anti-CD55. In addition, RBC alloantibodies such as anti-K, anti-C, anti-c, or anti-Fy(a) remained unaffected. Therefore, inhibition by recombinant CD59 is a useful diagnostic tool to detect alloantibodies in the presence of anti-CD59. CONCLUSION: This is the first demonstration of a human anti-CD59 alloantibody, which defines CD59 as an RBC blood group antigen. CD59 represents a candidate for a new blood group system. C1 [Anliker, Markus; von Zabern, Inge; Hoechsmann, Britta; Flegel, Willy A.; Schrezenmeier, Hubert; Weinstock, Christof] Univ Ulm, German Red Cross Blood Transfus Serv Baden Wurtte, Inst Clin Transfus Med & Immunogenet Ulm, D-89069 Ulm, Germany. [Anliker, Markus; von Zabern, Inge; Hoechsmann, Britta; Flegel, Willy A.; Schrezenmeier, Hubert; Weinstock, Christof] Univ Ulm, Inst Transfus Med, D-89069 Ulm, Germany. [Kyrieleis, Henriette] Hosp Bethanien, Dept Pediat, Moers, Germany. [Dohna-Schwake, Christian] Univ Hosp Essen, Dept Pediat, Essen, Germany. [Flegel, Willy A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Weinstock, C (reprint author), Inst Klin Transfus Med & Immungenet Ulm, Helmholtzstr 10, D-89081 Ulm, Germany. EM c.weinstock@blutspende.de FU Intramural NIH HHS [Z99 CL999999] NR 15 TC 6 Z9 7 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD JUL PY 2014 VL 54 IS 7 BP 1817 EP 1822 DI 10.1111/trf.12531 PG 6 WC Hematology SC Hematology GA AN4ZZ UT WOS:000340600100018 PM 24383981 ER PT J AU Storry, JR Castilho, L Daniels, G Flegel, WA Garratty, G de Haas, M Hyland, C Lomas-Francis, C Moulds, JM Nogues, N Olsson, ML Poole, J Reid, ME Rouger, P van der Schoot, E Scott, M Tani, Y Yu, LC Wendel, S Westhoff, C Yahalom, V Zelinski, T AF Storry, J. R. Castilho, L. Daniels, G. Flegel, W. A. Garratty, G. de Haas, M. Hyland, C. Lomas-Francis, C. Moulds, J. M. Nogues, N. Olsson, M. L. Poole, J. Reid, M. E. Rouger, P. van der Schoot, E. Scott, M. Tani, Y. Yu, L. -C. Wendel, S. Westhoff, C. Yahalom, V. Zelinski, T. TI International Society of Blood Transfusion Working Party on red cell immunogenetics and blood group terminology: Cancun report (2012) SO VOX SANGUINIS LA English DT Article DE blood groups; genetics; red blood cell; terminology ID HIGH-PREVALENCE ANTIGEN; GROUP SYSTEM; NULL ALLELES; MOLECULAR CHARACTERIZATION; FORSSMAN EXPRESSION; GENETIC-BASIS; ABCG2; ABCB6; POLYAGGLUTINATION; IDENTIFICATION AB The International Society of Blood Transfusion Working Party on red cell immunogenetics and blood group terminology convened during the International congress in Cancun, July 2012. This report details the newly identified antigens in existing blood group systems and presents three new blood group systems. C1 [Storry, J. R.] Univ & Reg Labs, SE-22185 Lund, Sweden. [Castilho, L.] Univ Estadual Campinas, Hemoctr, Campinas, SP, Brazil. [Daniels, G.; Poole, J.; Scott, M.] NHSBT, Bristol Inst Transfus Sci, Bristol, Avon, England. [Daniels, G.; Poole, J.; Scott, M.] NHSBT, IBGRL, Bristol, Avon, England. [Flegel, W. A.; van der Schoot, E.] Ctr Clin, Dept Transfus Med, Bethesda, MD USA. [Garratty, G.] Amer Red Cross Blood Serv, Pomona, CA USA. [de Haas, M.] Sanquin Blood Supply, Diagnost Serv, Amsterdam, Netherlands. [Hyland, C.] Australian Red Cross Blood Serv, Brisbane, Qld, Australia. [Lomas-Francis, C.; Reid, M. E.; Westhoff, C.] New York Blood Ctr, New York, NY 10021 USA. [Moulds, J. M.] LifeShare Blood Ctr, Shreveport, LA USA. [Nogues, N.] Banc Sang & Teixits, Barcelona, Spain. [Olsson, M. L.] Lund Univ, Div Haematol & Transfus Med, Dept Lab Med, S-22100 Lund, Sweden. [Rouger, P.] Ctr Natl Reference Grp Sanguines, Paris, France. [Tani, Y.] Japanese Red Cross Kinki Block Blood Ctr, Ibaraki, Japan. [Yu, L. -C.] Mackay Mem Hosp, Taipei, Taiwan. [Yu, L. -C.] Natl Taiwan Univ, Taipei 10764, Taiwan. [Wendel, S.] Blood Bank, Hosp Sirio Libanes, Sao Paulo, Brazil. [Yahalom, V.] NBGRL Magen David Adom, Ramat Gan, Israel. [Zelinski, T.] Rh Lab, Winnipeg, MB, Canada. RP Storry, JR (reprint author), Univ & Reg Labs, Klin Gatan 21, SE-22185 Lund, Sweden. EM jill.storry@med.lu.se RI Castilho, Lilian/F-6123-2012 OI Castilho, Lilian/0000-0002-3104-647X NR 29 TC 8 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0042-9007 EI 1423-0410 J9 VOX SANG JI Vox Sang. PD JUL PY 2014 VL 107 IS 1 BP 90 EP 96 DI 10.1111/vox.12127 PG 7 WC Hematology SC Hematology GA AN5YL UT WOS:000340668900012 PM 24372289 ER PT J AU Suguro, M Yoshida, N Umino, A Kato, H Tagawa, H Nakagawa, M Fukuhara, N Karnan, S Takeuchi, I Hocking, TD Arita, K Karube, K Tsuzuki, S Nakamura, S Kinoshita, T Seto, M AF Suguro, Miyuki Yoshida, Noriaki Umino, Akira Kato, Harumi Tagawa, Hiroyuki Nakagawa, Masao Fukuhara, Noriko Karnan, Sivasundaram Takeuchi, Ichiro Hocking, Toby D. Arita, Kotaro Karube, Kennosuke Tsuzuki, Shinobu Nakamura, Shigeo Kinoshita, Tomohiro Seto, Masao TI Clonal heterogeneity of lymphoid malignancies correlates with poor prognosis SO CANCER SCIENCE LA English DT Article DE Array comparative genomic hybridization; heterogeneity; malignant lymphoma; patient outcome assessment; tumor cell population ID B-CELL LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; COMPARATIVE GENOMIC HYBRIDIZATION; RITUXIMAB PLUS CYCLOPHOSPHAMIDE; CHROMOSOMAL IMBALANCES; SOMATIC MUTATIONS; MARGINAL ZONE; CODING GENOME; CANCER; EVOLUTION AB Clonal heterogeneity in lymphoid malignancies has been recently reported in adult T-cell lymphoma/leukemia, peripheral T-cell lymphoma, not otherwise specified, and mantle cell lymphoma. Our analysis was extended to other types of lymphoma including marginal zone lymphoma, follicular lymphoma and diffuse large B-cell lymphoma. To determine the presence of clonal heterogeneity, 332 cases were examined using array comparative genomic hybridization analysis. Results showed that incidence of clonal heterogeneity varied from 25% to 69% among different types of lymphoma. Survival analysis revealed that mantle cell lymphoma and diffuse large B-cell lymphoma with clonal heterogeneity showed significantly poorer prognosis, and that clonal heterogeneity was confirmed as an independent predictor of poor prognosis for both types of lymphoma. Interestingly, 8q24.1 (MYC) gain, 9p21.3 (CDKN2A/2B) loss and 17p13 (TP53, ATP1B2, SAT2, SHBG) loss were recurrent genomic lesions among various types of lymphoma with clonal heterogeneity, suggesting at least in part that alterations of these genes may play a role in clonal heterogeneity. C1 [Suguro, Miyuki; Yoshida, Noriaki; Umino, Akira; Arita, Kotaro; Karube, Kennosuke; Tsuzuki, Shinobu; Seto, Masao] Aichi Canc Ctr, Res Inst, Div Mol Med, Nagoya, Aichi 4648681, Japan. [Kato, Harumi; Kinoshita, Tomohiro] Aichi Canc Ctr Hosp, Dept Hematol & Cell Therapy, Nagoya, Aichi 464, Japan. [Tagawa, Hiroyuki] Akita Univ, Grad Sch Med, Dept Hematol Nephrol & Rheumatol, Akita 010, Japan. [Nakagawa, Masao] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Fukuhara, Noriko] Tohoku Univ, Grad Sch Med, Dept Hematol & Rheumatol, Sendai, Miyagi 980, Japan. [Karnan, Sivasundaram] Aichi Med Univ, Sch Med, Dept Biochem, Nagakute, Aichi 48011, Japan. [Takeuchi, Ichiro] Nagoya Inst Technol, Dept Comp Sci Sci & Engn Simulat, Nagoya, Aichi, Japan. [Hocking, Toby D.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Nakamura, Shigeo] Nagoya Univ Hosp, Dept Pathol & Clin Labs, Nagoya, Aichi, Japan. RP Seto, M (reprint author), Aichi Canc Ctr, Res Inst, Div Mol Med, Chikusa Ku, 1-1 Kanokoden, Nagoya, Aichi 4648681, Japan. EM mseto@aichi-cc.jp RI Nakamura, Shigeo/I-1571-2012 FU Ministry of Health, Labour and Welfare of Japan; Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Society for the Promotion of Science; Takeda Science Foundation FX This work was supported in part by a grant-in-Aid from the Ministry of Health, Labour and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Japan Society for the Promotion of Science and from the Takeda Science Foundation (M. Seto). NR 38 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1347-9032 EI 1349-7006 J9 CANCER SCI JI Cancer Sci. PD JUL PY 2014 VL 105 IS 7 BP 897 EP 904 DI 10.1111/cas.12442 PG 8 WC Oncology SC Oncology GA AN5BA UT WOS:000340602800021 PM 24815991 ER PT J AU Kim, EJ Bond, MR Love, DC Hanover, JA AF Kim, Eun J. Bond, Michelle R. Love, Dona C. Hanover, John A. TI Chemical tools to explore nutrient-driven O-GlcNAc cycling SO CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE O-GlcNAc; O-GlcNAc transferase; OGT's activity assays; OGT's catalytic mechanism; OGT's inhibitors ID LINKED-N-ACETYLGLUCOSAMINE; PANCREATIC BETA-CELLS; INSULIN-RESISTANCE; TRANSFERASE OGT; NUCLEOCYTOPLASMIC PROTEINS; TETRATRICOPEPTIDE REPEATS; HEXOSAMINE BIOSYNTHESIS; SUBSTRATE-SPECIFICITY; CRYSTALLOGRAPHIC ANALYSIS; CARDIOVASCULAR-SYSTEM AB Posttranslational modifications (PTM) including glycosylation, phosphorylation, acetylation, methylation and ubiquitination dynamically alter the proteome. The evolutionarily conserved enzymes O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase are responsible for the addition and removal, respectively, of the nutrient-sensitive PTM of protein serine and threonine residues with O-GlcNAc. Indeed, the O-GlcNAc modification acts at every step in the "central dogma'' of molecular biology and alters signaling pathways leading to amplified or blunted biological responses. The cellular roles of OGT and the dynamic PTM O-GlcNAc have been clarified with recently developed chemical tools including high-throughput assays, structural and mechanistic studies and potent enzyme inhibitors. These evolving chemical tools complement genetic and biochemical approaches for exposing the underlying biological information conferred by O-GlcNAc cycling. C1 [Kim, Eun J.] Daegu Univ, Dept Sci Educ Chem Major, Deagu, South Korea. [Bond, Michelle R.; Love, Dona C.; Hanover, John A.] NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Hanover, JA (reprint author), NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. EM jah@helix.nih.gov FU NIDDK intramural funds (NIH); National Research Foundation of Korea [2011-0027257] FX This work was supported by NIDDK intramural funds (NIH) and the National Research Foundation of Korea (2011-0027257). NR 137 TC 2 Z9 2 U1 5 U2 28 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-9238 EI 1549-7798 J9 CRIT REV BIOCHEM MOL JI Crit. Rev. Biochem. Mol. Biol. PD JUL-AUG PY 2014 VL 49 IS 4 BP 327 EP 342 DI 10.3109/10409238.2014.931338 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN2QG UT WOS:000340429800004 PM 25039763 ER PT J AU Vourganti, S Donaldson, J Johnson, L Turkbey, B Bratslavsky, G Kotula, L AF Vourganti, Srinivas Donaldson, Jeffrey Johnson, Linda Turkbey, Baris Bratslavsky, Gennady Kotula, Leszek TI Defining the radiobiology of prostate cancer progression: An important question in translational prostate cancer research SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Review DE Prostate cancer; magnetic resonance imaging; lymph node imaging; image-guided biopsy; radiobiology ID LYMPH-NODE METASTASES; SUPERPARAMAGNETIC IRON-OXIDE; TRANSGENIC MOUSE MODEL; DIFFUSION-WEIGHTED MRI; CONTRAST-ENHANCED MRI; RADICAL PROSTATECTOMY; BIOPSY; MICE; DISSECTION; MANAGEMENT AB Prostate cancer is one of the most common malignancies affecting men worldwide. High mortality rates from advanced and metastatic prostate cancer in the United States are contrasted by a relatively indolent course in the majority of cases. This gives hope for finding methods that could direct personalized diagnostic, preventative, and treatment approaches to patients with prostate cancer. Recent advances in multiparametric magnetic resonance imaging (MP-MRI) offer a noninvasive diagnostic intervention which allows correlation of prostate tumor image characteristics with underlying biologic evidence of tumor progression. The power of MP-MRI includes examination of both local invasion and nodal disease and might overcome the challenges of analyzing the multifocal nature of prostate cancer. Future directions include a careful analysis of the genomic signature of individual prostatic lesions utilizing image-guided biopsies. This review examines the diagnostic potential of MRI in prostate cancer. C1 [Vourganti, Srinivas; Donaldson, Jeffrey; Bratslavsky, Gennady; Kotula, Leszek] SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. [Kotula, Leszek] SUNY Upstate Med Univ, Dept Biochem & Mol Biol, Syracuse, NY 13210 USA. [Johnson, Linda; Turkbey, Baris] NCI, Mol Imaging Program, Urol Branch, NIH, Bethesda, MD 20892 USA. RP Vourganti, S (reprint author), SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. EM vourgans@upstate.edu; kotulal@upstate.edu FU National Cancer Institute [R01CA161018] FX This work was supported in part by the grant from National Cancer Institute (LK) R01CA161018. NR 71 TC 1 Z9 1 U1 1 U2 8 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1535-3702 EI 1535-3699 J9 EXP BIOL MED JI Exp. Biol. Med. PD JUL PY 2014 VL 239 IS 7 BP 805 EP 812 DI 10.1177/1535370214536669 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AN2PC UT WOS:000340426800004 PM 24879423 ER PT J AU de Maturana, EL Chanok, SJ Picornell, AC Rothman, N Herranz, J Calle, ML Garcia-Closas, M Marenne, G Brand, A Tardon, A Carrato, A Silverman, DT Kogevinas, M Gianola, D Real, FX Malats, N AF Lopez de Maturana, Evangelina Chanok, Stephen J. Picornell, Antoni C. Rothman, Nathaniel Herranz, Jesus Luz Calle, M. Garcia-Closas, Montserrat Marenne, Gaelle Brand, Angela Tardon, Adonina Carrato, Alfredo Silverman, Debra T. Kogevinas, Manolis Gianola, Daniel Real, Francisco X. Malats, Nuria TI Whole Genome Prediction of Bladder Cancer Risk With the Bayesian LASSO SO GENETIC EPIDEMIOLOGY LA English DT Article DE Bayesian shrinkage method; area under the ROC curve; urothelial carcinoma of the bladder; genomic predictive model ID WIDE ASSOCIATION; CONFERS SUSCEPTIBILITY; GENETIC-VARIATION; DISEASE; MARKERS; MODELS; METAANALYSES; INDIVIDUALS; VARIANTS; LOCUS AB To build a predictive model for urothelial carcinoma of the bladder (UCB) risk combining both genomic and nongenomic data, 1,127 cases and 1,090 controls from the Spanish Bladder Cancer/EPICURO study were genotyped using the HumanHap 1M SNP array. After quality control filters, genotypes from 475,290 variants were available. Nongenomic information comprised age, gender, region, and smoking status. Three Bayesian threshold models were implemented including: (1) only genomic information, (2) only nongenomic data, and (3) both sources of information. The three models were applied to the whole population, to only nonsmokers, to male smokers, and to extreme phenotypes to potentiate the UCB genetic component. The area under the ROC curve allowed evaluating the predictive ability of each model in a 10-fold cross-validation scenario. Smoking status showed the highest predictive ability of UCB risk (AUC(test) = 0.62). On the other hand, the AUC of all genetic variants was poorer (0.53). When the extreme phenotype approach was applied, the predictive ability of the genomic model improved 15%. This study represents a first attempt to build a predictive model for UCB risk combining both genomic and nongenomic data and applying state-of-the-art statistical approaches. However, the lack of genetic relatedness among individuals, the complexity of UCB etiology, as well as a relatively small statistical power, may explain the low predictive ability for UCB risk. The study confirms the difficulty of predicting complex diseases using genetic data, and suggests the limited translational potential of findings from this type of data into public health interventions. Genet Epidemiol 38: 467-476, 2014. (C) 2014 Wiley Periodicals, Inc. C1 [Lopez de Maturana, Evangelina; Picornell, Antoni C.; Herranz, Jesus; Marenne, Gaelle; Real, Francisco X.; Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Madrid 28029, Spain. [Chanok, Stephen J.; Rothman, Nathaniel; Garcia-Closas, Montserrat; Silverman, Debra T.] NCI, Div Canc Epidemiol & Genet, US Dept HHS, Bethesda, MD 20892 USA. [Luz Calle, M.] Univ Vic, Syst Biol Dept, Barcelona, Spain. [Brand, Angela] Maastricht Univ, Maastricht, Netherlands. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Tardon, Adonina] CIBERESP, Madrid, Spain. [Carrato, Alfredo] Hosp Univ Elche, Elche, Spain. [Carrato, Alfredo; Kogevinas, Manolis] Hosp Univ Ramon y Cajal, Madrid, Spain. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Kogevinas, Manolis] Hosp del Mar, Inst Municipal Invest Med, Barcelona, Spain. [Gianola, Daniel] Univ Wisconsin, Madison, WI USA. [Real, Francisco X.] Univ Pompeu Fabra, Barcelona, Spain. RP Malats, N (reprint author), Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Melchor Fernandez Almagro 3, Madrid 28029, Spain. EM nmalats@cnio.es RI Calle, M.Luz/D-2704-2015; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Real Arribas, Francisco/H-5275-2015; Kogevinas, Manolis/C-3918-2017; Herranz Valera, Jesus/M-8657-2014 OI Calle, M.Luz/0000-0001-9334-415X; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Real Arribas, Francisco/0000-0001-9501-498X; Lopez de Maturana, Evangelina/0000-0001-9425-3911; Herranz Valera, Jesus/0000-0002-7385-1311 FU Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Spain [G03/174, 00/0745, PI051436, PI061614, PI09-02102]; Fundacio la Marato de TV3 [050830]; Red Tematica de Investigacion Cooperativa en Cancer (RTICC) [C03/009, RD06/0020, RD12/0036/0050]; Asociacion Espanola Contra el Cancer (AECC) [EU-FP7-201663-UROMOL, NIH-RO1-CA089715, CA34627]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA FX The work was partially supported by the Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III (G03/174, 00/0745, PI051436, PI061614, PI09-02102, G03/174, and Sara Borrell fellowship to E. L. M.), Spain; Fundacio la Marato de TV3 (#050830); Red Tematica de Investigacion Cooperativa en Cancer (RTICC, (RTICC, #C03/009, #RD06/0020, and #RD12/0036/0050), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF) "Una manera de hacer Europa"); Asociacion Espanola Contra el Cancer (AECC); EU-FP7-201663-UROMOL; and NIH-RO1-CA089715 and CA34627; and by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA. NR 51 TC 3 Z9 3 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2014 VL 38 IS 5 BP 467 EP 476 DI 10.1002/gepi.21809 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA AN4KN UT WOS:000340556700011 PM 24796258 ER PT J AU Dagdug, L Berezhkovskii, AM Skvortsov, AT AF Dagdug, Leonardo Berezhkovskii, Alexander M. Skvortsov, Alexei T. TI Aris-Taylor dispersion in tubes with dead ends SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID BOUNDARY-CONDITIONS; FLOWS; HOMOGENIZATION; DIFFUSION; SURFACES; CHANNEL; TRANSPORT; PHYSICS; MODELS AB This paper deals with transport of point Brownian particles in a cylindrical tube with dead ends in the presence of laminar flow of viscous fluid in the cylindrical part of the tube (Poiseuille flow). It is assumed that the dead ends are identical and are formed by spherical cavities connected to the cylindrical part of the tube by narrow necks. The focus is on the effective velocity and diffusivity of the particles as functions of the mean flow velocity and geometric parameter of the tube. Entering a dead end, the particle interrupts its propagation along the tube axis. Later it returns, and the axial motion continues. From the axial propagation point of view, the particle entry into a dead end and its successive return to the flow is equivalent to the particle reversible binding to the tube wall. The effect of reversible binding on the transport parameters has been previously studied assuming that the particle survival probability in the bound state decays as a single exponential. However, this is not the case when the particle enters a dead end, since escape from the dead end is a non-Markovian process. Our analysis of the problem consists of two steps: First, we derive expressions for the effective transport parameters in the general case of non-Markovian binding. Second, we find the effective velocity and diffusivity by substituting into these expressions known results for the moments of the particle lifetime in the dead end [L. Dagdug, A. M. Berezhkovskii, Yu. A. Makhnovskii, and V. Yu. Zitserman, J. Chem. Phys. 127, 224712 (2007)]. To check the accuracy of our theory, we compare its predictions with the values of the effective velocity and diffusivity obtained from Brownian dynamics simulations. The comparison shows excellent agreement between the theoretical predictions and numerical results. C1 [Dagdug, Leonardo] Univ Autonoma Metropolitana Iztapalapa, Dept Phys, Mexico City 09340, DF, Mexico. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Skvortsov, Alexei T.] Def Sci & Technol Org, Maritime Div, Fishermans Bend, Vic 3207, Australia. RP Dagdug, L (reprint author), Univ Autonoma Metropolitana Iztapalapa, Dept Phys, Mexico City 09340, DF, Mexico. EM alex.skvortsov@dsto.defence.gov FU National of Institutes of Health (NIH), Center for Information Technology; Consejo Nacional de Ciencia y Tecnologia [176452] FX This study was supported by the Intramural Research Program of the National of Institutes of Health (NIH), Center for Information Technology. L.D. thanks Consejo Nacional de Ciencia y Tecnologia for partial support under Grant No. 176452. NR 49 TC 1 Z9 1 U1 1 U2 8 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 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD JUL PY 2014 VL 141 IS 2 AR 024705 DI 10.1063/1.4885854 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA AN0IY UT WOS:000340269200045 PM 25028036 ER PT J AU Shurin, SB Castle, VP AF Shurin, Susan B. Castle, Valerie P. TI Pediatric Research Impacts and Benefits from All of Biomedical Science SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID DISORDERS; COHORT C1 [Shurin, Susan B.] NHLBI, NIH, Bethesda, MD 20892 USA. [Castle, Valerie P.] Univ Michigan Hlth Syst, Mott Childrens Hosp, Dept Pediat, Ann Arbor, MI USA. RP Shurin, SB (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUL PY 2014 VL 165 IS 1 BP 4 EP 5 DI 10.1016/j.jpeds.2014.03.027 PG 2 WC Pediatrics SC Pediatrics GA AM3BS UT WOS:000339727100001 PM 24973158 ER PT J AU Wassermann, E AF Wassermann, Eric TI Transcranial magnetic stimulation may improve symptoms of hemiparesis SO JOURNAL OF PEDIATRICS LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Wassermann, E (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUL PY 2014 VL 165 IS 1 BP 208 EP 209 PG 2 WC Pediatrics SC Pediatrics GA AM3BS UT WOS:000339727100050 PM 24973163 ER PT J AU Martin, KR Koster, A Murphy, RA Van Domelen, DR Hung, MY Brychta, RJ Chen, KY Harris, TB AF Martin, Kathryn R. Koster, Annemarie Murphy, Rachel A. Van Domelen, Dane R. Hung, Ming-yang Brychta, Robert J. Chen, Kong Y. Harris, Tamara B. TI Changes in Daily Activity Patterns with Age in U.S. Men and Women: National Health and Nutrition Examination Survey 2003-04 and 2005-06 SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE NHANES 2003-2004; 2005-2006; physical activity; sedentary behavior; accelerometer; patterns of daily activity ID PHYSICAL-ACTIVITY; SEDENTARY BEHAVIORS; UNITED-STATES; ADULTS; TIME; ACCELEROMETER; INACTIVITY; VALIDATION; PROFILES; LIFE AB OBJECTIVES: To compare daily and hourly activity patterns according to sex and age. DESIGN: Cross-sectional, observational. SETTING: Nationally representative community sample: National Health and Nutrition Examination Survey (NHANES) 2003-04 and 2005-06. PARTICIPANTS: Individuals (n = 5,788) aged 20 and older with 4 or more valid days of monitor wear-time, no missing data on valid wear-time minutes, and covariates. MEASUREMENTS: Activity was examined as average counts per minute (CPM) during wear-time; percentage of time spent in nonsedentary activity; and time (minutes) spent in sedentary (<100 counts), light (100-759), and moderate to vigorous physical activity (MVPA (>= 760)). Analyses accounted for survey design, adjusted for covariates, and were sex specific. RESULTS: In adjusted models, men spent slightly more time (similar to 1-2%) in nonsedentary activity than women aged 20 to 34, with levels converging at age 35 to 59, although the difference was not significant. Women aged 60 and older spent significantly more time (similar to 3-4%) in nonsedentary activity than men, despite similarly achieved average CPM. With increasing age, all nonsedentary activity decreased in men; light activity remained constant in women (similar to 30%). Older men had fewer CPM at night (similar to 20), more daytime sedentary minutes (similar to 3), fewer daytime light physical activity minutes (similar to 4), and more MVPA minutes (similar to 1) until early evening than older women. CONCLUSION: Although sex differences in average CPM declined with age, differences in nonsedentary activity time emerged as men increased sedentary behavior and reduced MVPA time. Maintained levels of light-intensity activity suggest that women continue engaging in common daily activities into older age more than men. Findings may help inform the development of behavioral interventions to increase intensity and overall activity levels, particularly in older adults. C1 [Martin, Kathryn R.; Murphy, Rachel A.; Hung, Ming-yang; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. [Martin, Kathryn R.] Univ Aberdeen, Sch Med & Dent, Epidemiol Grp, Aberdeen, Scotland. [Koster, Annemarie] Maastricht Univ, Dept Social Med, CAPHRI Sch Publ Hlth & Primary Care, Maastricht, Netherlands. [Van Domelen, Dane R.] Emory Univ, Dept Biostat, Atlanta, GA 30322 USA. [Brychta, Robert J.; Chen, Kong Y.] NIDDKD, Diabet Endocrinol & Obes Branch, Bethesda, MD USA. RP Martin, KR (reprint author), Sch Med & Dent, Epidemiol Grp, Polwarth Bldg,Foresterhill, Aberdeen AB25 2ZD, Scotland. EM kathryn.martin@abdn.ac.uk RI Koster, Annemarie/E-7438-2010; OI Van Domelen, Dane/0000-0003-0051-7790; Chen, Kong/0000-0002-0306-1904 FU National Science Foundation [DGE-0940903] FX Sponsor's Role: This material is based upon work supported by the National Science Foundation Graduate Research Fellowship under Grant DGE-0940903 (DRV). NR 31 TC 14 Z9 14 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2014 VL 62 IS 7 BP 1263 EP 1271 DI 10.1111/jgs.12893 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AN3IX UT WOS:000340482000007 PM 24962323 ER PT J AU de Sancho, D Sirur, A Best, RB AF de Sancho, David Sirur, Anshul Best, Robert B. TI Molecular origins of internal friction effects on protein-folding rates SO NATURE COMMUNICATIONS LA English DT Article ID VISCOSITY DEPENDENCE; SOLVENT VISCOSITY; ALPHA-HELIX; ISOMERIZATION DYNAMICS; REACTION COORDINATE; ENERGY LANDSCAPE; CHAIN DYNAMICS; KINETICS; DIFFUSION; SIMULATIONS AB Recent experiments on protein-folding dynamics have revealed strong evidence for internal friction effects. That is, observed relaxation times are not simply proportional to the solvent viscosity as might be expected if the solvent were the only source of friction. However, a molecular interpretation of this remarkable phenomenon is currently lacking. Here, we use all-atom simulations of peptide and protein folding in explicit solvent, to probe the origin of the unusual viscosity dependence. We find that an important contribution to this effect, explaining the viscosity dependence of helix formation and the folding of a helix-containing protein, is the insensitivity of torsion angle isomerization to solvent friction. The influence of this landscape roughness can, in turn, be quantitatively explained by a rate theory including memory friction. This insensitivity of local barrier crossing to solvent friction is expected to contribute to the viscosity dependence of folding rates in larger proteins. C1 [de Sancho, David; Sirur, Anshul] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP de Sancho, D (reprint author), Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England. EM dd363@cam.ac.uk; robertbe@helix.nih.gov RI De Sancho, David/C-4995-2009; Best, Robert/H-7588-2016 OI De Sancho, David/0000-0002-8985-2685; Best, Robert/0000-0002-7893-3543 FU Engineering and Physical Sciences Research Council; Biotechnology and Biological Sciences Research Council studentship; Intramural Research Programme of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by a grant from the Engineering and Physical Sciences Research Council (D.d.S.), a Biotechnology and Biological Sciences Research Council studentship (A.S.) and by the Intramural Research Programme of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R.B.B.). This work made use of the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health and a PRACE computing allocation. We wish to acknowledge W.A. Eaton, A. Berezhkovskii, B. Schuler, A. Szabo, G. Papoian and F. Paillusson for helpful discussions, and V. Munoz for computational resources. NR 61 TC 22 Z9 22 U1 5 U2 45 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2014 VL 5 AR 4307 DI 10.1038/ncomms5307 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN5GI UT WOS:000340618300001 PM 24986114 ER PT J AU He, R Wang, YC Wang, XY Wang, ZT Liu, G Zhou, W Wen, LP Li, QX Wang, XP Chen, XY Zeng, J Hou, JG AF He, Rong Wang, You-Cheng Wang, Xiaoyong Wang, Zhantong Liu, Gang Zhou, Wei Wen, Longping Li, Qunxiang Wang, Xiaoping Chen, Xiaoyuan Zeng, Jie Hou, J. G. TI Facile synthesis of pentacle gold-copper alloy nanocrystals and their plasmonic and catalytic properties SO NATURE COMMUNICATIONS LA English DT Article ID SHAPE-CONTROLLED SYNTHESIS; NOBLE-METAL NANOCRYSTALS; HIGH-INDEX FACETS; HYBRID NANOSTRUCTURES; OXIDE NANOCRYSTALS; NANOPARTICLES; NANOWIRES; PD; REDUCTION; EVOLUTION AB The combination of gold and copper is a good way to pull down the cost of gold and ameliorate the instability of copper. Through shape control, the synergy of these two metals can be better exploited. Here, we report an aqueous phase route to the synthesis of pentacle gold-copper alloy nanocrystals with fivefold twinning, the size of which can be tuned in the range from 45 to 200 nm. The growth is found to start from a decahedral core, followed by protrusion of branches along twinning planes. Pentacle products display strong localized surface plasmon resonance peaks in the near-infrared region. Under irradiation by an 808-nm laser, 70-nm pentacle nanocrystals exhibit a notable photothermal effect to kill 4T1 murine breast tumours established on BALB/c mice. In addition, 70-nm pentacle nanocrystals show better catalytic activity than conventional citrate-coated 5-nm Au nanoparticles towards the reduction of p-nitrophenol to p-aminophenol by sodium borohydride. C1 [He, Rong; Wang, You-Cheng; Zhou, Wei; Wen, Longping; Li, Qunxiang; Wang, Xiaoping; Zeng, Jie; Hou, J. G.] Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China. [He, Rong; Wang, You-Cheng; Zhou, Wei; Wen, Longping; Li, Qunxiang; Wang, Xiaoping; Zeng, Jie; Hou, J. G.] Univ Sci & Technol China, Collaborat Innovat Ctr Suzhou Nano Sci & Technol, Hefei 230026, Anhui, Peoples R China. [He, Rong; Li, Qunxiang; Zeng, Jie] Univ Sci & Technol China, USTC, CAN, Hefei 230026, Anhui, Peoples R China. [He, Rong; Li, Qunxiang; Zeng, Jie] Univ Sci & Technol China, Dept Chem Phys, Hefei 230026, Anhui, Peoples R China. [Wang, Xiaoyong; Wang, Zhantong; Liu, Gang] Xiamen Univ, Sch Publ Hlth, State Key Lab Mol Vaccinol & Mol Diagnost, Xiamen 361102, Fujian, Peoples R China. [Wang, Xiaoyong; Wang, Zhantong; Liu, Gang] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361102, Fujian, Peoples R China. [Wang, Xiaoping; Hou, J. G.] Univ Sci & Technol China, Synerget Innovat Ctr Quantum Informat & Quantum P, Hefei 230026, Anhui, Peoples R China. [Chen, Xiaoyuan] NIH, NIBIB, Lab Mol Imaging & Nanomed LOMIN, Bethesda, MD 20892 USA. RP Zeng, J (reprint author), Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei 230026, Anhui, Peoples R China. EM zengj@ustc.edu.cn RI Zeng, Jie/H-1327-2011; Li, Qunxiang/D-3705-2009; Wang, Youcheng/G-3362-2014; OI Zeng, Jie/0000-0002-8812-0298; Li, Qunxiang/0000-0003-1988-1971; Wang, Youcheng/0000-0002-1851-3483; Zhou, Wei/0000-0001-6739-9480 FU MOST of China [2011CB921403, 2014CB932700, 2013CB733802]; NSFC [21121003, 21203173, 51273165, 51371164, 81101101, 81371596, J1030412]; Strategic Priority Research Program B of the CAS [XDB01020000]; Program for New Century Excellent Talents in University [NCET-13-0502]; Fundamental Research Funds for the Central Universities [WK2340000050, WK2060190025, 2013121039] FX This work was supported by MOST of China (2011CB921403, 2014CB932700 and 2013CB733802), NSFC under Grant Nos 21121003, 21203173, 51273165, 51371164, 81101101, 81371596 and J1030412, Strategic Priority Research Program B of the CAS under Grant No. XDB01020000, Program for New Century Excellent Talents in University (NCET-13-0502), and Fundamental Research Funds for the Central Universities (WK2340000050, WK2060190025 and 2013121039). NR 49 TC 75 Z9 75 U1 46 U2 286 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2014 VL 5 AR 4327 DI 10.1038/ncomms5327 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN5FI UT WOS:000340615500018 PM 24999674 ER PT J AU Lynch, DC Revil, T Schwartzentruber, J Bhoj, EJ Innes, AM Lamont, RE Lemire, EG Chodirker, BN Taylor, JP Zackai, EH McLeod, DR Kirk, EP Hoover-Fong, J Fleming, L Savarirayan, R Majewski, J Jerome-Majewska, LA Parboosingh, JS Bernier, FP AF Lynch, Danielle C. Revil, Timothee Schwartzentruber, Jeremy Bhoj, Elizabeth J. Innes, A. Micheil Lamont, Ryan E. Lemire, Edmond G. Chodirker, Bernard N. Taylor, Juliet P. Zackai, Elaine H. McLeod, D. Ross Kirk, Edwin P. Hoover-Fong, Julie Fleming, Leah Savarirayan, Ravi Majewski, Jacek Jerome-Majewska, Loydie A. Parboosingh, Jillian S. Bernier, Francois P. CA Care4Rare Canada TI Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome SO NATURE COMMUNICATIONS LA English DT Article ID MESSENGER-RNA; ULTRACONSERVED ELEMENTS; HUMAN GENOME; SPLICING REGULATORS; SEQUENCING DATA; HAPLOINSUFFICIENCY; IDENTIFICATION; MUTATIONS; ENHANCER; DEFECTS AB Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro-costo-mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development. C1 [Lynch, Danielle C.; Innes, A. Micheil; Lamont, Ryan E.; McLeod, D. Ross; Parboosingh, Jillian S.; Bernier, Francois P.] Univ Calgary, Dept Med Genet, Calgary, AB T2N 4N1, Canada. [Revil, Timothee; Majewski, Jacek; Jerome-Majewska, Loydie A.] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada. [Schwartzentruber, Jeremy; Majewski, Jacek] McGill Univ, Montreal, PQ H3A 0G1, Canada. [Schwartzentruber, Jeremy; Majewski, Jacek] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada. [Bhoj, Elizabeth J.; Zackai, Elaine H.] Childrens Hosp Philadelphia, Div Genet, Philadelphia, PA 19104 USA. [Innes, A. Micheil; Lamont, Ryan E.; McLeod, D. Ross; Parboosingh, Jillian S.; Bernier, Francois P.] Alberta Childrens Hosp Res Inst Child & Maternal, Calgary, AB T3B 6A8, Canada. [Lemire, Edmond G.] Univ Saskatchewan, Dept Pediat, Div Med Genet, Saskatoon, SK S7N 0W8, Canada. [Chodirker, Bernard N.] Univ Manitoba, Dept Pediat & Child Hlth, Winnipeg, MB R3A 1S1, Canada. [Chodirker, Bernard N.] Univ Manitoba, Fac Med, Dept Biochem & Med Genet, Winnipeg, MB R3A 1S1, Canada. [Taylor, Juliet P.] Genet Hlth Serv, Auckland 1142, New Zealand. [Kirk, Edwin P.] Sydney Childrens Hosp, Randwick, NSW 2031, Australia. [Kirk, Edwin P.] Univ New S Wales, Sch Womens & Childrens Hlth, Randwick, NSW 2031, Australia. [Hoover-Fong, Julie] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Greenberg Ctr Skeletal Dysplasias, Baltimore, MD 21287 USA. [Fleming, Leah] NHGRI, NIH, Bethesda, MD 20892 USA. [Savarirayan, Ravi] McGill Univ, Ctr Hlth, Dept Pediat, Montreal, PQ H3Z 2Z3, Canada. [Jerome-Majewska, Loydie A.] McGill Univ, Dept Pediat, Montreal Childrens Hosp, Montreal, PQ H3H 1P3, Canada. RP Bernier, FP (reprint author), Univ Calgary, Dept Med Genet, Calgary, AB T2N 4N1, Canada. EM francois.bernier@albertahealthservices.ca RI innes, allan micheil/A-9955-2017; OI Schwartzentruber, Jeremy/0000-0002-6183-2092 FU Genome Canada; Canadian Institutes of Health Research; Ontario Genomics Institute; Ontario Research Fund; Genome Quebec; Children's Hospital of Eastern Ontario Research Foundation; RI MUHC-Foundation of Stars at the Montreal Children's Hospital; Fonds de recherche du Quebec-Sante FX Supporting information can be found in the online Supplementary Material. We thank the patients and their families who participated in this study. Cell culture for the qRT-PCR experiments was performed by Nadine Gamache. The miniSmB construct was a gift from Dr Benjamin Blencowe. Drs Roy Gravel, Kym Boycott and Benedikt Hallgrimsson provided critical review of the manuscript. This work was performed under the Care4Rare Canada Consortium funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec and Children's Hospital of Eastern Ontario Research Foundation. We acknowledge the contribution of the high-throughput sequencing platform of the McGill University and Genome Quebec Innovation Centre, Montreal, Canada. We would like to thank Taila Hartley (Clinical Coordinator) and Chandree Beaulieu (Project Manager) at the Children's Hospital of Eastern Ontario Research Institute for their contribution to the infrastructure of Care4Rare. D.C.L. is supported by a graduate studentship from Alberta Innovates-Health Solutions. T.R. is supported in part by a fellowship from the RI MUHC-Foundation of Stars at the Montreal Children's Hospital. L.A.J.-M. is a member of the Research Institute of the McGill University Health Centre, which is supported in part by the Fonds de recherche du Quebec-Sante. NR 37 TC 7 Z9 8 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2014 VL 5 AR 4483 DI 10.1038/ncomms5483 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN5IF UT WOS:000340623400028 PM 25047197 ER PT J AU Morisaki, T Muller, WG Golob, N Mazza, D McNally, JG AF Morisaki, Tatsuya Mueller, Waltraud G. Golob, Nicole Mazza, Davide McNally, James G. TI Single-molecule analysis of transcription factor binding at transcription sites in live cells SO NATURE COMMUNICATIONS LA English DT Article ID GLUCOCORTICOID-RECEPTOR; NATURAL PROMOTER; LIVING CELLS; IN-VIVO; CHROMATIN; DYNAMICS; EXCHANGE; MECHANISMS; SCALE; LINE AB Although numerous live-cell measurements have shown that transcription factors (TFs) bind chromatin transiently, no measurements of transient binding have been reported at the endogenous response elements (REs) where transcription is normally induced. Here we show that at endogenous REs the transcriptionally productive specific binding of two TFs, p53 and the glucocorticoid receptor (GR), is transient. We also find that the transient residence times of GR at endogenous REs are roughly comparable to those at an artificial, multi-copy array of gene regulatory sites, supporting the use of multi-copy arrays for live-cell analysis of transcription. Finally, we find that at any moment only a small fraction of TF molecules are engaged in transcriptionally productive binding at endogenous REs. The small fraction of bound factors provides one explanation for gene bursting and it also indicates that REs may often be unoccupied, resulting in partial responses to transcriptional signals. C1 [Morisaki, Tatsuya; Mueller, Waltraud G.; McNally, James G.] NCI, Fluorescence Imaging Grp, NIH, Bethesda, MD 20892 USA. [Golob, Nicole] Inst Pathol, A-8036 Graz, Austria. [Mazza, Davide] Univ Vita Salute San Raffaele, I-20132 Milan, Italy. [Mazza, Davide] IRCCS Osped San Raffaele, I-20132 Milan, Italy. RP Mazza, D (reprint author), Univ Vita Salute San Raffaele, I-20132 Milan, Italy. EM Mazza.davide@hsr.it; james.mcnally@helmholtz-berlin.de RI Mazza, Davide/R-5340-2016 OI Mazza, Davide/0000-0003-2776-4142 FU intramural programme of the Center for Cancer Research; National Cancer Institute; US National Institutes of Health; Helmholtz-Zentrum Berlin; Japan Society for the Promotion of Science (JSPS); Marie Curie international incoming fellowship [GA: 27432] FX We thank Dan Larson and Myong-He Sung for comments on the manuscript. W.G.M. and J.G.M. were supported by the intramural programme of the Center for Cancer Research, National Cancer Institute, US National Institutes of Health, and by the Helmholtz-Zentrum Berlin (J.G.M.). T.M. was supported by the Japan Society for the Promotion of Science (JSPS). D.M. was supported by a Marie Curie international incoming fellowship (GA: 27432). NR 33 TC 30 Z9 30 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2014 VL 5 AR 4456 DI 10.1038/ncomms5456 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN5IF UT WOS:000340623400001 PM 25034201 ER PT J AU Wang, C Wu, HX Evron, T Vardy, E Han, GW Huang, XP Hufeisen, SJ Mangano, TJ Urban, DJ Katritch, V Cherezov, V Caron, MG Roth, BL Stevens, RC AF Wang, Chong Wu, Huixian Evron, Tama Vardy, Eyal Han, Gye Won Huang, Xi-Ping Hufeisen, Sandy J. Mangano, Thomas J. Urban, Dan J. Katritch, Vsevolod Cherezov, Vadim Caron, Marc G. Roth, Bryan L. Stevens, Raymond C. TI Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs SO NATURE COMMUNICATIONS LA English DT Article ID HEDGEHOG SIGNAL-TRANSDUCTION; A(2A) ADENOSINE RECEPTOR; BASAL-CELL CARCINOMA; CRYSTAL-STRUCTURE; SEROTONIN RECEPTORS; LIPIDIC MESOPHASES; MEMBRANE-PROTEINS; BINDING; PATHWAY; ANTAGONIST AB The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumours; however, mutations at SMO have been found to abolish their antitumour effects, a phenomenon known as chemoresistance. Here we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the agonist, SAG1.5, at 2.6-2.8 A resolution. The long and narrow cavity in the transmembrane domain of SMO harbours multiple ligand binding sites, where SANT1 binds at a deeper site as compared with other ligands. Distinct interactions at D473(6.54f) elucidated the structural basis for the differential effects of chemoresistance mutations on SMO antagonists. The agonist SAG1.5 induces a conformational rearrangement of the binding pocket residues, which could contribute to SMO activation. Collectively, these studies reveal the structural basis for the modulation of SMO by small molecules. C1 [Wang, Chong; Wu, Huixian; Han, Gye Won; Katritch, Vsevolod; Cherezov, Vadim; Stevens, Raymond C.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Evron, Tama; Caron, Marc G.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. [Vardy, Eyal; Huang, Xi-Ping; Hufeisen, Sandy J.; Mangano, Thomas J.; Urban, Dan J.; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Natl Inst Mental Hlth, Chapel Hill, NC 27514 USA. [Vardy, Eyal; Huang, Xi-Ping; Hufeisen, Sandy J.; Mangano, Thomas J.; Urban, Dan J.; Roth, Bryan L.] Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Div Chem Biol & Med Chem,Psychoact Drug Screening, Chapel Hill, NC 27514 USA. RP Stevens, RC (reprint author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM stevens@scripps.edu RI Wu, Huixian/N-6353-2014; Roth, Bryan/F-3928-2010; Cherezov, Vadim/L-9812-2013; Katritch, Vsevolod/Q-8357-2016; Stevens, Raymond/K-7272-2015; OI Wu, Huixian/0000-0003-1357-9747; Cherezov, Vadim/0000-0002-5265-3914; Stevens, Raymond/0000-0002-4522-8725; Katritch, Vsevolod/0000-0003-3883-4505 FU National Institutes of Health Roadmap [P50 GM073197]; PSI: Biology for biological studies and structure production [U54 GM094618, GPCR-131]; National Institute of Mental Health Psychoactive Drug Screening Program; Michael Hooker Chair of Pharmacology [DA-029925, MH-073853]; National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; [R01 MH61887]; [U19 MH82441]; [R01 DA27170] FX This work was supported by National Institutes of Health Roadmap grant P50 GM073197 for technology development (V.C. and R.C.S.); PSI: Biology grant U54 GM094618 for biological studies and structure production (target GPCR-131; V.K., V.C. and R.C.S.); R01 MH61887, U19 MH82441, R01 DA27170; the National Institute of Mental Health Psychoactive Drug Screening Program (X.-P. H. and B.L.R.); and the Michael Hooker Chair of Pharmacology (B.L.R.) and DA-029925 and MH-073853 (M.G.C.). We thank D. Stout and A. Sather for their help in solution of SANT1 bound structure; J. Velasquez for help on molecular biology; T. Trinh and M. Chu for their help on baculovirus expression; K. Kadyshevskaya for assistance with figure preparation; A. Walker for assistance with manuscript preparation; J. Smith, R. Fischetti and N. Sanishvili for their assistance in development and use of the minibeam and beamtime at GM/CA-CAT beamline 23-ID at the Advanced Photon Source, which is supported by National Cancer Institute grant Y1-CO-1020 and National Institute of General Medical Sciences grant Y1-GM-1104. NR 56 TC 48 Z9 50 U1 2 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2014 VL 5 AR 4355 DI 10.1038/ncomms5355 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN5FI UT WOS:000340615500046 PM 25008467 ER PT J AU Holliday, MA Kim, HJ Zalewski, CK Wafa, T Dewan, R King, KA Brewer, CC Butman, JA Asthagiri, AR AF Holliday, Michael A. Kim, Hung Jeffrey Zalewski, Christopher K. Wafa, Talah Dewan, Ramita King, Kelly A. Brewer, Carmen C. Butman, John A. Asthagiri, Ashok R. TI Audiovestibular Characteristics of Small Cochleovestibular Schwannomas in Neurofibromatosis Type 2 SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE neurofibromatosis type 2; audiogram; ABER; ABR; vestibular tests; VEMP; caloric tests; MRI ID EVOKED MYOGENIC POTENTIALS; BRAIN-STEM RESPONSE; VESTIBULAR-SCHWANNOMA; HEARING PRESERVATION; ACOUSTIC NEUROMAS; FOSSA APPROACH; GROWTH; ORIGIN; MRI AB Objective. Describe the relationship between cochleovestibular schwannoma (CVS) volume, audiovestibular characteristics, and magnetic resonance imaging (MRI) findings in patients with neurofibromatosis type 2 (NF2). Study Design. Subgroup analysis of NF2 prospective natural history study from 2008 to 2011. Setting. Quaternary medical research institute. Subjects and Methods. NF2 patients with small treatment-naive CVSs (volume < 1000 mm(3)) by ear; N = 49 ears (32 patients). Cross-sectional analysis of the following parameters was performed: tumor size, auditory brainstem response (ABR), 4-frequency pure-tone average (4f-PTA; 0.5, 1, 2, and 4KHz), cervical vestibular evoked myogenic potential (cVEMP), caloric testing, 240 degrees velocity step test (VST), and MRI findings. Results. For all physiologic measures but the 4f-PTA, larger tumors correlated with abnormal responses (P <. 05). For abnormal ABR, mean tumor volume was 405 vs 151 mm 3 (P = .0007) for normal ABR. Similarly, larger tumors correlated with weak caloric responses (mean 521 vs 165 mm 3; P = .0007) and weak cVEMP (mean 357 vs 192 mm 3; P = .0262). Tumor volume was not significantly correlated with 4f-PTA. Elevated intralabyrinthine protein on MRI fluid-attenuated inversion recovery sequences was correlated with larger tumor volume (mean 333 vs 55 mm(3); P = .001) and abnormal ABR and 4f-PTA (P <. 05) but did not correlate with cVEMP, VST, or caloric responses. Conclusion. In our cohort, ABR, caloric response, cVEMP, and elevated intralabyrinthine protein correlated with tumor volume, but 4f-PTA did not. Abnormal ABR and 4f- PTA correlated with elevated intralabyrinthine protein. These findings may provide insight on the effect of small CVS on the inner ear and cochleovestibular nerves, which may aid in their optimal management. C1 [Holliday, Michael A.; Kim, Hung Jeffrey] Georgetown Univ Hosp, Dept Otolaryngol Head & Neck Surg, Washington, DC 20007 USA. [Kim, Hung Jeffrey] Natl Inst Deafness & Other Commun Disorders, Off Clin Director, NIH, Bethesda, MD USA. [Zalewski, Christopher K.; Wafa, Talah; King, Kelly A.; Brewer, Carmen C.] Natl Inst Deafness & Other Commun Disorders, Audiol Unit, Otolaryngol Branch, NIH, Bethesda, MD USA. [Dewan, Ramita; Asthagiri, Ashok R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Butman, John A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Holliday, MA (reprint author), Georgetown Univ Hosp, Dept Otolaryngol Head & Neck Surg, 1 Gorman,3800 Reservoir Rd NW, Washington, DC 20007 USA. EM michael.a.holliday@gunet.georgetown.edu RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 FU National Institute of Neurologic Disorders and Stroke, National Institute on Deafness and Other Communication Disorders; Clinical Center at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Neurologic Disorders and Stroke, National Institute on Deafness and Other Communication Disorders, and the Clinical Center 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 28 TC 1 Z9 1 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD JUL PY 2014 VL 151 IS 1 BP 117 EP 124 DI 10.1177/0194599814529081 PG 8 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AN2YQ UT WOS:000340452400020 PM 24718755 ER PT J AU Buggert, M Tauriainen, J Yamamoto, T Frederiksen, J Ivarsson, MA Michaelsson, J Lund, O Hejdeman, B Jansson, M Sonnerborg, A Koup, RA Betts, MR Karlsson, AC AF Buggert, Marcus Tauriainen, Johanna Yamamoto, Takuya Frederiksen, Juliet Ivarsson, Martin A. Michaelsson, Jakob Lund, Ole Hejdeman, Bo Jansson, Marianne Sonnerborg, Anders Koup, Richard A. Betts, Michael R. Karlsson, Annika C. TI T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+T Cells in HIV Infection SO PLOS PATHOGENS LA English DT Article ID CHRONIC VIRAL-INFECTION; TRANSCRIPTION FACTOR EOMESODERMIN; HIGHLY PATHOGENIC SIV; C VIRUS-INFECTION; DISEASE PROGRESSION; PD-1 EXPRESSION; CUTTING EDGE; EFFECTOR FUNCTION; MEMORY; IMMUNE AB CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-bet(dim)Eomes(hi) expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-bet(dim)Eomes hi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-bet(dim)Eomes(hi) virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation. C1 [Buggert, Marcus; Tauriainen, Johanna; Sonnerborg, Anders; Karlsson, Annika C.] Karolinska Inst, Dept Lab Med, Div Clin Microbiol, Stockholm, Sweden. [Yamamoto, Takuya; Koup, Richard A.] NIH, Immunol Lab, Bethesda, MD 20892 USA. [Frederiksen, Juliet; Lund, Ole] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Ivarsson, Martin A.; Michaelsson, Jakob] Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden. [Hejdeman, Bo] Soder Sjukhuset, Stockholm South Gen Hosp, Dept Infect Dis Venhalsan, Stockholm, Sweden. [Jansson, Marianne] Lund Univ, Dept Lab Med, Lund, Sweden. [Jansson, Marianne] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Sonnerborg, Anders] Karolinska Inst, Dept Med Huddinge, Infect Dis Unit, Karolinska Univ Hosp Huddinge, Stockholm, Sweden. [Betts, Michael R.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. RP Buggert, M (reprint author), Karolinska Inst, Dept Lab Med, Div Clin Microbiol, Stockholm, Sweden. EM marcus.buggert@ki.se RI Lund, Ole/F-4437-2014; OI Lund, Ole/0000-0003-1108-0491; Tauriainen, Johanna/0000-0002-3780-2512; Buggert, Marcus/0000-0003-0633-1719; Yamamoto, Takuya/0000-0003-3753-1211 FU Lakare mot AIDS; Swedish Research Council [K2010-56X-20345-04-3, K2014-57X-22451-01-5]; Magnus Bergvalls foundation; Karolinska Institutet FX We thank the funding agencies including Lakare mot AIDS, the Swedish Research Council (Grants K2010-56X-20345-04-3 and K2014-57X-22451-01-5), Magnus Bergvalls foundation, and Karolinska Institutet. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 37 Z9 39 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2014 VL 10 IS 7 AR e1004251 DI 10.1371/journal.ppat.1004251 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AN4IL UT WOS:000340551000038 PM 25032686 ER PT J AU Chen, YP Pettis, JS Corona, M Chen, WP Li, CJ Spivak, M Visscher, PK DeGrandi-Hoffman, G Boncristiani, H Zhao, Y Vanengelsdorp, D Delaplane, K Solter, L Drummond, F Kramer, M Lipkin, WI Palacios, G Hamilton, MC Smith, B Huang, SK Zheng, HQ Li, JL Zhang, X Zhou, AF Wu, LY Zhou, JZ Lee, ML Teixeira, EW Li, ZG Evans, JD AF Chen, Yan Ping Pettis, Jeffery S. Corona, Miguel Chen, Wei Ping Li, Cong Jun Spivak, Marla Visscher, P. Kirk DeGrandi-Hoffman, Gloria Boncristiani, Humberto Zhao, Yan Vanengelsdorp, Dennis Delaplane, Keith Solter, Leellen Drummond, Francis Kramer, Matthew Lipkin, W. Ian Palacios, Gustavo Hamilton, Michele C. Smith, Barton Huang, Shao Kang Zheng, Huo Qing Li, Ji Lian Zhang, Xuan Zhou, Ai Fen Wu, Li You Zhou, Ji Zhong Lee, Myeong-L. Teixeira, Erica W. Li, Zhi Guo Evans, Jay D. TI Israeli Acute Paralysis Virus: Epidemiology, Pathogenesis and Implications for Honey Bee Health SO PLOS PATHOGENS LA English DT Article ID COLONY COLLAPSE DISORDER; DEFORMED-WING VIRUS; APIS-MELLIFERA; VARROA-DESTRUCTOR; ANTIVIRAL RESPONSE; UNITED-STATES; PCR ANALYSIS; DROSOPHILA; PATHWAY; TOLL AB Israeli acute paralysis virus (IAPV) is a widespread RNA virus of honey bees that has been linked with colony losses. Here we describe the transmission, prevalence, and genetic traits of this virus, along with host transcriptional responses to infections. Further, we present RNAi-based strategies for limiting an important mechanism used by IAPV to subvert host defenses. Our study shows that IAPV is established as a persistent infection in honey bee populations, likely enabled by both horizontal and vertical transmission pathways. The phenotypic differences in pathology among different strains of IAPV found globally may be due to high levels of standing genetic variation. Microarray profiles of host responses to IAPV infection revealed that mitochondrial function is the most significantly affected biological process, suggesting that viral infection causes significant disturbance in energy-related host processes. The expression of genes involved in immune pathways in adult bees indicates that IAPV infection triggers active immune responses. The evidence that silencing an IAPV-encoded putative suppressor of RNAi reduces IAPV replication suggests a functional assignment for a particular genomic region of IAPV and closely related viruses from the Family Dicistroviridae, and indicates a novel therapeutic strategy for limiting multiple honey bee viruses simultaneously and reducing colony losses due to viral diseases. We believe that the knowledge and insights gained from this study will provide a new platform for continuing studies of the IAPV-host interactions and have positive implications for disease management that will lead to mitigation of escalating honey bee colony losses worldwide. C1 [Chen, Yan Ping; Pettis, Jeffery S.; Corona, Miguel; Hamilton, Michele C.; Smith, Barton; Evans, Jay D.] USDA ARS, Bee Res Lab, Beltsville, MD 20705 USA. [Chen, Wei Ping] NIDDK, Microarray Core Facil, NIH, Bethesda, MD USA. [Li, Cong Jun] USDA ARS, Bovine Funct Genom Lab, Beltsville, MD USA. [Spivak, Marla] Univ Minnesota, Dept Entomol, St Paul, MN USA. [Visscher, P. Kirk] Univ Calif Riverside, Dept Entomol, Riverside, CA 92521 USA. [DeGrandi-Hoffman, Gloria] USDA ARS, Carl Hayden Bee Res Ctr, Tucson, AZ USA. [Boncristiani, Humberto] Univ N Carolina, Dept Biol, Greensboro, NC 27412 USA. [Zhao, Yan] USDA ARS, Mol Plant Pathol Lab, Beltsville, MD USA. [Vanengelsdorp, Dennis] Univ Maryland, Dept Entomol, College Pk, MD 20742 USA. [Delaplane, Keith] Univ Georgia, Dept Entomol, Athens, GA 30602 USA. [Solter, Leellen] Univ Illinois, Illinois Nat Hist Survey, Urbana, IL 61801 USA. [Drummond, Francis] Univ Maine, Sch Biol & Ecol, Orono, ME USA. [Kramer, Matthew] USDA ARS, Biometr Consulting Serv, Beltsville, MD USA. [Lipkin, W. Ian] Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY USA. [Palacios, Gustavo] George Mason Univ, Natl Ctr Biodef & Infect Dis, Manassas, VA USA. [Huang, Shao Kang] Fujian Agr & Forestry Univ, Coll Bee Sci, Fuzhou, Fujian, Peoples R China. [Zheng, Huo Qing; Li, Zhi Guo] Zhejiang Univ, Coll Anim Sci, Hangzhou 310003, Zhejiang, Peoples R China. [Li, Ji Lian] Chinese Acad Agr Sci, Inst Apicultural Res, Beijing 100193, Peoples R China. [Zhang, Xuan] Yunnan Agr Univ, Eastern Bee Res Inst, Kunming, Peoples R China. [Zhou, Ai Fen; Wu, Li You; Zhou, Ji Zhong] Univ Oklahoma, IEG, Norman, OK 73019 USA. [Lee, Myeong-L.] RDA, Natl Acad Agr Sci, Sericulture & Apiculture Dept, Suwon, South Korea. [Teixeira, Erica W.] Agencia Paulista Tecnol Agronegocios SAA SP, Sao Paulo, Brazil. RP Chen, YP (reprint author), USDA ARS, Bee Res Lab, BARC East Bldg, Beltsville, MD 20705 USA. EM judy.chen@ars.usda.gov RI Evans, Jay/C-8408-2012; vanEngelsdorp, Dennis/E-7934-2010; Palacios, Gustavo/I-7773-2015 OI Evans, Jay/0000-0002-0036-4651; Palacios, Gustavo/0000-0001-5062-1938 FU USDA-CAP [2009-85118-05718]; NIH [AI1057158]; Department of Defense FX This research was supported by the USDA-CAP grant (2009-85118-05718). WIL and GP received support from NIH award AI1057158 (Northeast Biodefense Center-Lipkin) and the Department of Defense. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 30 Z9 33 U1 11 U2 89 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2014 VL 10 IS 7 AR e1004261 DI 10.1371/journal.ppat.1004261 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AN4IL UT WOS:000340551000041 PM 25079600 ER PT J AU Richter, LM Mofenson, LM AF Richter, Linda M. Mofenson, Lynne M. TI Children born into families affected by HIV SO AIDS LA English DT Article C1 [Richter, Linda M.] Univ Witwatersrand, DST NRF Ctr Excellence Human Dev, ZA-4001 Durban, South Africa. [Richter, Linda M.] Univ KwaZulu Natal, ZA-4001 Durban, South Africa. [Richter, Linda M.] Human Sci Res Council, ZA-4001 Durban, South Africa. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. RP Richter, LM (reprint author), 750 Francois Rd, ZA-4001 Durban, South Africa. EM lrichter@hsrc.ac.za NR 20 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUL PY 2014 VL 28 SU 3 BP S241 EP S244 DI 10.1097/QAD.0000000000000361 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AM8XD UT WOS:000340161500001 PM 24991894 ER PT J AU Diekstra, FP Van Deerlin, VM van Swieten, JC Al-Chalabi, A Ludolph, AC Weishaupt, JH Hardiman, O Landers, JE Brown, RH van Es, MA Pasterkamp, RJ Koppers, M Andersen, PM Estrada, K Rivadeneira, F Hofman, A Uitterlinden, AG van Damme, P Melki, J Meininger, V Shatunov, A Shaw, CE Leigh, PN Shaw, PJ Morrison, KE Fogh, I Chio, A Traynor, BJ Czell, D Weber, M Heutink, P de Bakker, PIW Silani, V Robberecht, W van den Berg, LH Veldink, JH AF Diekstra, Frank P. Van Deerlin, Vivianna M. van Swieten, John C. Al-Chalabi, Ammar Ludolph, Albert C. Weishaupt, Jochen H. Hardiman, Orla Landers, John E. Brown, Robert H., Jr. van Es, Michael A. Pasterkamp, R. Jeroen Koppers, Max Andersen, Peter M. Estrada, Karol Rivadeneira, Fernando Hofman, Albert Uitterlinden, Andre G. van Damme, Philip Melki, Judith Meininger, Vincent Shatunov, Aleksey Shaw, Christopher E. Leigh, P. Nigel Shaw, Pamela J. Morrison, Karen E. Fogh, Isabella Chio, Adriano Traynor, Bryan J. Czell, David Weber, Markus Heutink, Peter de Bakker, Paul I. W. Silani, Vincenzo Robberecht, Wim van den Berg, Leonard H. Veldink, Jan H. TI C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: A Genome-Wide Meta-Analysis SO ANNALS OF NEUROLOGY LA English DT Article ID HEREDITARY SPASTIC PARAPLEGIA; LOBAR DEGENERATION; HEXANUCLEOTIDE REPEAT; COGNITIVE IMPAIRMENT; SUSCEPTIBILITY LOCI; ASSOCIATION; ALS; DISEASES; MUTATIONS; VARIANTS AB Objective: Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods: We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results: Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 x 10(-12)) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 x 10(-11)) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 x 10(-7)) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 x 10(-7)). Interpretation: We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP. C1 [Diekstra, Frank P.; van Es, Michael A.; Koppers, Max; van den Berg, Leonard H.; Veldink, Jan H.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, NL-3584 CX Utrecht, Netherlands. [Van Deerlin, Vivianna M.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. [van Swieten, John C.; Heutink, Peter] Vrije Univ Amsterdam Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands. [van Swieten, John C.] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Al-Chalabi, Ammar; Shatunov, Aleksey; Shaw, Christopher E.; Leigh, P. Nigel; Fogh, Isabella] Kings Coll London, Inst Psychiat, Med Res Council Ctr Neurodegenerat Res, Dept Clin Neurosci, London WC2R 2LS, England. [Ludolph, Albert C.; Weishaupt, Jochen H.] Univ Ulm, Dept Neurol, D-89069 Ulm, Germany. [Hardiman, Orla] Beaumont Hosp, Dept Neurol, Dublin 9, Ireland. [Hardiman, Orla] Univ Dublin Trinity Coll, Dept Neurol, Dublin 2, Ireland. [Landers, John E.; Brown, Robert H., Jr.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Landers, John E.; Brown, Robert H., Jr.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Pasterkamp, R. Jeroen; Koppers, Max] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurosci & Pharmacol, NL-3584 CX Utrecht, Netherlands. [Andersen, Peter M.] Umea Univ, Dept Pharmacol & Clin Neurosci, Umea, Sweden. [Estrada, Karol; Rivadeneira, Fernando; Hofman, Albert; Uitterlinden, Andre G.] Erasmus Univ, Dept Epidemiol & Biostat, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [van Damme, Philip; Robberecht, Wim] Univ Leuven, Univ Hosp Leuven, Dept Neurol, Leuven, Belgium. [van Damme, Philip; Robberecht, Wim] Flanders Inst Biotechnol, Vesalius Res Ctr, Neurobiol Lab, Leuven, Belgium. [Melki, Judith] INSERM, UMR 986, Paris, France. [Melki, Judith] Univ Paris 11, Bicetre Hosp, Paris, France. [Meininger, Vincent] Univ Paris 06, Salpetriere Hosp, Dept Neurol, Paris, France. [Shaw, Pamela J.] Univ Sheffield, Sheffield Inst Translat Neurosci, Dept Neurosci, Acad Neurol Unit, Sheffield, S Yorkshire, England. [Morrison, Karen E.] Univ Birmingham, Coll Med & Dent, Sch Clin & Expt Med, Birmingham, W Midlands, England. [Morrison, Karen E.] Univ Hosp Birmingham, Div Neurosci, Birmingham, W Midlands, England. [Fogh, Isabella; Silani, Vincenzo] IRCCS Italian Auxol Inst, Dept Neurol, Milan, Italy. [Fogh, Isabella; Silani, Vincenzo] IRCCS Italian Auxol Inst, Neurosci Lab, Milan, Italy. [Chio, Adriano] Univ Turin, Dept Neurosci, Turin, Italy. [Chio, Adriano] City Hosp Hlth & Sci, Turin, Italy. [Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Brain Sci Inst, Baltimore, MD 21218 USA. [Czell, David; Weber, Markus] St Gallen Cantonal Hosp, Neuromuscular Dis Unit, St Gallen, Switzerland. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CX Utrecht, Netherlands. [Silani, Vincenzo] Univ Milan, Dino Ferrari Ctr, Dept Pathophysiol & Transplantat, Milan, Italy. RP Veldink, JH (reprint author), Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. EM j.h.veldink@umcutrecht.nl RI Van Damme, Philip/A-6464-2009; de Bakker, Paul/B-8730-2009; Rivadeneira, Fernando/O-5385-2015; OI Van Damme, Philip/0000-0001-6384-0611; de Bakker, Paul/0000-0001-7735-7858; Rivadeneira, Fernando/0000-0001-9435-9441; Koppers, Max/0000-0002-7751-1082; Chio, Adriano/0000-0001-9579-5341; Silani, Vincenzo/0000-0002-7698-3854; Pasterkamp, Jeroen/0000-0003-1631-6440; van Swieten, John /0000-0001-6278-6844; Hardiman, Orla/0000-0003-2610-1291 FU Prinses Beatrix Fonds (Kersten Foundation); VSB Fonds; Netherlands ALS Foundation; J. R. van Dijk, and the Adessium Foundation; Brain Foundation of the Netherlands; Thierry Latran Foundation; Prinses Beatrix Fonds; Netherlands Organization of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative/Netherlands Organization for Scientific Research [050-060-810]; European Community [259867]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Ministry of Education, Culture, and Science; Ministry for Health, Welfare, and Sports; European Commission (DG XII); Municipality of Rotterdam; German Federal Ministry of Education and Research (network for ALS research [MND-NET]) [01GI0704]; Charcot Foundation for ALS Research; Swabian ALS Registry; Muscular Dystrophy Association (USA); Health Research Board of Ireland; Irish Neurological Association Travel Award; Irish Motor Neuron Disease Research Foundation; Swedish Brain Research Foundation; Hallstens Research Foundation; Swedish Medical Society; Bjorklund Foundation for ALS Research; Swedish Association for the Neurologically Disabled; Swiss ALS Association; University of Leuven (Methusalem); Interuniversity Attraction Poles program of the Belgian Federal Science Policy Office [P6/43]; Associazione Centro Dino Ferrari; Italian Ministry of Health (GWA-SLA, Ricerca Finalizzata) [31]; ALS-FTD, Ricerca Finalizzata [276]; Fondazione Istituto Auxologico Italiano; Italian Health Ministry (Ricerca Sanitaria Finalizzata); Fondazione Vialli e Mauro ONLUS; Federazione Italiana Giuoco Calcio; Association pour la recherche sur la sclerose laterale amyotrophique; Association Reseau SLA Ile de France; ALS Therapy Alliance; Project ALS; Angel Fund; Pierre L. de Bourgknecht ALS Research Foundation; Al-Athel ALS Research Foundation; ALS Family Charitable Foundation; NIH National Institute of Neurological Disorders and Stroke [NS050557, 1R01NS073873]; NIH [AG017586]; Intramural Research Program of the NIH, National Institute on Aging; Research Motor Neurone; Motor Neurone Disease Association UK FX This work was supported by the Prinses Beatrix Fonds (Kersten Foundation), VSB Fonds, the Netherlands ALS Foundation and J. R. van Dijk, and the Adessium Foundation (L.H.v.d.B.). J.H.V. is supported by the Brain Foundation of the Netherlands and the Thierry Latran Foundation. R.J.P. is supported by the Prinses Beatrix Fonds and the Thierry Latran Foundation. The GWAS was funded by the Netherlands Organization of Scientific Research NWO Investments (grants 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015), and the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (project number 050-060-810). In addition, the research leading to these results has received funding from the European Community's Health Seventh Framework Program (FP7/2007-2013; grant agreement number 259867). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare, and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The work was also supported by grants from the German Federal Ministry of Education and Research (01GI0704; network for ALS research [MND-NET]), the Charcot Foundation for ALS Research (A. C. L., J. H. W.), and the Swabian ALS Registry. The Irish study was funded by the Muscular Dystrophy Association (USA), the Health Research Board of Ireland, the Irish Neurological Association Travel Award, and the Irish Motor Neuron Disease Research Foundation. In Sweden, this project was supported by the Swedish Brain Research Foundation, the Hallstens Research Foundation, the Swedish Medical Society, the Bjorklund Foundation for ALS Research, and the Swedish Association for the Neurologically Disabled (P. M. A.). In Switzerland, this study was supported by the Swiss ALS Association. W. R. was supported by grants from the University of Leuven (Methusalem) and the Interuniversity Attraction Poles program P6/43 of the Belgian Federal Science Policy Office. In Italy, this study has been funded by grants from the Associazione Centro Dino Ferrari, Italian Ministry of Health (GWA-SLA, Ricerca Finalizzata 2007, grant number 31 and ALS-FTD, Ricerca Finalizzata 2009, grant number 276; I. F., V. S.), and Fondazione Istituto Auxologico Italiano. Also in Italy, the study was financed by the Italian Health Ministry (Ricerca Sanitaria Finalizzata 2007), Fondazione Vialli e Mauro ONLUS, and Federazione Italiana Giuoco Calcio (A. C.). In France, this study was funded by the Association pour la recherche sur la sclerose laterale amyotrophique and the Association Reseau SLA Ile de France. Support was also provided by the ALS Therapy Alliance, Project ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation, and the NIH National Institute of Neurological Disorders and Stroke (NS050557). J. E. L. received funding from the NIH National Institute of Neurological Disorders and Stroke (1R01NS073873). V. M. V. D. was supported by NIH grant AG017586. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (B.J.T.). O.H. was supported by a grant from Research Motor Neurone. K.E.M. was supported by a grant from Motor Neurone Disease Association UK. NR 38 TC 9 Z9 9 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2014 VL 76 IS 1 BP 120 EP 133 DI 10.1002/ana.24198 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AM7JQ UT WOS:000340043200012 PM 24931836 ER PT J AU Shechner, T Hong, M Britton, JC Pine, DS Fox, NA AF Shechner, Tomer Hong, Melanie Britton, Jennifer C. Pine, Daniel S. Fox, Nathan A. TI Fear conditioning and extinction across development: Evidence from human studies and animal models SO BIOLOGICAL PSYCHOLOGY LA English DT Review DE Classical conditioning; Fear conditioning; Extinction; Development; Animal models; Human studies ID VENTROMEDIAL PREFRONTAL CORTEX; HIPPOCAMPAL INACTIVATION DISRUPTS; DEFICIT HYPERACTIVITY DISORDER; UNILATERAL TEMPORAL LOBECTOMY; POSTTRAUMATIC-STRESS-DISORDER; ANXIETY DISORDERS; FACIAL EXPRESSIONS; HUMAN AMYGDALA; UNCONDITIONAL STIMULUS; EXTINGUISHED FEAR AB The ability to differentiate danger and safety through associative processes emerges early in life. Understanding the mechanisms underlying associative learning of threat and safety can clarify the processes that shape development of normative fears and pathological anxiety. Considerable research has used fear conditioning and extinction paradigms to delineate underlying mechanisms in animals and human adults; however, little is known about these mechanisms in children and adolescents. The current paper summarizes the empirical data on the development of fear conditioning and extinction. It reviews methodological considerations and future directions for research on fear conditioning and extinction in pediatric populations. (C) 2014 Elsevier B. V. All rights reserved. C1 [Shechner, Tomer] Univ Haifa, Dept Psychol, IL-31999 Haifa, Israel. [Hong, Melanie; Fox, Nathan A.] Univ Maryland, Dept Human Dev & Quantitat Methodol, College Pk, MD USA. [Britton, Jennifer C.] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. [Pine, Daniel S.] NIMH, Bethesda, MD USA. RP Shechner, T (reprint author), Univ Haifa, Dept Psychol, IL-31999 Haifa, Israel. EM tshechner@psy.haifa.ac.il FU NIMH Intramural Research Program FX This study was supported (partially) by the NIMH Intramural Research Program. NR 98 TC 19 Z9 19 U1 12 U2 46 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 JUL PY 2014 VL 100 BP 1 EP 12 DI 10.1016/j.biopsycho.2014.04.001 PG 12 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA AM6SA UT WOS:000339993800001 PM 24746848 ER PT J AU Chauret, M La Buissonniere-Ariza, V Tremblay, VL Suffren, S Servonnet, A Pine, DS Maheu, FS AF Chauret, Melissa La Buissonniere-Ariza, Valerie Tremblay, Vickie Lamoureux Suffren, Sabrina Servonnet, Alice Pine, Daniel S. Maheu, Francoise S. TI The conditioning and extinction of fear in youths: What's sex got to do with it? SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Sex; Gender; Youth; Fear conditioning; Fear extinction; Skin conductance ID MEDIAL PREFRONTAL CORTEX; FACIAL EXPRESSIONS; ANXIETY DISORDERS; ADOLESCENCE; CHILDREN; EMOTION; HUMANS; WOMEN; FACE; RECOGNITION AB Adult work shows differences in emotional processing influenced by sexes of both the viewer and expresser of facial expressions. We investigated this in 120 healthy youths (57 boys; 10-17 years old) randomly assigned to fear conditioning and extinction tasks using either neutral male or female faces as the conditioned threat and safety cues, and a fearful face paired with a shrieking scream as the unconditioned stimulus. Fear ratings and skin conductance responses (SCRs) were assessed. Male faces triggered increased fear ratings in all participants during conditioning and extinction. Greater differential SCRs were observed in boys viewing male faces and in girls viewing female faces during conditioning. During extinction, differential SCR findings remained significant in boys viewing male faces. Our findings demonstrate how sex of participant and sex of target interact to shape fear responses in youths, and how the type of measure may lead to distinct profiles of fear responses. (C) 2014 Elsevier B.V. All rights reserved. C1 [Chauret, Melissa; La Buissonniere-Ariza, Valerie; Tremblay, Vickie Lamoureux; Suffren, Sabrina; Servonnet, Alice; Maheu, Francoise S.] Ste Justine Univ Hosp, Res Ctr, Montreal, PQ H3T 1C5, Canada. [Chauret, Melissa] Univ Quebec, Dept Psychol, Montreal, PQ H3C 3P8, Canada. [La Buissonniere-Ariza, Valerie; Tremblay, Vickie Lamoureux; Suffren, Sabrina] Univ Montreal, Dept Psychol, Montreal, PQ H2V 2S9, Canada. [La Buissonniere-Ariza, Valerie; Tremblay, Vickie Lamoureux; Suffren, Sabrina; Maheu, Francoise S.] Univ Montreal, Ctr Rech Neuropsychol & Cognit CERNEC, Dept Psychol, Montreal, PQ H3C 3J7, Canada. [Pine, Daniel S.] NIMH USA, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Maheu, Francoise S.] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada. RP Maheu, FS (reprint author), Ste Justine Univ Hosp, Res Ctr, 3175 Cote Ste Catherine, Montreal, PQ H3T 1C5, Canada. EM francoise.maheu@umontreal.ca FU Canadian Institutes Health Research (CIHR) [MOP-97983]; Fonds de recherche en sante du Quebec (FRSQ); CIHR; FRSQ; Fonds Quebecois de la Recherche sur la Societe et la Culture (FQRSC); Foundation of Stars/Research Center of the Ste-Justine University Hospital FX This research was supported by a grant from the Canadian Institutes Health Research (CIHR; MOP-97983) to FSM. FSM is a recipient of the CIHR New Investigator Award and Fonds de recherche en sante du Quebec (FRSQ) Junior 1 Award. MC and VLB received PhD fellowships from the CIHR and the FRSQ. SS receiveda PhD fellowship from the Fonds Quebecois de la Recherche sur la Societe et la Culture (FQRSC) and the Foundation of Stars/Research Center of the Ste-Justine University Hospital. We acknowledge Drs. Pierre Rainville and Etienne Vachon-Presseau for their help and expertise with SCR analyses. We also thank the participants for taking part in this study. NR 65 TC 1 Z9 1 U1 1 U2 8 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 JUL PY 2014 VL 100 BP 97 EP 105 DI 10.1016/j.biopsycho.2014.06.001 PG 9 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA AM6SA UT WOS:000339993800012 PM 24929048 ER PT J AU Coronado, GD Vollmer, WM Petrik, A Taplin, SH Burdick, TE Meenan, RT Green, BB AF Coronado, Gloria D. Vollmer, William M. Petrik, Amanda Taplin, Stephen H. Burdick, Timothy E. Meenan, Richard T. Green, Beverly B. TI Strategies and Opportunities to STOP Colon Cancer in Priority Populations: Design of a cluster-randomized pragmatic trial SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Colorectal cancer screening; Fecal immunochemical test; Pragmatic study; Cluster-randomized study ID COLORECTAL-CANCER; LOW-INCOME; CLINICAL-TRIAL; INTERVENTIONS; DIVERSE; IMPACT; CARE; US AB Background: Colorectal cancer is the second-leading cause of cancer deaths in the United States. The Strategies and Opportunities to Stop Colorectal Cancer (STOP CRC) in Priority Populations study is a pragmatic trial and a collaboration between two research institutions and a network of more than 200 safety net clinics. The study will assess the effectiveness of a system-based intervention designed to improve the rates of colorectal-cancer screening using fecal immunochemical testing (FIT) in federally qualified health centers in Oregon and Northern California. Material and methods: STOP CRC is a cluster-randomized comparative-effectiveness pragmatic trial enrolling 26 clinics. Clinics will be randomized to one of two arms. Clinics in the intervention arm (1) will use an automated, data-driven, electronic health record-embedded program to identify patients due for colorectal screening and mail FIT kits (with pictographic instructions) to them; (2) will conduct an improvement process (e.g. Plan-Do-Study-Act) to enhance the adoption, reach, and effectiveness of the program. Clinics in the control arm will provide opportunistic colorectal-cancer screening to patients at clinic visits. The primary outcomes are: proportion of age- and screening-eligible patients completing a FIT within 12 months; and cost, cost-effectiveness, and return on investment of the intervention. Conclusions: This large-scale pragmatic trial will leverage electronic health record information and existing clinic staff to enroll a broad range of patients, including many with historically low colorectal-cancer screening rates. If successful, the program will provide a model for a cost-effective and scalable method to raise colorectal-cancer screening rates. (C) 2014 Elsevier Inc. All rights reserved. C1 [Coronado, Gloria D.; Vollmer, William M.; Petrik, Amanda; Meenan, Richard T.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR 97227 USA. [Taplin, Stephen H.] NCI, Proc Care Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Burdick, Timothy E.] OCHIN Inc, Portland, OR 97201 USA. [Burdick, Timothy E.] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97219 USA. [Green, Beverly B.] Grp Hlth Res Inst, Seattle, WA 98101 USA. RP Coronado, GD (reprint author), 3800 N Interstate Ave, Portland, OR 97227 USA. EM Gloria.d.coronado@kpchr.org; William.vollmer@kpchr.org; Amanda.f.petrik@kpchr.org; Taplins@mail.nih.gov; burdickt@ochin.org; Richard.meenan@kpchr.org; Green.b@ghc.org FU National Institutes of Health through the National Center for Complementary & Alternative Medicine [UH2AT007782]; National Cancer Institute [4UH3CA188640-02] FX The research reported in this publication was supported by the National Institutes of Health through the National Center for Complementary & Alternative Medicine under Award Number UH2AT007782 and the National Cancer Institute under Award Number 4UH3CA188640-02. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Complementary & Alternative Medicine or the National Cancer Institute. The authors would like to acknowledge Leslie Bienen, DVM, and Chrissy Wilkins who provided support to edit and format the manuscript. NR 29 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JUL PY 2014 VL 38 IS 2 BP 344 EP 349 DI 10.1016/j.cct.2014.06.006 PG 6 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AN0VF UT WOS:000340301400023 PM 24937017 ER PT J AU Prasad, A Mumford, SL Louis, GMB Ahrens, KA Sjaarda, LA Schliep, KC Perkins, NJ Kissell, KA Wactawski-Wende, J Schisterman, EF AF Prasad, Ankita Mumford, Sunni L. Louis, Germaine M. Buck Ahrens, Katherine A. Sjaarda, Lindsey A. Schliep, Karen C. Perkins, Neil J. Kissell, Kerri A. Wactawski-Wende, Jean Schisterman, Enrique F. TI Sexual activity, endogenous reproductive hormones and ovulation in premenopausal women SO HORMONES AND BEHAVIOR LA English DT Article DE Ovulation; Reproductive hormones; Sexual activity ID MENSTRUAL-CYCLE; INTERCOURSE; CONCEPTION; MOTIVATION; PREGNANCY; BIOCYCLE; STRESS; MOOD AB We investigated whether sexual activity was associated with reproductive function in the BioCycle Study, a prospective cohort study that followed 259 regularly menstruating women aged 18 to 44 years for one (n = 9) or two (n = 250) menstrual cycles in 2005-2007. Women were not attempting pregnancy nor using hormonal contraceptives. History of ever having been sexually active was assessed at baseline and frequency of sexual activity, defined as vaginal-penile intercourse, was self-reported daily throughout the study. Serum concentrations of estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and testosterone were measured up to 8 times/cycle. Sporadic anovulation was identified using peak progesterone concentration. Linear mixed models were used to estimate associations between sexual activity and reproductive hormone concentrations and generalized linear models were used to estimate associations with sporadic anovulation. Models were adjusted for age, race, body mass index, perceived stress, and alcohol consumption and accounted for repeated measures within women. Elevated concentrations of estrogen (+ 14.6%, P<.01), luteal progesterone (+ 41.0%, P <.01) and mid-cycle LH (+ 23.4%, P <.01), but not FSH (P =.33) or testosterone (P =.37), were observed in sexually active women compared with sexually inactive women (no prior and no study-period sexual activity); sexually active women had lower odds of sporadic anovulation (adjusted odds ratio = 0.34,95% confidence interval: 0.16-0.73). Among sexually active women, frequency of sexual activity was not associated with hormones or sporadic anovulation (all P>.23). Findings from our study suggest that ever having been sexually active is associated with improved reproductive function, even after controlling for factors such as age. Published by Elsevier Inc. C1 [Prasad, Ankita; Mumford, Sunni L.; Louis, Germaine M. Buck; Ahrens, Katherine A.; Sjaarda, Lindsey A.; Schliep, Karen C.; Perkins, Neil J.; Kissell, Kerri A.; Schisterman, Enrique F.] NIH, Div Intramural Populat Hlth Res, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD 20852 USA. [Kissell, Kerri A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14214 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd,7803M, Rockville, MD 20852 USA. EM aprasad128@gmail.com; mumfords@mail.nih.gov; louisg@mail.nih.gov; ahrenska@mail.nih.gov; lindsey.sjaarda@nih.gov; schliepkc2@mail.nih.gov; perkinsn@mail.nih.gov; kissellka@mail.nih.gov; jww@buffalo.edu; schistee@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Sjaarda, Lindsey/0000-0003-0539-8110; Schisterman, Enrique/0000-0003-3757-641X; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland [HHSN275200403394C] FX This study was funded by Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland (contract # HHSN275200403394C). The sources of funding had no role in study design, data collection, analysis, interpretation, writing the report, or in the decision to submit the article for publication. NR 41 TC 8 Z9 9 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0018-506X EI 1095-6867 J9 HORM BEHAV JI Horm. Behav. PD JUL PY 2014 VL 66 IS 2 BP 330 EP 338 DI 10.1016/j.yhbeh.2014.06.012 PG 9 WC Behavioral Sciences; Endocrinology & Metabolism SC Behavioral Sciences; Endocrinology & Metabolism GA AM9PB UT WOS:000340212400014 PM 24954690 ER PT J AU Spruijt-Metz, D Nilsen, W AF Spruijt-Metz, Donna Nilsen, Wendy TI Dynamic Models of Behavior for Just-in-Time Adaptive Interventions SO IEEE PERVASIVE COMPUTING LA English DT Article C1 [Spruijt-Metz, Donna] Univ So Calif, Dornsife Ctr Econ & Social Res, USC mHlth Collaboratory, Los Angeles, CA 90089 USA. [Nilsen, Wendy] NIH, Bethesda, MD USA. RP Spruijt-Metz, D (reprint author), Univ So Calif, Dornsife Ctr Econ & Social Res, USC mHlth Collaboratory, Los Angeles, CA 90089 USA. EM dmetz@usc.edu; nilsenwj@od.nih.gov NR 8 TC 18 Z9 18 U1 1 U2 8 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 1536-1268 EI 1558-2590 J9 IEEE PERVAS COMPUT JI IEEE Pervasive Comput. PD JUL-SEP PY 2014 VL 13 IS 3 BP 13 EP 17 PG 5 WC Computer Science, Information Systems; Engineering, Electrical & Electronic; Telecommunications SC Computer Science; Engineering; Telecommunications GA AM8AJ UT WOS:000340090800004 ER PT J AU Baranello, L Kouzine, F Wojtowicz, D Cui, KR Przytycka, TM Zhao, KJ Levens, D AF Baranello, Laura Kouzine, Fedor Wojtowicz, Damian Cui, Kairong Przytycka, Teresa M. Zhao, Keji Levens, David TI DNA Break Mapping Reveals Topoisomerase II Activity Genome-Wide SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Article DE topoisomerases; DNA damage; transcription ID DOUBLE-STRAND BREAK; CLEAVABLE COMPLEXES; TRANSCRIPTION; REPAIR; BETA; CHROMATIN; DISEASE; DAMAGE; ALPHA; CELLS AB Genomic DNA is under constant assault by endogenous and exogenous DNA damaging agents. DNA breakage can represent a major threat to genome integrity but can also be necessary for genome function. Here we present approaches to map DNA double-strand breaks (DSBs) and single-strand breaks (SSBs) at the genome-wide scale by two methods called DSB- and SSB-Seq, respectively. We tested these methods in human colon cancer cells and validated the results using the Topoisomerase II (Top2)-poisoning agent etoposide (ETO). Our results show that the combination of ETO treatment with break-mapping techniques is a powerful method to elaborate the pattern of Top2 enzymatic activity across the genome. C1 [Baranello, Laura; Kouzine, Fedor; Levens, David] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wojtowicz, Damian; Przytycka, Teresa M.] NCBI, Computat Biol Branch, NLM, NIH, Bethesda, MD 20894 USA. [Cui, Kairong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Kouzine, F (reprint author), NCI, Pathol Lab, NIH, Bldg 10 Rm 2N106,10 Ctr Dr, Bethesda, MD 20892 USA. EM baranellolf@mail.nih.gov; kouzinef@mail.nih.gov; wojtowda@mail.nih.gov; cuik@mail.nih.gov; przytyck@mail.nih.gov; zhaok@mail.nih.gov; levens@helix.nih.gov RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X FU Intramural Research Program of the National Cancer Institute (Center for Cancer Research); National Library of Medicine; National Heart, Lung and Blood Institute of the U.S. National Institutes of Health; University of Bologna PhD Program in Cellular and Molecular Biology FX This study was supported in part by the Intramural Research Program of the National Cancer Institute (Center for Cancer Research), the National Library of Medicine, the National Heart, Lung and Blood Institute of the U.S. National Institutes of Health and the University of Bologna PhD Program in Cellular and Molecular Biology (to L.B.). NR 30 TC 7 Z9 7 U1 1 U2 14 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD JUL PY 2014 VL 15 IS 7 BP 13111 EP 13122 DI 10.3390/ijms150713111 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA AM7ID UT WOS:000340038500118 PM 25056547 ER PT J AU Wei, CY Hoff, A Villabo, MA Peterman, J Kendall, PC Piacentini, J McCracken, J Walkup, JT Albano, AM Rynn, M Sherrill, J Sakolsky, D Birmaher, B Ginsburg, G Keeton, C Gosch, E Compton, SN March, J AF Wei, Chiaying Hoff, Alexandra Villabo, Marianne A. Peterman, Jeremy Kendall, Philip C. Piacentini, John McCracken, James Walkup, John T. Albano, Anne Marie Rynn, Moira Sherrill, Joel Sakolsky, Dara Birmaher, Boris Ginsburg, Golda Keeton, Courtney Gosch, Elizabeth Compton, Scott N. March, John TI Assessing Anxiety in Youth with the Multidimensional Anxiety Scale for Children SO JOURNAL OF CLINICAL CHILD AND ADOLESCENT PSYCHOLOGY LA English DT Article ID TEST-RETEST RELIABILITY; CHILDHOOD ANXIETY; DSM-IV; DISORDERED YOUTH; PARENT VERSIONS; PRIMARY-CARE; ADOLESCENTS; COMORBIDITY; MASC; PREVALENCE AB The present study examined the psychometric properties, including discriminant validity and clinical utility, of the youth self-report and parent-report forms of the Multidimensional Anxiety Scale for Children (MASC) among youth with anxiety disorders. The sample included parents and youth (N = 488, 49.6% male) ages 7 to 17 who participated in the Child/Adolescent Anxiety Multimodal Study. Although the typical low agreement between parent and youth self-reports was found, the MASC evidenced good internal reliability across MASC subscales and informants. The main MASC subscales (i.e., Physical Symptoms, Harm Avoidance, Social Anxiety, and Separation/Panic) were examined. The Social Anxiety and Separation/Panic subscales were found to be significantly predictive of the presence and severity of social phobia and separation anxiety disorder, respectively. Using multiple informants improved the accuracy of prediction. The MASC subscales demonstrated good psychometric properties and clinical utilities in identifying youth with anxiety disorders. C1 [Wei, Chiaying; Hoff, Alexandra; Peterman, Jeremy; Kendall, Philip C.] Temple Univ, Dept Psychol, Philadelphia, PA 19087 USA. [Villabo, Marianne A.] Ctr Child & Adolescent Mental Hlth, Salt Lake City, UT USA. [Piacentini, John; McCracken, James] Univ Calif Los Angeles, Div Child & Adolescent Psychiat, Los Angeles, CA 90024 USA. [Walkup, John T.] Weill Cornell Med Coll, Div Child & Adolescent Psychiat, New York, NY USA. [Walkup, John T.] New York Presbyterian Hosp, New York, NY USA. [Albano, Anne Marie; Rynn, Moira] Columbia Univ, Dept Psychiat, New York, NY 10027 USA. [Sherrill, Joel] NIMH, Washington, DC USA. [Sakolsky, Dara; Birmaher, Boris] Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Pittsburgh, PA 15260 USA. [Ginsburg, Golda; Keeton, Courtney] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21218 USA. [Gosch, Elizabeth] Philadelphia Coll Osteopath Med, Dept Psychol, Philadelphia, PA USA. [Compton, Scott N.; March, John] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. RP Wei, CY (reprint author), Temple Univ, Dept Psychol, Weiss Hall,1701 North 13th St, Philadelphia, PA 19087 USA. EM chiaying.wei@temple.edu; pkendall@temple.edu FU NIMH NIH HHS [R01 MH063747, R01 MH064003, U01 MH064088, U01 MH064107, U01 MH064089, K24 MH096760, U01 MH063747, U01 MH064003, U01 MH064092] NR 37 TC 5 Z9 5 U1 2 U2 17 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1537-4416 EI 1537-4424 J9 J CLIN CHILD ADOLESC JI J. Clin. Child Adolesc. Psychol. PD JUL-AUG PY 2014 VL 43 IS 4 BP 566 EP 578 DI 10.1080/15374416.2013.814541 PG 13 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA AM8JM UT WOS:000340120200003 PM 23845036 ER PT J AU Lansford, JE Sharma, C Malone, PS Woodlief, D Dodge, KA Oburu, P Pastorelli, C Skinner, AT Sorbring, E Tapanya, S Tirado, LMU Zelli, A Al-Hassan, SM Alampay, LP Bacchini, D Bombi, AS Bornstein, MH Chang, L Deater-Deckard, K Di Giunta, L AF Lansford, Jennifer E. Sharma, Chinmayi Malone, Patrick S. Woodlief, Darren Dodge, Kenneth A. Oburu, Paul Pastorelli, Concetta Skinner, Ann T. Sorbring, Emma Tapanya, Sombat Tirado, Liliana Maria Uribe Zelli, Arnaldo Al-Hassan, Suha M. Alampay, Liane Pena Bacchini, Dario Bombi, Anna Silvia Bornstein, Marc H. Chang, Lei Deater-Deckard, Kirby Di Giunta, Laura TI Corporal Punishment, Maternal Warmth, and Child Adjustment: A Longitudinal Study in Eight Countries SO JOURNAL OF CLINICAL CHILD AND ADOLESCENT PSYCHOLOGY LA English DT Article ID PHYSICAL DISCIPLINE; PSYCHOLOGICAL ADJUSTMENT; EXTERNALIZING BEHAVIORS; PARENTING ATTRIBUTIONS; HARSH DISCIPLINE; UNITED-STATES; ATTITUDES; MOTHERS; FATHERS; AMERICAN AB Two key tasks facing parents across cultures are managing children's behaviors (and misbehaviors) and conveying love and affection. Previous research has found that corporal punishment generally is related to worse child adjustment, whereas parental warmth is related to better child adjustment. This study examined whether the association between corporal punishment and child adjustment problems (anxiety and aggression) is moderated by maternal warmth in a diverse set of countries that vary in a number of sociodemographic and psychological ways. Interviews were conducted with 7- to 10-year-old children (N = 1,196; 51% girls) and their mothers in 8 countries: China, Colombia, Italy, Jordan, Kenya, the Philippines, Thailand, and the United States. Follow-up interviews were conducted 1 and 2 years later. Corporal punishment was related to increases, and maternal warmth was related to decreases, in children's anxiety and aggression over time; however, these associations varied somewhat across groups. Maternal warmth moderated the effect of corporal punishment in some countries, with increases in anxiety over time for children whose mothers were high in both warmth and corporal punishment. The findings illustrate the overall association between corporal punishment and child anxiety and aggression as well as patterns specific to particular countries. Results suggest that clinicians across countries should advise parents against using corporal punishment, even in the context of parent-child relationships that are otherwise warm, and should assist parents in finding other ways to manage children's behaviors. C1 [Lansford, Jennifer E.; Sharma, Chinmayi; Dodge, Kenneth A.; Skinner, Ann T.] Duke Univ, Ctr Child & Family Policy, Durham, NC 27708 USA. [Malone, Patrick S.; Woodlief, Darren] Univ S Carolina, Dept Psychol, Columbia, SC 29208 USA. [Oburu, Paul] Maseno Univ, Dept Educ Psychol, Maseno, Kenya. [Pastorelli, Concetta; Tirado, Liliana Maria Uribe; Bombi, Anna Silvia; Di Giunta, Laura] Univ Roma La Sapienza, Dept Psychol, Rome, Italy. [Tapanya, Sombat] Chiang Mai Univ, Dept Psychiat, Chiang Mai, Thailand. [Tirado, Liliana Maria Uribe] Univ San Buenaventura, Bogota, Colombia. [Zelli, Arnaldo] Univ Rome Foro Italico, Dept Educ Sci Sport & Phys Act, Rome, Italy. [Al-Hassan, Suha M.] Hashemite Univ, Queen Rania Fac Childhood, Zarqa, Abdallah Ghoshe, Jordan. [Alampay, Liane Pena] Ateneo Manila Univ, Dept Psychol, Lungsod Quezon, Philippines. [Bacchini, Dario] Univ Naples 2, Dept Psychol, Caserta, Italy. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. [Chang, Lei] Chinese Univ Hong Kong, Dept Educ Psychol, Hong Kong, Hong Kong, Peoples R China. [Deater-Deckard, Kirby] Virginia Tech, Dept Psychol, Blacksburg, VA USA. RP Lansford, JE (reprint author), Duke Univ, Ctr Child & Family Policy, Box 90545, Durham, NC 27708 USA. EM lansford@duke.edu RI ZELLI, ARNALDO/N-2333-2015; OI ZELLI, ARNALDO/0000-0003-4020-8159; Bacchini, Dario/0000-0001-6140-9377 FU FIC NIH HHS [R03 TW008141, R03-TW008141]; NICHD NIH HHS [R01-HD054805, R01 HD054805]; NIDA NIH HHS [2K05DA015226, K01 DA024116, K01DA024116, K05 DA015226] NR 68 TC 21 Z9 21 U1 6 U2 40 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1537-4416 EI 1537-4424 J9 J CLIN CHILD ADOLESC JI J. Clin. Child Adolesc. Psychol. PD JUL-AUG PY 2014 VL 43 IS 4 BP 670 EP 685 DI 10.1080/15374416.2014.893518 PG 16 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA AM8JM UT WOS:000340120200011 PM 24885184 ER PT J AU Kruse, AC Li, JH Hu, JX Kobilka, BK Wess, J AF Kruse, Andrew C. Li, Jianhua Hu, Jianxin Kobilka, Brian K. Wess, Juergen TI Novel Insights into M-3 Muscarinic Acetylcholine Receptor Physiology and Structure SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article; Proceedings Paper CT 14th International Symposium on Cholinergic Mechanisms (ISCM) CY MAY, 2013 CL Hangzhou, PEOPLES R CHINA DE Muscarinic acetylcholine receptor; G protein-coupled receptor; X-ray structure; Mutant mouse models; Muscarinic receptor physiology ID BETA-CELL FUNCTION; PROTEIN-COUPLED RECEPTOR; IN-VIVO; G(Q)-COUPLED RECEPTOR; TRANSCRIPTION FACTORS; HORMONAL-REGULATION; LIVER; MICE; ACTIVATION; GLUCOSE AB Recent studies with M-3 muscarinic acetylcholine receptor (M3R) mutant mice suggest that drugs selectively targeting this receptor subtype may prove useful for the treatment of various pathophysiological conditions. Moreover, the use of M3R-based designer G protein-coupled receptors (GPCRs) has provided novel insights into how G(q)-coupled GPCRs can modulate whole-body glucose homeostasis by acting on specific peripheral cell types. More recently, we succeeded in using X-ray crystallography to determine the structure of the M3R bound to the bronchodilating drug tiotropium, a muscarinic antagonist (inverse agonist). This new structural information should facilitate the development of orthosteric or allosteric M3R-selective drugs that are predicted to have considerable therapeutic potential. C1 [Kruse, Andrew C.; Kobilka, Brian K.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. [Li, Jianhua; Hu, Jianxin; Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, Bldg 8A,Room B1A-05,8 Ctr Dr, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov FU Intramural NIH HHS [ZIA DK031129-06]; NIGMS NIH HHS [U19 GM106990, T32 GM008294] NR 48 TC 3 Z9 3 U1 2 U2 8 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD JUL PY 2014 VL 53 IS 3 BP 316 EP 323 DI 10.1007/s12031-013-0127-0 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AM6ES UT WOS:000339956700005 PM 24068573 ER PT J AU Narayanan, M Huynh, JL Wang, K Yang, X Yoo, S McElwee, J Zhang, B Zhang, CS Lamb, JR Xie, T Suver, C Molony, C Melquist, S Johnson, AD Fan, GP Stone, DJ Schadt, EE Casaccia, P Emilsson, V Zhu, J AF Narayanan, Manikandan Huynh, Jimmy L. Wang, Kai Yang, Xia Yoo, Seungyeul McElwee, Joshua Zhang, Bin Zhang, Chunsheng Lamb, John R. Xie, Tao Suver, Christine Molony, Cliona Melquist, Stacey Johnson, Andrew D. Fan, Guoping Stone, David J. Schadt, Eric E. Casaccia, Patrizia Emilsson, Valur Zhu, Jun TI Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE differential co-expression; dysregulatory gene networks; epigenetic regulation of neural differentiation; network alignment; neurodegenerative diseases ID ALZHEIMERS-DISEASE; HUNTINGTONS-DISEASE; DNA METHYLATION; GENE-EXPRESSION; EPIGENETIC MECHANISMS; HUMAN BRAIN; DIFFERENTIATION; OLIGODENDROCYTES; TRANSCRIPTION; NEURONS AB Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non-demented controls, we investigated global disruptions in the co-regulation of genes in two neurodegenerative diseases, late-onset Alzheimer's disease (AD) and Huntington's disease (HD). We identified networks of differentially co-expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242-gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter-connected processes, chromatin organization and neural differentiation, and included DNA methyl-transferases, DNMT1 and DNMT3A, of which we predicted the former but not latter as a key regulator. To validate the inter-connection of these two processes and our key regulator prediction, we generated two brain-specific knockout (KO) mice and show that Dnmt1 KO signature significantly overlaps with the subnetwork (P = 3.1 x 10(-12)), while Dnmt3a KO signature does not (P = 0.017). C1 [Narayanan, Manikandan] NIAID, Bethesda, MD 20892 USA. [Huynh, Jimmy L.; Casaccia, Patrizia] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Huynh, Jimmy L.; Yoo, Seungyeul; Zhang, Bin; Schadt, Eric E.; Casaccia, Patrizia; Zhu, Jun] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Wang, Kai; McElwee, Joshua; Zhang, Chunsheng; Lamb, John R.; Xie, Tao; Molony, Cliona; Melquist, Stacey; Stone, David J.] Merck & Co Inc, Merck Res Labs, Whitehouse Stn, NJ USA. [Yang, Xia] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA USA. [Suver, Christine] Sage Bionetworks, Seattle, WA USA. [Johnson, Andrew D.] NHLBI, Bethesda, MD 20892 USA. [Fan, Guoping] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. [Emilsson, Valur] Iceland Heart Assoc, Kopavogur, Iceland. [Emilsson, Valur] Univ Iceland, Fac Pharmaceut Sci, Reykjavik, Iceland. RP Narayanan, M (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM manikandan.narayanan@nih.gov; jun.zhu@mssm.edu OI Suver, Christine/0000-0002-2986-385X FU NIH-NIMH [R01MH090948-01]; NIH-NINDS [R37NS042925-10, F31NS077504]; Intramural Research Program of the NIH; Brain Tissue Resource Center [R24 MH068855] FX This research was supported in part by NIH-NIMH (R01MH090948-01 to JZ), NIH-NINDS (R37NS042925-10 to PC and F31NS077504 to JLH), and the Intramural Research Program of the NIH (specifically NIAID and NHLBI institutes for MN and AJ, respectively). We thank the Harvard Brain Tissue Resource Center (which was supported in part by PHS Grant R24 MH068855, http://www.brainbank.mclean.org/) for generously gifting human brain postmortem samples used in this study. We thank John Tsang for useful discussions related to enrichment analysis, Carlo Colantuoni for timely access to the adjusted expression dataset described in his publication, and Yuri Kotliarov, Bhaskar Dutta and Zhi Xie for helpful discussions. The network figures were generated using the Cytoscape software (www.cytoscape.org). NR 73 TC 15 Z9 15 U1 5 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD JUL PY 2014 VL 10 IS 7 AR 743 DI 10.15252/msb.20145304 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN0TB UT WOS:000340295800009 PM 25080494 ER PT J AU Lucassen, EB Sterling, NW Lee, EY Chen, HL Lewis, MM Kong, L Huang, XM AF Lucassen, Elisabeth B. Sterling, Nicholas W. Lee, Eun-Young Chen, Honglei Lewis, Mechelle M. Kong, Lan Huang, Xuemei TI History of Smoking and Olfaction in Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE smoking; Parkinson's disease; olfactory; cigarette ID COGNITIVE IMPAIRMENT; TRANSDERMAL NICOTINE; CIGARETTE-SMOKING; RISK; DEMENTIA; DYSFUNCTION; SURVIVAL; VALIDITY; EXPOSURE AB Objective: Olfactory dysfunction is the most common pre-motor symptom in Parkinson's disease (PD), and smoking is known to be associated with lower risk of PD. This study tested the hypothesis that smoking is associated with better olfaction in PD. Methods: Smoking history was obtained from 76 PD subjects (22 with a history of smoking [smokers], 54 who never smoked [nonsmokers]), and 70 controls (17 smokers, 53 nonsmokers). Olfaction was assessed using the 40-item University of Pennsylvania Smell Identification Test (UPSIT). The olfactory scores between groups and subgroups were compared using analysis of covariance with adjustment for age, gender, and monoamine oxidase B (MAO-B) inhibitor usage. Results: Overall the olfactory score was lower in PD compared with controls (olfactory scores: 21.5 vs. 33.5, P < 0.0001). Among controls, there was no significant difference in olfaction between smokers and nonsmokers (olfactory scores, 33.2 vs. 34.2; P = 0.95). Among PD subjects, however, smokers scored significantly better regarding olfaction compared with nonsmokers (olfactory scores: 24.4 vs. 19.9, P = 0.02). Conclusions: These data suggest that a history of smoking is associated with better olfaction among PD patients. The finding may be related to why smoking may be protective against PD. Further studies are needed to confirm this finding and investigate the underlying mechanisms. (C) 2014 International Parkinson and Movement Disorder Society C1 [Lucassen, Elisabeth B.; Sterling, Nicholas W.; Lee, Eun-Young; Lewis, Mechelle M.; Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Sterling, Nicholas W.; Kong, Lan; Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Publ Hlth Sci, Hershey, PA 17033 USA. [Lewis, Mechelle M.; Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Kinesiol, Hershey, PA 17033 USA. [Chen, Honglei] NIEHS, Res Triangle Pk, NC 27709 USA. RP Huang, XM (reprint author), Penn State Hershey Med Ctr, Dept Neurol, 500 Univ Dr,H-037, Hershey, PA 17033 USA. EM xuemei@psu.edu OI Chen, Honglei/0000-0003-3446-7779 FU NIH [NS060722]; Penn State Hershey Medical Center CTSI [NIH UL1 TR000127]; GCRC Construction [C06 RR016499]; CTSI [TL1 TR000125]; NIH, the National Institute of Environmental Health Sciences [Z01-ES-101986] FX This study was supported by NIH NS060722, Penn State Hershey Medical Center CTSI (NIH UL1 TR000127), GCRC Construction (C06 RR016499), and CTSI (TL1 TR000125) research grants. Dr. Chen is supported by the intramural research program of the NIH, the National Institute of Environmental Health Sciences (Z01-ES-101986). NR 33 TC 3 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 2014 VL 29 IS 8 BP 1069 EP 1074 DI 10.1002/mds.25912 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AM8AA UT WOS:000340089300019 PM 24833119 ER PT J AU Lundin, NB Niciu, MJ Luckenbaugh, DA Ionescu, DF Richards, EM Vande Voort, JL Brutsche, NE Machado-Vieira, R Zarate, CA AF Lundin, N. B. Niciu, M. J. Luckenbaugh, D. A. Ionescu, D. F. Richards, E. M. Vande Voort, J. L. Brutsche, N. E. Machado-Vieira, R. Zarate, C. A., Jr. TI Baseline Vitamin B12 and Folate Levels Do Not Predict Improvement in Depression After a Single Infusion of Ketamine SO PHARMACOPSYCHIATRY LA English DT Article DE vitamin B12; folate; ketamine; bipolar depression; major depressive disorder ID RESISTANT MAJOR DEPRESSION; D-ASPARTATE ANTAGONIST; ADD-ON TRIAL; BIPOLAR DEPRESSION; ANTIDEPRESSANT EFFICACY; GENDER-DIFFERENCES; DOUBLE-BLIND; DISORDER AB Introduction: Deficiencies in both vitamin B12 and folate have been associated with depression. Recently, higher baseline vitamin B12 levels were observed in individuals with bipolar depression who responded to the antidepressant ketamine at 7 days post-infusion. This study sought to replicate this result by correlating peripheral vitamin levels with ketamine's antidepressant efficacy in bipolar depression and major depressive disorder (MDD). Methods: Baseline vitamin B12 and folate levels were obtained in 49 inpatients with treatment-resistant MDD and 34 inpatients with treatment-resistant bipolar depression currently experiencing a major depressive episode. All subjects received a single intravenous ketamine infusion. Post-hoc Pearson correlations were performed between baseline vitamin B12 and folate levels, as well as antidepressant response assessed by percent change in Hamilton Depression Rating Scale (HDRS) scores from baseline to 230 min, 1 day, and 7 days post-infusion. Results: No significant correlation was observed between baseline vitamin B12 or folate and percent change in HDRS for any of the 3 time points in either MDD or bipolar depression. Discussion: Ketamine's antidepressant efficacy may occur independently of baseline peripheral vitamin levels. C1 [Lundin, N. B.; Niciu, M. J.; Luckenbaugh, D. A.; Ionescu, D. F.; Richards, E. M.; Vande Voort, J. L.; Brutsche, N. E.; Machado-Vieira, R.; Zarate, C. A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Intramural Res Program, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), Bldg 10,CRC Room 7-5342,10 Ctr Dr, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI Ionescu, Dawn/K-5675-2015; MACHADO-VIEIRA, RODRIGO/D-8293-2012; Niciu, Mark/J-1766-2014 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Niciu, Mark/0000-0002-5612-3021 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX The authors gratefully acknowledge the support of the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). loline Henter provided invaluable editorial assistance. NR 25 TC 4 Z9 4 U1 2 U2 3 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0176-3679 EI 1439-0795 J9 PHARMACOPSYCHIATRY JI Pharmacopsychiatry PD JUL PY 2014 VL 47 IS 4-5 BP 141 EP 144 DI 10.1055/s-0034-1377042 PG 4 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA AM9WH UT WOS:000340231200003 PM 24955551 ER PT J AU Bolton, JL Hayward, C Direk, N Lewis, JG Hammond, GL Hill, LA Anderson, A Huffman, J Wilson, JF Campbell, H Rudan, I Alan, W Hastie, N Wild, SH Velders, FP Hofman, A Uitterlinden, AG Lahti, J Raikkonen, K Kajantie, E Widen, E Palotie, A Eriksson, JG Kaakinen, M Jarvelin, MR Timpson, NJ Smith, GD Ring, SM Evans, DM St Pourcain, B Tanaka, T Milaneschi, Y Bandinelli, S Ferrucci, L van der Harst, P Rosmalen, JGM Bakker, SJL Verweij, N Dullaart, RPF Mahajan, A Lindgren, CM Morris, A Lind, L Ingelsson, E Anderson, LN Pennell, CE Lye, SJ Matthews, SG Eriksson, J Mellstrom, D Ohlsson, C Price, JF Strachan, MWJ Reynolds, RM Tiemeier, H Walker, BR AF Bolton, Jennifer L. Hayward, Caroline Direk, Nese Lewis, John G. Hammond, Geoffrey L. Hill, Lesley A. Anderson, Anna Huffman, Jennifer Wilson, James F. Campbell, Harry Rudan, Igor Wright, Alan Hastie, Nicholas Wild, Sarah H. Velders, Fleur P. Hofman, Albert Uitterlinden, Andre G. Lahti, Jari Raikkonen, Katri Kajantie, Eero Widen, Elisabeth Palotie, Aarno Eriksson, Johan G. Kaakinen, Marika Jarvelin, Marjo-Riitta Timpson, Nicholas J. Smith, George Davey Ring, Susan M. Evans, David M. St Pourcain, Beate Tanaka, Toshiko Milaneschi, Yuri Bandinelli, Stefania Ferrucci, Luigi van der Harst, Pim Rosmalen, Judith G. M. Bakker, Stephen J. L. Verweij, Niek Dullaart, Robin P. F. Mahajan, Anubha Lindgren, Cecilia M. Morris, Andrew Lind, Lars Ingelsson, Erik Anderson, Laura N. Pennell, Craig E. Lye, Stephen J. Matthews, Stephen G. Eriksson, Joel Mellstrom, Dan Ohlsson, Claes Price, Jackie F. Strachan, Mark W. J. Reynolds, Rebecca M. Tiemeier, Henning Walker, Brian R. CA CORtisol Network CORNET Consortium TI Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin SO PLOS GENETICS LA English DT Article ID INSULIN-RESISTANCE SYNDROME; ADRENAL AXIS ACTIVITY; LOW-BIRTH-WEIGHT; GENERAL-POPULATION; BLOOD-PRESSURE; DISEASE; MEN; STRESS; WOMEN; RISK AB Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding alpha 1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases. C1 [Bolton, Jennifer L.; Anderson, Anna; Strachan, Mark W. J.; Reynolds, Rebecca M.; Walker, Brian R.] Univ Edinburgh, Queens Med Res Inst, Univ BHF Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. [Hayward, Caroline; Huffman, Jennifer; Wright, Alan; Hastie, Nicholas] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland. [Direk, Nese; Velders, Fleur P.; Hofman, Albert; Uitterlinden, Andre G.; Tiemeier, Henning] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Lewis, John G.] Canterbury Hlth Labs, Christchurch, New Zealand. [Hammond, Geoffrey L.; Hill, Lesley A.] Univ British Columbia, Inst Life Sci, Dept Cellular & Physiol Sci, Vancouver, BC V5Z 1M9, Canada. [Wilson, James F.; Campbell, Harry; Rudan, Igor; Wild, Sarah H.; Price, Jackie F.] Univ Edinburgh, Ctr Populat Hlth Sci, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Lahti, Jari; Raikkonen, Katri] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Kajantie, Eero; Eriksson, Johan G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Widen, Elisabeth; Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Palotie, Aarno] Univ Cent Hosp, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Helsinki Univ Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Kaakinen, Marika; Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Kaakinen, Marika; Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Children & Young People & Families, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, MRC HPA Ctr Environm & Hlth, London, England. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland. [Timpson, Nicholas J.; Smith, George Davey; Evans, David M.] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Analyses Translat Epidemiol, Bristol, Avon, England. [Ring, Susan M.; St Pourcain, Beate] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Tanaka, Toshiko; Milaneschi, Yuri; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD USA. [Milaneschi, Yuri] Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, GGZ InGeest, Amsterdam, Netherlands. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [van der Harst, Pim; Verweij, Niek] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [van der Harst, Pim] Durrer Ctr Cardiogenet Res, ICIN Netherlands Heart Inst, Utrecht, Netherlands. [Rosmalen, Judith G. M.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Bakker, Stephen J. L.; Dullaart, Robin P. F.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands. [Mahajan, Anubha; Lindgren, Cecilia M.; Morris, Andrew] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Lind, Lars; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Anderson, Laura N.; Lye, Stephen J.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Pennell, Craig E.] Univ Western Australia, Sch Womens & Infants Hlth, Crawley, Australia. [Matthews, Stephen G.] Univ Toronto, Dept Physiol, Toronto, ON, Canada. [Eriksson, Joel; Mellstrom, Dan; Ohlsson, Claes] Univ Gothenburg, Sahlgrenska Acad, Inst Medicin, Ctr Bone & Arthrit Res, Gothenburg, Sweden. RP Bolton, JL (reprint author), Univ Edinburgh, Queens Med Res Inst, Univ BHF Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. EM b.walker@ed.ac.uk RI Lye, Stephen/E-7269-2013; Reynolds, Rebecca/C-3044-2008; Study, Raine/G-9547-2015; Bakker, Stephan/J-4023-2015; Wilson, James F/A-5704-2009; Fox, Laura /C-6249-2016; Rudan, Igor/I-1467-2012; Hayward, Caroline/M-8818-2016; Verweij, Niek/A-4499-2017; Davey Smith, George/A-7407-2013; OI Tiemeier, Henning/0000-0002-4395-1397; St Pourcain, Beate/0000-0002-4680-3517; Verweij, Niek/0000-0002-4303-7685; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Timpson, Nicholas/0000-0002-7141-9189; Eriksson, Johan/0000-0002-2516-2060; Evans, David/0000-0003-0663-4621; Lahti, Jari/0000-0002-4310-5297; Raikkonen, Katri/0000-0003-3124-3470; Kaakinen, Marika/0000-0002-9228-0462; Bakker, Stephan/0000-0003-3356-6791; Wilson, James F/0000-0001-5751-9178; Rudan, Igor/0000-0001-6993-6884; Hayward, Caroline/0000-0002-9405-9550; Davey Smith, George/0000-0002-1407-8314; Lewis, John/0000-0003-2757-4111 FU Chief Scientist Office of the Scottish Government [CZB-4-733]; British Heart Foundation [RG11/4/28734]; Medical Research Council (UK); Republic of Croatia Ministry of Science, Education and Sports research grants [108-1080315-0302]; European Commission [LSHG-CT-2006-018947, QLK4-CT-2002-02528]; Chief Scientist Office of the Scottish Government; Royal Society; MRC Human Genetics Unit; Arthritis Research UK; European Union [LSHG-CT-2006-018947]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research [050-060-810]; Erasmus MC; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (Directorate-General XII); Municipality of Rotterdam; Netherlands Organization for the Health Research and Development [2009-017.106.370]; Netherlands Consortium for Healthy Ageing; Academy of Finland; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Wellcome Trust [WT089062, 092731, WT098017, WT064890, WT090532]; Academy of Finland [104781, 120315, 129418]; Academy of Finland Center of Excellence in Complex Disease Genetics and Public Health Challenges Research Program (SALVE); University Hospital Oulu, Biocenter, University of Oulu, Finland [75617]; European Commission [EUROBLCS] [QLG1-CT-2000-01643]; National Heart, Lung and Blood Institute through the SNP Typing for Association [5R01HL087679-02]; Multiple Phenotypes from Existing Epidemiologic Data (STAMPEED) program [1RL1MH083268-01]; National Institute of Health/The National Institute of Mental Health [5R01MH63706:02]; European Network of Genomic and Genetic Epidemiology (ENGAGE) project [HEALTH-F4-2007-201413]; Medical Research Council, UK [PrevMetSyn/Public Health Challenges Research Program (SALVE)] [G0500539, G0600705]; UK Medical Research Council; University of Bristol; Italian Ministry of Health; U.S. National Institute on Aging; Uppsala University; Uppsala University Hospital; Swedish Research Council; Swedish Heart-Lung Foundation; Dutch Kidney Foundation [E.033]; Groningen University Medical Center (Beleidsruimte); Bristol Myers Squibb; Dade Behring; Ausam; Roche; Abbott; The Netherlands Organization of Scientific Research; Dutch Heart Foundation; De Cock Foundation; UK Medical Research Council [G0500877]; National Health and Medical Research Council of Australia [353514, 572613, 403981]; Canadian Institutes of Health Research [MOP82893]; University of Western Australia (UWA); Raine Medical Research Foundation; Telethon Institute for Child Health Research; UWA Faculty of Medicine, Dentistry and Health Sciences; Women and Infants Research Foundation; Curtin University; Swedish Foundation for Strategic Research; ALF/LUA research grant in Gothenburg; Lundberg Foundation; Torsten and Ragnar Soderber's Foundation; Petrus and Augusta Hedlunds Foundation FX The CORtisol NETwork Consortium is funded by the Chief Scientist Office of the Scottish Government (grant CZB-4-733) and the British Heart Foundation (grant RG11/4/28734). The CROATIA-Vis, CROATIA-Korcula and CROATIA-Split studies were funded by grants from the Medical Research Council (UK), the Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302), and European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). In the Rotterdam Study, the generation and management of genome-wide association study genotype data are supported by the Netherlands Organisation of Scientific Research Investments (number 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015) and the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research project number 050-060-810. The Rotterdam Study is funded by Erasmus MC and Erasmus University, Rotterdam, the Netherlands Organization for the Health Research and Development, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (Directorate-General XII), and the Municipality of Rotterdam. HT was supported by the Vidi Grant of Netherlands Organization for the Health Research and Development (2009-017.106.370). ND was supported by the Netherlands Consortium for Healthy Ageing. The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhalsan Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). The Northern Finland Birth Cohort 1966 study is supported by the Academy of Finland [project grants 104781, 120315, 129418, Center of Excellence in Complex Disease Genetics and Public Health Challenges Research Program (SALVE)], University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission [EUROBLCS, Framework 5 award QLG1-CT-2000-01643], The National Heart, Lung and Blood Institute [5R01HL087679-02] through the SNP Typing for Association with Multiple Phenotypes from Existing Epidemiologic Data (STAMPEED) program [1RL1MH083268-01], The National Institute of Health/The National Institute of Mental Health [5R01MH63706:02], European Network of Genomic and Genetic Epidemiology (ENGAGE) project and grant agreement [HEALTH-F4-2007-201413], and the Medical Research Council, UK [G0500539, G0600705, PrevMetSyn/Public Health Challenges Research Program (SALVE)]. ALSPAC was funded by the UK Medical Research Council and the Wellcome Trust (Grant ref: 092731) and the University of Bristol. The InCHIANTI study has been supported by the Italian Ministry of Health and the U.S. National Institute on Aging. The PIVUS study was supported by Wellcome Trust Grants WT098017, WT064890, WT090532, Uppsala University, Uppsala University Hospital, the Swedish Research Council and the Swedish Heart-Lung Foundation. The PREVEND Study has been supported by the Dutch Kidney Foundation (Grant E.; 033), the Groningen University Medical Center (Beleidsruimte), Bristol Myers Squibb, Dade Behring, Ausam, Roche, Abbott, The Netherlands Organization of Scientific Research, The Dutch Heart Foundation, and the De Cock Foundation. The Edinburgh Type 2 Diabetes Study was funded by the UK Medical Research Council (G0500877). For the Raine Study, this work was supported by funding for the 17 year follow-up and genotyping provided by the National Health and Medical Research Council of Australia (353514, 572613, 403981) and the Canadian Institutes of Health Research (MOP82893). Core funding for the Raine Study is provided by the University of Western Australia (UWA), Raine Medical Research Foundation, the Telethon Institute for Child Health Research, UWA Faculty of Medicine, Dentistry and Health Sciences, the Women and Infants Research Foundation and Curtin University. The MrOS-Sweden study was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, European Commission Grant QLK4-CT-2002-02528, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Soderber's Foundation, Petrus and Augusta Hedlunds Foundation, and the Novo Nordisk Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 17 Z9 17 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2014 VL 10 IS 7 AR e1004474 DI 10.1371/journal.pgen.1004474 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA AM5ME UT WOS:000339902600028 PM 25010111 ER PT J AU Brohl, AS Solomon, DA Chang, W Wang, JJ Song, Y Sindiri, S Patidar, R Hurd, L Chen, L Shern, JF Liao, HL Wen, XY Gerard, J Kim, JS Guerrero, JAL Machado, I Wai, DH Picci, P Triche, T Horvai, AE Miettinen, M Wei, JS Catchpool, D Llombart-Bosch, A Waldman, T Khan, J AF Brohl, Andrew S. Solomon, David A. Chang, Wendy Wang, Jianjun Song, Young Sindiri, Sivasish Patidar, Rajesh Hurd, Laura Chen, Li Shern, Jack F. Liao, Hongling Wen, Xinyu Gerard, Julia Kim, Jung-Sik Lopez Guerrero, Jose Antonio Machado, Isidro Wai, Daniel H. Picci, Piero Triche, Timothy Horvai, Andrew E. Miettinen, Markku Wei, Jun S. Catchpool, Daniel Llombart-Bosch, Antonio Waldman, Todd Khan, Javed TI The Genomic Landscape of the Ewing Sarcoma Family of Tumors Reveals Recurrent STAG2 Mutation SO PLOS GENETICS LA English DT Article ID ETV6-NTRK3 GENE FUSION; POLYMORPHIC STOP CODON; BLADDER-CANCER; P53 MUTATIONS; PROGNOSTIC IMPACT; RHABDOMYOSARCOMA; TRANSCRIPTS; EXPRESSION; COHESION; BRCA2 AB The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing. C1 [Brohl, Andrew S.; Chang, Wendy; Wang, Jianjun; Song, Young; Sindiri, Sivasish; Patidar, Rajesh; Hurd, Laura; Chen, Li; Shern, Jack F.; Liao, Hongling; Wen, Xinyu; Wei, Jun S.; Khan, Javed] NCI, Oncogen Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Brohl, Andrew S.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Solomon, David A.; Horvai, Andrew E.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Gerard, Julia; Kim, Jung-Sik; Catchpool, Daniel] Childrens Hosp Westmead, Tumour Bank, Childrens Canc Res Unit, Westmead, NSW, Australia. [Lopez Guerrero, Jose Antonio; Machado, Isidro; Llombart-Bosch, Antonio] Univ Valencia, Dept Pathol, Valencia, Spain. [Wai, Daniel H.; Triche, Timothy] Univ So Calif, Childrens Hosp Los Angeles, Ctr Personalized Med, Los Angeles, CA USA. [Picci, Piero] Rizzoli Inst, Expt Oncol Lab, Bologna, Italy. [Miettinen, Markku] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Waldman, Todd] Georgetown Univ, Sch Med, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Brohl, AS (reprint author), NCI, Oncogen Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM khanjav@mail.nih.gov RI Picci, Piero/J-5979-2016; Khan, Javed/P-9157-2014 OI Picci, Piero/0000-0002-8519-4101; sindiri, sivasish/0000-0003-2516-969X; Khan, Javed/0000-0002-5858-0488 FU NIH, National Cancer Institute, Center for Cancer Research FX WC, JW, YS, SS, RP, LH, LC, JFS, HL, XW, JSW, and JK are supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 69 Z9 70 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2014 VL 10 IS 7 AR e1004475 DI 10.1371/journal.pgen.1004475 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AM5ME UT WOS:000339902600029 PM 25010205 ER PT J AU Li, QT Wang, HY Chepelev, I Zhu, QY Wei, G Zhao, K Wang, RF AF Li, Qingtian Wang, Helen Y. Chepelev, Iouri Zhu, Qingyuan Wei, Gang Zhao, Keji Wang, Rong-Fu TI Stage-Dependent and Locus-Specific Role of Histone Demethylase Jumonji D3 (JMJD3) in the Embryonic Stages of Lung Development SO PLOS GENETICS LA English DT Article ID SURFACTANT PROTEIN-B; GENE-EXPRESSION; MEDIATED REPRESSION; RESPIRATORY-FAILURE; H3K27 DEMETHYLASE; TRANSGENIC MICE; NEURAL CREST; CELLS; MOUSE; UTX AB Histone demethylases have emerged as important players in developmental processes. Jumonji domain containing-3 (Jmjd3) has been identified as a key histone demethylase that plays a critical role in the regulation of gene expression; however, the in vivo function of Jmjd3 in embryonic development remains largely unknown. To this end, we generated Jmjd3 global and conditional knockout mice. Global deletion of Jmjd3 induces perinatal lethality associated with defective lung development. Tissue and stage-specific deletion revealed that Jmjd3 is dispensable in the later stage of embryonic lung development. Jmjd3 ablation downregulates the expression of genes critical for lung development and function, including AQP-5 and SP-B. Jmjd3-mediated alterations in gene expression are associated with locus-specific changes in the methylation status of H3K27 and H3K4. Furthermore, Jmjd3 is recruited to the SP-B promoter through interactions with the transcription factor Nkx2.1 and the epigenetic protein Brg1. Taken together, these findings demonstrate that Jmjd3 plays a stage-dependent and locus-specific role in the mouse lung development. Our study provides molecular insights into the mechanisms by which Jmjd3 regulates target gene expression in the embryonic stages of lung development. C1 [Li, Qingtian; Wang, Helen Y.; Zhu, Qingyuan; Wang, Rong-Fu] Houston Methodist Res Inst, Ctr Inflammat & Epigenet, Houston, TX 77030 USA. [Chepelev, Iouri] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45229 USA. [Wei, Gang] Chinese Acad Sci, CAS MPG Partner Inst Computat Biol, Shanghai Inst Biol Sci, Shanghai, Peoples R China. [Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Li, QT (reprint author), Houston Methodist Res Inst, Ctr Inflammat & Epigenet, Houston, TX 77030 USA. EM rwang3@tmhs.org FU National Cancer Institute, National Institutes of Health [R01 CA09327, R01 CA121191] FX This work was supported in part by grants from National Cancer Institute, National Institutes of Health (R01 CA09327, R01 CA121191 to RFW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 16 Z9 17 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2014 VL 10 IS 7 AR e1004524 DI 10.1371/journal.pgen.1004524 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA AM5ME UT WOS:000339902600056 PM 25079229 ER PT J AU Makinen, VP Civelek, M Meng, QY Zhang, B Zhu, J Levian, C Huan, TX Segre, AV Ghosh, S Vivar, J Nikpay, M Stewart, AFR Nelson, CP Willenborg, C Erdmann, J Blakenberg, S O'Donnell, CJ Marz, W Laaksonen, R Epstein, SE Kathiresan, S Shah, SH Hazen, SL Reilly, MP Lusis, AJ Samani, NJ Schunkert, H Quertermous, T McPherson, R Yang, X Assimes, TL AF Makinen, Ville-Petteri Civelek, Mete Meng, Qingying Zhang, Bin Zhu, Jun Levian, Candace Huan, Tianxiao Segre, Ayellet V. Ghosh, Sujoy Vivar, Juan Nikpay, Majid Stewart, Alexandre F. R. Nelson, Christopher P. Willenborg, Christina Erdmann, Jeanette Blakenberg, Stefan O'Donnell, Christopher J. Marz, Winfried Laaksonen, Reijo Epstein, Stephen E. Kathiresan, Sekar Shah, Svati H. Hazen, Stanley L. Reilly, Muredach P. Lusis, Aldons J. Samani, Nilesh J. Schunkert, Heribert Quertermous, Thomas McPherson, Ruth Yang, Xia Assimes, Themistocles L. CA Coronary ARtery DIs Genome-Wide TI Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease SO PLOS GENETICS LA English DT Article ID EVENTS ILLUMINATE TRIAL; LIPID-LEVEL MANAGEMENT; WIDE ASSOCIATION; HEART-DISEASE; FUNCTIONAL VARIATION; CANDIDATE GENES; EXPRESSION; IDENTIFICATION; ATHEROSCLEROSIS; LOCI AB The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions. C1 [Makinen, Ville-Petteri; Meng, Qingying; Levian, Candace; Yang, Xia] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA. [Makinen, Ville-Petteri] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. [Makinen, Ville-Petteri] Univ Adelaide, Sch Mol & Biomed Sci, Adelaide, SA, Australia. [Civelek, Mete; Lusis, Aldons J.] Univ Calif Los Angeles, David Geffen Sch Med, Div Cardiol, Dept Med, Los Angeles, CA 90095 USA. [Zhang, Bin; Zhu, Jun] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Huan, Tianxiao; O'Donnell, Christopher J.; Kathiresan, Sekar] NHLBI, Framingham Heart Study, Framingham, MA USA. [Segre, Ayellet V.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Ghosh, Sujoy; Vivar, Juan] N Carolina Cent Univ, Dept Cardiovasc & Metab Res, Biomed Biotechnol Res Inst, Durham, NC USA. [Ghosh, Sujoy] Duke NUS Grad Med Sch, Program Cardiovasc & Metab Disorders & Ctr Comput, Singapore, Singapore. [Nikpay, Majid; McPherson, Ruth] Univ Ottawa, Inst Heart, Atherogen Lab, Ottawa, ON, Canada. [Stewart, Alexandre F. R.] Univ Ottawa, Inst Heart, John & Jennifer Ruddy Canadian Cardiovasc Res, Ottawa, ON, Canada. [Nelson, Christopher P.; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Hosp, Natl Inst Hlth Res NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Willenborg, Christina; Erdmann, Jeanette] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23538 Lubeck, Germany. [Erdmann, Jeanette] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany. [Blakenberg, Stefan] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. [O'Donnell, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Ctr Human Genet Res, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA USA. [Marz, Winfried] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth Social & Prevent Med, Mannheim, Germany. [Marz, Winfried] Synlab Acad, Mannheim, Germany. [Laaksonen, Reijo] Tampere Univ Hosp, Ctr Sci, Tampere, Finland. [Epstein, Stephen E.] Washington Hosp Ctr, Cardiovasc Res Inst, Washington, DC 20010 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Shah, Svati H.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Hazen, Stanley L.] Cleveland Clin, Cleveland, OH 44106 USA. [Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Schunkert, Heribert] DZHK German Res Ctr Cardiovasc Res, Munich, Germany. [Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Quertermous, Thomas; Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. RP Makinen, VP (reprint author), Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA. EM xyang123@ucla.edu; tassimes@stanford.edu RI Willenborg, Christina/D-2668-2012; Erdmann, Jeanette/P-7513-2014; OI Willenborg, Christina/0000-0001-5217-6882; Makinen, Ville-Petteri/0000-0002-7262-2656; Stewart, Alexandre/0000-0003-2673-9164; Erdmann, Jeanette/0000-0002-4486-6231; GHOSH, SUJOY/0000-0002-7601-165X; Civelek, Mete/0000-0002-8141-0284; Assimes, Themistocles/0000-0003-2349-0009; Kleber, Marcus/0000-0003-0663-7275 FU American Heart Association; Finnish Cultural Foundation Postdoc Pool; Heart and Stroke Foundation of Canada [T-7268]; Canadian Institutes of Health Research [MOP2390941]; Ruth L. Kirschstein National Research Service Award [T32HL69766]; Transatlantic Networks of Excellence Award from Foundation Leducq; NIH-NIDDK [1R21DK088319]; NIH-NIMH [D2P20MD000175-11, R21MH097156-01A1]; NIH-NIA [R01AG046170]; NIH-NCI [R01CA163772]; NIH-NIAID [U01AI111598] FX The study was funded by American Heart Association (VPM, XY, SG), The Finnish Cultural Foundation Postdoc Pool (VPM), Heart and Stroke Foundation of Canada T-7268 (RM), Canadian Institutes of Health Research MOP2390941 (RM), Ruth L. Kirschstein National Research Service Award T32HL69766 (MC), Transatlantic Networks of Excellence Award from Foundation Leducq (MC, AJL, XY), NIH-NIDDK 1R21DK088319 (SG), NIH-NIMH D2P20MD000175-11 (SG), NIH-NIA R01AG046170 (BZ), NIH-NIMH R21MH097156-01A1 (BZ), NIH-NCI R01CA163772 (BZ), and NIH-NIAID U01AI111598-01 (BZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 49 Z9 49 U1 2 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2014 VL 10 IS 7 AR e1004502 DI 10.1371/journal.pgen.1004502 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA AM5ME UT WOS:000339902600047 PM 25033284 ER PT J AU Rawal, Y Qiu, HF Hinnebusch, AG AF Rawal, Yashpal Qiu, Hongfang Hinnebusch, Alan G. TI Accumulation of a Threonine Biosynthetic Intermediate Attenuates General Amino Acid Control by Accelerating Degradation of Gcn4 via Pho85 and Cdk8 SO PLOS GENETICS LA English DT Article ID TRANSCRIPTION FACTOR GCN4; RNA-POLYMERASE-II; SACCHAROMYCES-CEREVISIAE; IN-VIVO; ACTIVATOR GCN4P; SRB MEDIATOR; HOMOSERINE DEHYDROGENASE; BINDING PROTEIN; SHUTTLE VECTORS; YEAST AB Gcn4 is a master transcriptional regulator of amino acid and vitamin biosynthetic enzymes subject to the general amino acid control (GAAC), whose expression is upregulated in response to amino acid starvation in Saccharomyces cerevisiae. We found that accumulation of the threonine pathway intermediate beta-aspartate semialdehyde (ASA), substrate of homoserine dehydrogenase (Hom6), attenuates the GAAC transcriptional response by accelerating degradation of Gcn4, already an exceedingly unstable protein, in cells starved for isoleucine and valine. The reduction in Gcn4 abundance on ASA accumulation requires Cdk8/Srb10 and Pho85, cyclin-dependent kinases (CDKs) known to mediate rapid turnover of Gcn4 by the proteasome via phosphorylation of the Gcn4 activation domain under nonstarvation conditions. Interestingly, rescue of Gcn4 abundance in hom6 cells by elimination of SRB10 is not accompanied by recovery of transcriptional activation, while equivalent rescue of UAS-bound Gcn4 in hom6 pho85 cells restores greater than wild-type activation of Gcn4 target genes. These and other findings suggest that the two CDKs target different populations of Gcn4 on ASA accumulation, with Srb10 clearing mostly inactive Gcn4 molecules at the promoter that are enriched for sumoylation of the activation domain, and Pho85 clearing molecules unbound to the UAS that include both fully functional and inactive Gcn4 species. C1 [Rawal, Yashpal; Qiu, Hongfang; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Rawal, Y (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov FU National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 1 Z9 1 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2014 VL 10 IS 7 AR e1004534 DI 10.1371/journal.pgen.1004534 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA AM5ME UT WOS:000339902600058 PM 25079372 ER PT J AU Szabo, R Peters, DE Kosa, P Camerer, E Bugge, TH AF Szabo, Roman Peters, Diane E. Kosa, Peter Camerer, Eric Bugge, Thomas H. TI Regulation of Feto-Maternal Barrier by Matriptase- and PAR-2-Mediated Signaling Is Required for Placental Morphogenesis and Mouse Embryonic Survival SO PLOS GENETICS LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; PROTEASE-ACTIVATED RECEPTOR-2; NEURAL-TUBE CLOSURE; SERINE-PROTEASE; THROMBIN RECEPTOR; EPIDERMAL BARRIER; ENDOTHELIAL-CELLS; BREAST-CANCER; FETAL-GROWTH; MICE AB The development of eutherian mammalian embryos is critically dependent on the selective bi-directional transport of molecules across the placenta. Here, we uncover two independent and partially redundant protease signaling pathways that include the membrane-anchored serine proteases, matriptase and prostasin, and the G protein-coupled receptor PAR-2 that mediate the establishment of a functional feto-maternal barrier. Mice with a combined matriptase and PAR-2 deficiency do not survive to term and the survival of matriptase-deficient mice heterozygous for PAR-2 is severely diminished. Embryos with the combined loss of PAR-2 and matriptase or PAR-2 and the matriptase partner protease, prostasin, uniformly die on or before embryonic day 14.5. Despite the extensive co-localization of matriptase, prostasin, and PAR-2 in embryonic epithelia, the overall macroscopic and histological analysis of the double-deficient embryos did not reveal any obvious developmental abnormalities. In agreement with this, the conditional deletion of matriptase from the embryo proper did not affect the prenatal development or survival of PAR-2-deficient mice, indicating that the critical redundant functions of matriptase/prostasin and PAR-2 are limited to extraembryonic tissues. Indeed, placentas of the double-deficient animals showed decreased vascularization, and the ability of placental epithelium to establish a functional feto-maternal barrier was severely diminished. Interestingly, molecular analysis suggested that the barrier defect was associated with a selective deficiency in the expression of the tight junction protein, claudin-1. Our results reveal unexpected complementary roles of matriptase-prostasin-and PAR-2-dependent proteolytic signaling in the establishment of placental epithelial barrier function and overall embryonic survival. C1 [Szabo, Roman; Peters, Diane E.; Kosa, Peter; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Sect, NIH, Bethesda, MD 20892 USA. [Peters, Diane E.] Tufts Univ, Sch Med, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. [Camerer, Eric] INSERM, Paris Cardiovasc Res Ctr, U970, Paris, France. [Camerer, Eric] Univ Paris 05, Paris, France. RP Szabo, R (reprint author), Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Sect, NIH, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov FU NIDCR Intramural Research Program; INSERM Avenir, Marie Curie Actions; French National Research Agency; Ile-de-France Region FX The study was supported by the NIDCR Intramural Research Program (THB), and the INSERM Avenir, Marie Curie Actions, The French National Research Agency and the Ile-de-France Region (EC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 4 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2014 VL 10 IS 7 AR e1004470 DI 10.1371/journal.pgen.1004470 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AM5ME UT WOS:000339902600026 PM 25078604 ER PT J AU Traylor, M Makela, KM Kilarski, LL Holliday, EG Devan, WJ Nalls, MA Wiggins, KL Zhao, W Cheng, YC Achterberg, S Malik, R Sudlow, C Bevan, S Raitoharju, E Oksala, N Thijs, V Lemmens, R Lindgren, A Slowik, A Maguire, JM Walters, M Algra, A Sharma, P Attia, JR Boncoraglio, GB Rothwell, PM de Bakker, PIW Bis, JC Saleheen, D Kittner, SJ Mitchell, BD Rosand, J Meschia, JF Levi, C Dichgans, M Lehtimaki, T Lewis, C Markus, HS AF Traylor, Matthew Makela, Kari-Matti Kilarski, Laura L. Holliday, Elizabeth G. Devan, William J. Nalls, Mike A. Wiggins, Kerri L. Zhao, Wei Cheng, Yu-Ching Achterberg, Sefanja Malik, Rainer Sudlow, Cathie Bevan, Steve Raitoharju, Emma Oksala, Niku Thijs, Vincent Lemmens, Robin Lindgren, Arne Slowik, Agnieszka Maguire, Jane M. Walters, Matthew Algra, Ale Sharma, Pankaj Attia, John R. Boncoraglio, Giorgio B. Rothwell, Peter M. Bakker, Paul I. W. de Bis, Joshua C. Saleheen, Danish Kittner, Steven J. Mitchell, Braxton D. Rosand, Jonathan Meschia, James F. Levi, Christopher Dichgans, Martin Lehtimaki, Terho M. Lewis, Cathryn Markus, Hugh S. CA Metastroke Int Stroke Wellcome Trust Case Consortium TI A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach SO PLOS GENETICS LA English DT Article ID ISCHEMIC-STROKE; MATRIX METALLOPROTEINASE-12; GENOTYPE IMPUTATION; ATRIAL-FIBRILLATION; LIFETIME RISK; METAANALYSIS; MACROPHAGES; VARIANTS; PLAQUES; STABILITY AB Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5x10(-7)), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6x10(-8)). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2x10(-15); fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS. C1 [Traylor, Matthew; Kilarski, Laura L.] St Georges Univ London, Stroke & Dementia Res Ctr, London, England. [Makela, Kari-Matti; Raitoharju, Emma; Oksala, Niku; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Makela, Kari-Matti; Raitoharju, Emma; Oksala, Niku; Lehtimaki, Terho] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Holliday, Elizabeth G.; Maguire, Jane M.; Attia, John R.] Univ Newcastle, Ctr Clin Epidemiol & Biostat, Sch Med & Publ Hlth, Callaghan, NSW 2308, Australia. [Holliday, Elizabeth G.; Maguire, Jane M.; Attia, John R.; Levi, Christopher] Hunter Med Res Inst, New Lambton Hts, NSW, Australia. [Devan, William J.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Devan, William J.; Bakker, Paul I. W. de; Rosand, Jonathan] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Nalls, Mike A.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Wiggins, Kerri L.; Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Zhao, Wei] Univ Penn, Div Translat Med & Human Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Cheng, Yu-Ching; Mitchell, Braxton D.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Cheng, Yu-Ching; Kittner, Steven J.] Vet Affairs Maryland Hlth Care Syst, Res & Dev Program, Baltimore, MD USA. [Achterberg, Sefanja; Algra, Ale] Univ Med Ctr Utrecht, Dept Neurol & Neurosurg, Brain Ctr Rudolf Magnus, Utrecht, Netherlands. [Malik, Rainer; Dichgans, Martin] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Sudlow, Cathie] Univ Edinburgh, Div Clin Neurosci, Edinburgh, Midlothian, Scotland. [Sudlow, Cathie] Univ Edinburgh, Insititute Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Bevan, Steve; Markus, Hugh S.] Univ Cambridge, Cambridge, England. [Oksala, Niku] Tampere Univ Hosp, Dept Surg, Tampere, Finland. [Thijs, Vincent; Lemmens, Robin] Katholieke Univ Leuven, Dept Neurosci, Neurobiol Lab, Leuven, Belgium. [Thijs, Vincent; Lemmens, Robin] VIB, Vesalius Res Ctr, Leuven, Belgium. [Thijs, Vincent; Lemmens, Robin] Univ Hosp Leuven, Dept Neurol, Leuven, Belgium. [Lindgren, Arne] Lund Univ, Dept Clin Sci Lund, Lund, Sweden. [Lindgren, Arne] Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden. [Slowik, Agnieszka] Jagiellonian Univ, Dept Neurol, Krakow, Poland. [Maguire, Jane M.] Univ Newcastle, Sch Nursing & Midwifery, Callaghan, NSW 2308, Australia. [Maguire, Jane M.; Attia, John R.; Levi, Christopher] Univ Newcastle, Ctr Translat Neurosci & Mental Hlth, Callaghan, NSW 2308, Australia. [Walters, Matthew] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Algra, Ale; Bakker, Paul I. W. de] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Sharma, Pankaj] Univ London Imperial Coll Sci Technol & Med, Imperial Coll Cerebrovasc Res Unit ICCRU, London, England. [Boncoraglio, Giorgio B.] Fdn Ist Ricovero & Cura & Carattere Sci, Ist Neurol Carlo Besta, Dept Cereberovasc Dis, Milan, Italy. [Rothwell, Peter M.] Univ Oxford, Nuffield Dept Clin Neurosci, Stroke Prevent Res Unit, Oxford, England. [Bakker, Paul I. W. de] Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands. [Bakker, Paul I. W. de] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Saleheen, Danish] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Dichgans, Martin] Univ Munich, Munich Cluster Syst Neurol SyNergy, Munich, Germany. [M. Lewis, Cathryn] Kings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England. [M. Lewis, Cathryn] Kings Coll London, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. RP Traylor, M (reprint author), St Georges Univ London, Stroke & Dementia Res Ctr, London, England. EM mtraylor@sgul.ac.uk RI Thijs, Vincent/C-3647-2009; de Bakker, Paul/B-8730-2009; Boncoraglio, Giorgio/B-8647-2011; Lewis, Cathryn/A-5225-2010 OI Thijs, Vincent/0000-0002-6614-8417; Kilarski, Laura/0000-0003-0645-3134; Traylor, Matthew/0000-0001-6624-8621; Zhao, Wei/0000-0002-8301-9297; Bevan, Steve/0000-0003-0490-6830; Mitchell, Braxton/0000-0003-4920-4744; de Bakker, Paul/0000-0001-7735-7858; Lewis, Cathryn/0000-0002-8249-8476 FU Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project [085475/B/08/Z, 085475/Z/08/Z, WT084724MA]; NIHR Senior Investigator award; NIHR Biomedical Research Centre at Cambridge; National Institutes of Health Research Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust; King's College London; Netherlands Heart Foundation [2005B031]; Dutch Brain Foundation [2008(1).10]; University of Newcastle; Australian National and Medical Health Research Council (NHMRC) [569257]; Australian National Heart Foundation (NHF) [G 04S 1623]; Gladys M Brawn Fellowship scheme; Vincent Fairfax Family Foundation in Australia; Australian NHMRC Fellowship scheme; National Institutes of Health Genes, Environment and Health Initiative (GEI) Grant [U01 HG004436]; GENEVA consortium under GEI; Mid-Atlantic Nutrition and Obesity Research Center [P30 DK072488]; Office of Research and Development, Medical Research Service; Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; National Institutes of Health [HHSN268200782096C]; Division of Adult and Community Health, Centers for Disease Control; National Institute of Neurological Disorders and Stroke (NINDS); NIH Office of Research on Women's Health [R01 NS45012, U01 NS069208-01]; NHLBI [R01 HL085251, R01 HL073410]; Intramural Research Program of the National Institute on Aging, NIH project [Z01 AG-000954-06, Z01 AG-000015-50, 2003-078]; NIH-NINDS Grant [R01 NS-42733, R01 NS-39987]; National Institute of Neurological Disorders and Stroke [U01 NS069208]; American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010N]; National Institutes of Health; National Heart, Lung, and Blood Institute's STAMPEED genomics research program [R01 HL087676]; National Center for Research Resources [U54 RR020278]; Italian Ministry of Health [RC 2007/LR6, RC 2008/LR6, RC 2009/LR8, RC 2010/LR8]; Medical Research Council; Stroke Association; Dunhill Medical Trust; National Institute of Health Research (NIHR); NIHR Biomedical Research Centre, Oxford; Wellcome Trust; Binks Trust; German Federal Ministry of Education and Research (BMBF); FP7 European Union project [261123]; Scottish Funding Council; Chief Scientist Office; Vascular Dementia Research Foundation; Medical Research Council [WT095219MA, G1001799]; European Union [201668]; Finnish Foundation of Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Tampere University Hospital Medical Fund [9M048, 9N035]; Foundation of Clinical Chemistry FX The principal funding for this study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). HSM is supported by an NIHR Senior Investigator award and the NIHR Biomedical Research Centre at Cambridge. We acknowledge support from the National Institutes of Health Research Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. The PROMISe Study (The Netherlands) was made possible, in part, by a Complementation Grant to PIWdB from the Biobanking and Biomolecular Resources Research Infrastructure in the Netherlands (BBMRI-NL). SA is supported in part by a grant from the Netherlands Heart Foundation (grant no. 2005B031) and a grant from the Dutch Brain Foundation (project 2008(1).10). The Australian Stroke Genetics Collaboration (ASGC) Australian population control data was derived from the Hunter Community Study. We also thank the University of Newcastle for funding and the men and women of the Hunter region who participated in this study. This research was funded by grants from the Australian National and Medical Health Research Council (NHMRC Project Grant ID: 569257), the Australian National Heart Foundation (NHF Project Grant ID: G 04S 1623), the University of Newcastle, the Gladys M Brawn Fellowship scheme and the Vincent Fairfax Family Foundation in Australia. EGH is supported by the Australian NHMRC Fellowship scheme. The Genetics of Early Onset Stroke (GEOS) Study, Baltimore, USA was supported by the National Institutes of Health Genes, Environment and Health Initiative (GEI) Grant U01 HG004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488); and the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University (contract number HHSN268200782096C). Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG 004446; PI Bruce S Weir). Study recruitment and assembly of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and by grants from the National Institute of Neurological Disorders and Stroke (NINDS) and the NIH Office of Research on Women's Health (R01 NS45012, U01 NS069208-01). The Heart and Vascular Health Study (HVH) research reported in this article was funded by NHLBI grants R01 HL085251 and R01 HL073410 The Ischemic Stroke Genetics Study (ISGS)/Siblings With Ischemic Stroke Study (SWISS) study was supported in part by the Intramural Research Program of the National Institute on Aging, NIH project Z01 AG-000954-06. ISGS/SWISS used samples and clinical data from the NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), human subjects protocol numbers 2003-081 and 2004-147. ISGS/SWISS used stroke-free participants from the Baltimore Longitudinal Study of Aging (BLSA) as controls.; The inclusion of BLSA samples was supported in part by the Intramural Research Program of the National Institute on Aging, NIH project Z01 AG-000015-50, human subjects protocol number 2003-078. The ISGS study was funded by NIH-NINDS Grant R01 NS-42733 (JFM, P. I.). The SWISS study was funded by NIH-NINDS Grant R01 NS-39987 (JFM, P. I.). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http://biowulf.nih.gov). The MGH Genes Affecting Stroke Risk and Outcome Study (MGH-GASROS) GASROS was supported by The National Institute of Neurological Disorders and Stroke (U01 NS069208), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research 0775010N, the National Institutes of Health and National Heart, Lung, and Blood Institute's STAMPEED genomics research program (R01 HL087676) and a grant from the National Center for Research Resources. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research resources. Milano - Besta Stroke Register Collection and genotyping of the Milan cases within CEDIR were supported by Annual Research Funding of the Italian Ministry of Health (Grant Numbers: RC 2007/LR6, RC 2008/LR6; RC 2009/LR8; RC 2010/LR8). FP6 LSHM-CT-2007-037273 for the PROCARDIS control samples. The Wellcome Trust Case-Control Consortium 2 (WTCCC2) The principal funding for the WTCCC2 stroke study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). The Stroke Association provided additional support for collection of some of the St George's, London cases. The Oxford cases were collected as part of the Oxford Vascular Study which is funded by the Medical Research Council, Stroke Association, Dunhill Medical Trust, National Institute of Health Research (NIHR) and the NIHR Biomedical Research Centre, Oxford. PMR has a Wellcome Trust Senior Investigator Award and an NIHR Senior Investigator Award. The Edinburgh Stroke Study was supported by the Wellcome Trust (clinician scientist award to CS), and the Binks Trust. Sample processing occurred in the Genetics Core Laboratory of the Wellcome Trust Clinical Research Facility, Western General Hospital, Edinburgh. This work was supported by grants received from the German Federal Ministry of Education and Research (BMBF) in the context of the e: Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123) to Martin Dichgans. Much of the neuroimaging occurred in the Scottish Funding Council Brain Imaging Research Centre (www.sbirc.ed.ac.uk), Division of Clinical Neurosciences, University of Edinburgh, a core area of the Wellcome Trust Clinical Research Facility and part of the SINAPSE (Scottish Imaging Network - A Platform for Scientific Excellence) collaboration (www.sinapse.ac.uk), funded by the Scottish Funding Council and the Chief Scientist Office. Collection of the Munich cases and data analysis was supported by the Vascular Dementia Research Foundation. This work made use of data and samples generated by the 1958 Birth Cohort (NCDS). Access to these resources was enabled via the 58READIE Project funded by Wellcome Trust and Medical Research Council (grant numbers WT095219MA and G1001799). A full list of the financial, institutional and personal contributions to the development of the 1958 Birth Cohort Biomedical resource is available at http://www2.le.ac.uk/projects/birthcohort.; Tampere Vascular Study (TVS) was supported by the European Union 7th Framework Programme funding for the AtheroRemo project [201668], the Finnish Foundation of Cardiovascular Research (TL), the Finnish Cultural Foundation, the Tampere Tuberculosis Foundation, the Emil Aaltonen Foundation (NO & TL), the Tampere University Hospital Medical Fund (grant 9M048 and 9N035) and the the Foundation of Clinical Chemistry. Immunochip case data for UK, Polish, Belgian, German and Swedish cohorts was genotyped by the Sanger Centre, Cambridge, UK as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA), as were the UK and Polish control cohorts. German Control Genotypes was provided through the POPGEN Consortium. Swedish Immunochip Control Samples were provided by the Swedish SLE network and the Uppsala Bioresource. Belgian Immunochip Control Sample Genotypes were provided through the efforts of the International Multiple Sclerosis Genetics Consortium (IMSGC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 21 Z9 21 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2014 VL 10 IS 7 AR e1004469 DI 10.1371/journal.pgen.1004469 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA AM5ME UT WOS:000339902600025 PM 25078452 ER PT J AU Wistow, GJ Slingsby, C AF Wistow, Graeme J. Slingsby, Christine TI Editorial for special issue: Crystallins of the eye SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY LA English DT Editorial Material C1 [Wistow, Graeme J.] NEI, Sect Mol Struct & Funct Genom, NIH, Bethesda, MD 20892 USA. [Slingsby, Christine] Birkbeck Coll, Dept Biol Sci, Inst Struct & Mol Biol, London WC1E 7HX, England. RP Slingsby, C (reprint author), Birkbeck Coll, Dept Biol Sci, Inst Struct & Mol Biol, Malet St, London WC1E 7HX, England. EM c.slingsby@mail.cryst.bbk.ac.uk FU Medical Research Council [G0801846] NR 0 TC 1 Z9 1 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6107 J9 PROG BIOPHYS MOL BIO JI Prog. Biophys. Mol. Biol. PD JUL PY 2014 VL 115 IS 1 BP 1 EP 2 DI 10.1016/j.pbiomolbio.2014.05.003 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AM9RX UT WOS:000340219800001 PM 24844429 ER PT J AU Slingsby, C Wistow, GJ AF Slingsby, Christine Wistow, Graeme J. TI Functions of crystallins in and out of lens: Roles in elongated and post-mitotic cells SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY LA English DT Review DE Crystallins; Chaperone; Lens; Retina; Epithelial cell; Stress ID ALPHA-B-CRYSTALLIN; BETA-GAMMA-CRYSTALLIN; HEAT-SHOCK PROTEINS; FISH HAPLOCHROMIS-BURTONI; HUMAN-MALIGNANT MELANOMA; SEQUENCE TAG ANALYSIS; SPLICE-SITE MUTATION; VERTEBRATE EYE LENS; OPTIC-NERVE; MACULAR DEGENERATION AB The vertebrate lens evolved to collect light and focus it onto the retina. In development, the lens grows through massive elongation of epithelial cells possibly recapitulating the evolutionary origins of the lens. The refractive index of the lens is largely dependent on high concentrations of soluble proteins called crystallins. All vertebrate lenses share a common set of crystallins from two superfamilies (although other lineage specific crystallins exist). The alpha-crystallins are small heat shock proteins while the beta- and gamma-crystallins belong to a superfamily that contains structural proteins of uncertain function. The crystallins are expressed at very high levels in lens but are also found at lower levels in other cells, particularly in retina and brain. All these proteins have plausible connections to maintenance of cytoplasmic order and chaperoning of the complex molecular machines involved in the architecture and function of cells, particularly elongated and post-mitotic cells. They may represent a suite of proteins that help maintain homeostasis in such cells that are at risk from stress or from the accumulated insults of aging. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Slingsby, Christine] Birkbeck Coll, Dept Biol Sci, Inst Struct & Mol Biol, London WC1E 7HX, England. [Wistow, Graeme J.] NEI, Sect Mol Struct & Funct Genom, NIH, Bethesda, MD 20892 USA. RP Slingsby, C (reprint author), Birkbeck Coll, Dept Biol Sci, Inst Struct & Mol Biol, Malet St, London WC1E 7HX, England. EM c.slingsby@mail.cryst.bbk.ac.uk FU Medical Research Council, UK [G0801846]; synchrotron beamline staff at the European Synchrotron Radiation Facility (Grenoble, France); Diamond Light Source (Oxfordshire, UK); Soleil, France; Intramural program of the National Eye Institute, National Institutes of Health, USA FX CS is grateful for the financial support of the Medical Research Council, UK (grant G0801846), and the synchrotron beamline staff at the European Synchrotron Radiation Facility (Grenoble, France) the Diamond Light Source (Oxfordshire, UK) and Soleil, France (partially funded through BIOSTRUCT-X). GW is supported by the Intramural program of the National Eye Institute, National Institutes of Health, USA. We thank Dr Alice Clark for many useful discussions. NR 191 TC 12 Z9 12 U1 1 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6107 J9 PROG BIOPHYS MOL BIO JI Prog. Biophys. Mol. Biol. PD JUL PY 2014 VL 115 IS 1 BP 52 EP 67 DI 10.1016/j.pbiomolbio.2014.02.006 PG 16 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AM9RX UT WOS:000340219800007 PM 24582830 ER PT J AU Bryan, RN Bilello, M Davatzikos, C Lazar, RM Murray, A Horowitz, K Lovato, J Miller, ME Williamson, J Launer, LJ AF Bryan, R. Nick Bilello, Michel Davatzikos, Christos Lazar, Ronald M. Murray, Anne Horowitz, Karen Lovato, James Miller, Michael E. Williamson, Jeff Launer, Lenore J. TI Effect of Diabetes on Brain Structure: The Action to Control Cardiovascular Risk in Diabetes MR Imaging Baseline Data SO RADIOLOGY LA English DT Article ID WHITE-MATTER LESIONS; ALZHEIMERS-DISEASE; COGNITIVE IMPAIRMENT; ELDERLY-PEOPLE; MELLITUS; DEMENTIA; HEALTH; SEGMENTATION; POPULATION; ROTTERDAM AB Purpose: To investigate the association of characteristics of type 2 diabetes mellitus (duration and biochemical severity of diabetes) to brain structure measured on magnetic resonance (MR) images, specifically testing whether more severity in metrics of diabetes is inversely correlated with brain volumes and positively correlated with ischemic lesion volumes. Materials and Methods: This study protocol was approved by the institutional review board of each center and participants provided written informed consent. Baseline severity of diabetes was evaluated by testing fasting plasma glucose levels, hemoglobin A(1c) levels, and duration of diabetes. MR imaging was performed with fluid-attenuated inversion recovery, proton-density, T2-weighted, and T1-weighted sequences, which were postprocessed with an automated computer algorithm that classified brain tissue as gray or white matter and as normal or ischemic. Separate linear regression models adjusted for potential confounding factors were used to investigate the relationship of the diabetes measures to MR imaging outcomes in 614 participants (mean age, 62 years; mean duration of type 2 diabetes mellitus, 9.9 years). Results: The mean volumes of total gray matter (463.9 cm(3)) and total white matter (463.6 cm(3)) were similar. The mean volume of abnormal tissue was 2.5 cm(3), mostly in the white matter (81% white matter, 5% gray matter, 14% deep gray and white matter). Longer duration of diabetes and higher fasting plasma glucose level were associated with lower normal (beta = -0.431 and -0.053, respectively; P < .01) and total gray matter volumes (beta = -0.428 and -0.053, respectively; P < .01). Fasting plasma glucose was also inversely correlated with ischemic lesion volume (beta = 20.006; P < .04). Hemoglobin A(1c) level was not associated with any MR imaging measure. Conclusion: Longer duration of diabetes is associated with brain volume loss, particularly in the gray matter, possibly reflecting direct neurologic insult; biochemical measures of glycemia were less consistently related to MR imaging changes. Contrary to common clinical belief, in this sample of patients with type 2 diabetes mellitus, there was no association of diabetes characteristics with small vessel C1 [Bryan, R. Nick; Bilello, Michel; Davatzikos, Christos] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Lazar, Ronald M.] Columbia Univ, Dept Radiol, New York, NY USA. [Murray, Anne] Hennepin Cty Med Ctr, Dept Radiol, Minneapolis, MN 55415 USA. [Horowitz, Karen] Case Western Reserve Univ, Dept Radiol, Cleveland, OH 44106 USA. [Lovato, James; Miller, Michael E.; Williamson, Jeff] Wake Forest Univ, Dept Radiol, Winston Salem, NC 27109 USA. [Launer, Lenore J.] NIA, Bethesda, MD 20892 USA. RP Bryan, RN (reprint author), Univ Penn, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA. EM Nick.bryan@uphs.upenn.edu FU ACCORD-MIND [AG-0002]; NIA Intramural Research Program FX ACCORD-MIND was funded through an intra-agency agreement between NIA and NHLBI (AG-0002) and the NIA Intramural Research Program. NR 26 TC 8 Z9 9 U1 0 U2 13 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 JUL PY 2014 VL 272 IS 1 BP 210 EP 216 DI 10.1148/radiol.14131494 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AM7GU UT WOS:000340034300022 PM 24779562 ER PT J AU Piao, YL Hung, SSC Lim, SY Wong, RCB Ko, MSH AF Piao, Yulan Hung, Sandy Shen-Chi Lim, Shiang Y. Wong, Raymond Ching-Bong Ko, Minoru S. H. TI Efficient Generation of Integration-Free Human Induced Pluripotent Stem Cells From Keratinocytes by Simple Transfection of Episomal Vectors SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Derivation of human induced pluripotent stem cells; Keratinocytes; Integration-free; Episomal vectors; Lipid mediated transfection ID HUMAN IPS CELLS; SOMATIC-CELLS; DIFFERENTIATION; DERIVATION AB Keratinocytes represent an easily accessible cell source for derivation of human induced pluripotent stem (hiPS) cells, reportedly achieving higher reprogramming efficiency than fibroblasts. However, most studies utilized a retroviral or lentiviral method for reprogramming of keratinocytes, which introduces undesirable transgene integrations into the host genome. Moreover, current protocols of generating integration-free hiPS cells from keratinocytes are mostly inefficient. In this paper, we describe a more efficient, simple-to-use, and cost-effective method for generating integration-free hiPS cells from keratinocytes. Our improved method using lipid-mediated transfection achieved a reprogramming efficiency of similar to 0.14% on average. Keratinocyte-derived hiPS cells showed no integration of episomal vectors, expressed stem cell-specific markers and possessed potentials to differentiate into all three germ layers by in vitro embryoid body formation as well as in vivo teratoma formation. To our knowledge, this represents the most efficient method to generate integration-free hiPS cells from keratinocytes. C1 [Piao, Yulan; Hung, Sandy Shen-Chi; Wong, Raymond Ching-Bong; Ko, Minoru S. H.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Hung, Sandy Shen-Chi; Wong, Raymond Ching-Bong] Univ Melbourne, Dept Ophthalmol, Ctr Eye Res Australia, Melbourne, Vic 3010, Australia. [Lim, Shiang Y.] OBrien Inst, Fitzroy, Vic, Australia. [Lim, Shiang Y.] Univ Melbourne, St Vincents Hosp, Dept Surg, Melbourne, Vic 3010, Australia. [Ko, Minoru S. H.] Keio Univ, Sch Med, Sakaguchi Lab, Dept Syst Med,Shinjuku Ku, Tokyo 1608582, Japan. RP Ko, MSH (reprint author), Keio Univ, Sch Med, Sakaguchi Lab, Dept Syst Med,Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan. EM KoM@z7.keio.jp OI Ko, Minoru/0000-0002-3530-3015 FU NIA/NIH Intramural Research Program; Cranbourne Foundation Fellowship FX The authors thank Hong Yu (National Institute on Aging, National Institutes of Health [NIA/NIH]) and Priyadharshini Sivakumaran for technical assistance. This work was supported in part by the NIA/NIH Intramural Research Program (Y.P., S.S.-C.H., R.C.-B.W., M.S.H.K.) and the Cranbourne Foundation Fellowship (R.C.-B.W.). NR 17 TC 17 Z9 18 U1 6 U2 14 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD JUL PY 2014 VL 3 IS 7 BP 787 EP 791 DI 10.5966/sctm.2013-0036 PG 5 WC Cell & Tissue Engineering SC Cell Biology GA AM7DO UT WOS:000340025100008 PM 24904173 ER PT J AU Luo, YQ Liu, CY Cerbini, T San, H Lin, YS Chen, GK Rao, MS Zou, JZ AF Luo, Yongquan Liu, Chengyu Cerbini, Trevor San, Hong Lin, Yongshun Chen, Guokai Rao, Mahendra S. Zou, Jizhong TI Stable Enhanced Green Fluorescent Protein Expression After Differentiation and Transplantation of Reporter Human Induced Pluripotent Stem Cells Generated by AAVS1 Transcription Activator-Like Effector Nucleases SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Genome editing; Human induced pluripotent stem cells; Transplantation; Transcription activator-like effector nuclease (TALEN); AAVS1; Differentiation ID INTEGRATION; LOCUS; GENE; DNA; CARDIOMYOCYTES; IDENTIFICATION; DERIVATION; INSULATOR; PROMOTER; GENOME AB Human induced pluripotent stem (hiPS) cell lines with tissue-specific or ubiquitous reporter genes are extremely useful for optimizing in vitro differentiation conditions as well as for monitoring transplanted cells in vivo. The adeno-associated virus integration site 1 (AAVS1) locus has been used as a "safe harbor" locus for inserting transgenes because of its open chromatin structure, which permits transgene expression without insertional mutagenesis. However, it is not clear whether targeted transgene expression at the AAVS1 locus is always protected from silencing when driven by various promoters, especially after differentiation and transplantation from hiPS cells. In this paper, we describe a pair of transcription activator-like effector nucleases (TALENs) that enable more efficient genome editing than the commercially available zinc finger nuclease at the AAVS1 site. Using these TALENs for targeted gene addition, we find that the cytomegalovirus-immediate early enhancer/chicken beta-actin/rabbit beta-globin (CAG) promoter is better than cytomegalovirus 7 and elongation factor la short promoters in driving strong expression of the transgene. The two independent AAVS1, CAG, and enhanced green fluorescent protein (EGFP) hiPS cell reporter lines that we have developed do not show silencing of EGFP either in undifferentiated hiPS cells or in randomly and lineage-specifically differentiated cells or in teratomas. Transplanting cardiomyocytes from an engineered AAVS1-CAG-EGFP hiPS cell line in a myocardial infarcted mouse model showed persistent expression of the transgene for at least 7 weeks in vivo. Our results show that high-efficiency targeting can be obtained with open-source TALENs and that careful optimization of the reporter and transgene constructs results in stable and persistent expression in vitro and in vivo. C1 [Luo, Yongquan; Cerbini, Trevor; Rao, Mahendra S.; Zou, Jizhong] NIAMSD, NIH, Ctr Regenerat Med, Lab Stem Cell Biol, Bethesda, MD 20892 USA. [Liu, Chengyu; San, Hong; Lin, Yongshun; Chen, Guokai] NHLBI, Ctr Mol Med, Div Intramural Res, Bethesda, MD 20892 USA. RP Zou, JZ (reprint author), NIAMSD, NIH, Ctr Regenerat Med, Lab Stem Cell Biol, 50 South Dr,Room 1146, Bethesda, MD 20892 USA. EM zouj2@mail.nih.gov FU NIH Common Fund; Intramural Research Program of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases; Intramural Research Program of the National Heart, Lung, and Blood Institute FX This research was supported by the NIH Common Fund, the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal, and Skin Diseases, and the Intramural Research Program of the National Heart, Lung, and Blood Institute. NR 29 TC 10 Z9 12 U1 1 U2 6 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD JUL PY 2014 VL 3 IS 7 BP 821 EP 835 DI 10.5966/sctm.2013-0212 PG 15 WC Cell & Tissue Engineering SC Cell Biology GA AM7DO UT WOS:000340025100012 PM 24833591 ER PT J AU Phillips, MD Kuznetsov, SA Cherman, N Park, K Chen, KG McClendon, BN Hamilton, RS McKay, RDG Chenoweth, JG Mallon, BS Robey, PG AF Phillips, Matthew D. Kuznetsov, Sergei A. Cherman, Natasha Park, Kyetoon Chen, Kevin G. McClendon, Britney N. Hamilton, Rebecca S. McKay, Ronald D. G. Chenoweth, Josh G. Mallon, Barbara S. Robey, Pamela G. TI Directed Differentiation of Human Induced Pluripotent Stem Cells Toward Bone and Cartilage: In Vitro Versus In Vivo Assays SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Induced pluripotent stem cells; Bone; Osteoblast; Chondrogenesis; Transplantation ID MARROW STROMAL FIBROBLASTS; OSTEOGENIC DIFFERENTIATION; FORM BONE; OSTEOBLASTS; DERIVATION; PROMOTES; CULTURE AB The ability to differentiate induced pluripotent stem cells (iPSCs) into committed skeletal progenitors could allow for an unlimited autologous supply of such cells for therapeutic uses; therefore, we attempted to create novel bone-forming cells from human iPSCs using lines from two distinct tissue sources and methods of differentiation that we previously devised for osteogenic differentiation of human embryonic stem cells, and as suggested by other publications. The resulting cells were assayed using in vitro methods, and the results were compared with those obtained from in vivo transplantation assays. Our results show that true bone was formed in vivo by derivatives of several iPSC but that the successful cell lines and differentiation methodologies were not predicted by the results of the in vitro assays. In addition, bone was formed equally well from iPSCs originating from skin or bone marrow stromal cells (also known as bone marrow-derived mesenchymal stem cells), suggesting that the iPSCs did not retain a "memory" of their previous life. Furthermore, one of the iPSC-derived cell lines formed verifiable cartilage in vivo, which likewise was not predicted by in vitro assays. C1 [Phillips, Matthew D.; Kuznetsov, Sergei A.; Cherman, Natasha; McClendon, Britney N.; Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Div Intramural Res, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Park, Kyetoon; Chen, Kevin G.; Hamilton, Rebecca S.; Mallon, Barbara S.] NINDS, NIH, Stem Cell Unit, Div Intramural Res,US Dept HHS, Bethesda, MD 20892 USA. [McKay, Ronald D. G.; Chenoweth, Josh G.] Lieber Inst Brain Dev, Baltimore, MD USA. RP Robey, PG (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, US Dept HHS, 30 Convent Dr MSC 4320,Bldg 30 Room 228, Bethesda, MD 20892 USA. EM probey@dir.nidcr.nih.gov RI Chen, Kevin/D-6769-2011; Robey, Pamela/H-1429-2011 OI Chen, Kevin/0000-0003-2983-6330; Robey, Pamela/0000-0002-5316-5576 FU Division of Intramural Research of the National Institute of Dental and Craniofacial Research; Division of Intramural Research of the National Institute of Neurological Disorders and Stroke; Intramural Research Program; NIH; U.S. Department of Health and Human Services; NIH Center for Regenerative Medicine FX We thank Dr. Linda Wolff (National Cancer Institute, NIH, U.S..Department of Health and Human Services) for kindly providing the gp293 cells. We are also indebted to Zimmer, Inc. for its gift of HA/TCP, and to Li Li (National Institute of Dental and Craniofacial Research, NIH, U.S. Department of Health and Human Services) for her excellent histotechnical assistance. This study was supported by the Division of Intramural Research of the National Institute of Dental and Craniofacial Research, the Division of Intramural Research of the National Institute of Neurological Disorders and Stroke, in the Intramural Research Program, NIH, U.S. Department of Health and Human Services, and by an award from the NIH Center for Regenerative Medicine in 2010. NR 42 TC 21 Z9 21 U1 1 U2 20 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD JUL PY 2014 VL 3 IS 7 BP 867 EP 878 DI 10.5966/sctm.2013-0154 PG 12 WC Cell & Tissue Engineering SC Cell Biology GA AM7DO UT WOS:000340025100016 PM 24855277 ER PT J AU Hirschberg, R Ward, LA Kilgore, N Kurnat, R Schiltz, H Albrecht, MT Christopher, GW Nuzum, E AF Hirschberg, Rona Ward, Lucy A. Kilgore, Nicole Kurnat, Rebecca Schiltz, Helen Albrecht, Mark T. Christopher, George W. Nuzum, Ed TI Challenges, Progress, and Opportunities: Proceedings of the Filovirus Medical Countermeasures Workshop SO VIRUSES-BASEL LA English DT Article DE Ebola; Sudan; ebolavirus; Marburg virus; marburgvirus; Filoviridae; filovirus medical countermeasures; Filovirus Animal Non-clinical Group; FANG ID MARBURG VIRUS-INFECTIONS; HIV-1 ENV VACCINE; NONHUMAN-PRIMATES; EBOLA-VIRUS; GUINEA-PIGS; IPCAVD 001; ADENOVIRUS; PROTECTION; IMMUNOGENICITY; RESPONSES AB On August 22-23, 2013, agencies within the United States Department of Defense (DoD) and the Department of Health and Human Services (HHS) sponsored the Filovirus Medical Countermeasures (MCMs) Workshop as an extension of the activities of the Filovirus Animal Non-clinical Group (FANG). The FANG is a federally-recognized multi-Agency group established in 2011 to coordinate and facilitate U. S. government (USG) efforts to develop filovirus MCMs. The workshop brought together government, academic and industry experts to consider the needs for filovirus MCMs and evaluate the status of the product development pipeline. This report summarizes speaker presentations and highlights progress and challenges remaining in the field. C1 [Hirschberg, Rona; Ward, Lucy A.; Schiltz, Helen; Nuzum, Ed] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. [Kilgore, Nicole; Kurnat, Rebecca] Med Countermeasure Syst, Dept Def, Frederick, MD 21702 USA. [Albrecht, Mark T.] Biodefense Adv Res & Dev Author, Assistant Secretary Preparedness & Response, Dept Hlth & Human Serv, Washington, DC 20201 USA. [Christopher, George W.] Dept Def, Med Countermeasure Syst, Ft Belvoir, VA 22060 USA. RP Ward, LA (reprint author), NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Rona.Hirschberg@verizon.net; lward@niaid.nih.gov; nicole.r.kilgore.civ@mail.mil; rebecca.kurnat.civ@mail.mil; hschiltz@niaid.nih.gov; mark.albrecht@hhs.gov; george.w.christopher.civ@mail.mil; enuzum@niaid.nih.gov NR 34 TC 13 Z9 14 U1 0 U2 27 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD JUL PY 2014 VL 6 IS 7 BP 2673 EP 2697 DI 10.3390/v6072673 PG 25 WC Virology SC Virology GA AM7HZ UT WOS:000340038000006 PM 25010768 ER PT J AU Brunoni, AR Baeken, C Machado-Vieira, R Gattaz, WF Vanderhasselt, MA AF Brunoni, Andre R. Baeken, Chris Machado-Vieira, Rodrigo Gattaz, Wagner F. Vanderhasselt, Marie-Anne TI BDNF blood levels after electroconvulsive therapy in patients with mood disorders: A systematic review and meta-analysis SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Review DE electroconvulsive therapy; brain-derived neurotrophic factor; mood disorders; meta-analysis; systematic review ID RESISTANT DEPRESSED-PATIENTS; NEUROTROPHIC FACTOR BDNF; NEURON-SPECIFIC ENOLASE; MAJOR DEPRESSION; RAT-BRAIN; ECT; PLASTICITY; EFFICACY; SEIZURES; PROTEIN AB Objectives. To evaluate whether electroconvulsive therapy (ECT), a very effective non-pharmacological treatment for mood disorders, induces neurotrophic effects, indexed by the measurement of peripheral brain-derived neurotrophic factor (BDNF) levels. Methods. Systematic review and meta-analysis of clinical trials published in PubMed/Medline from the first date available to October 2013. We included studies measuring pre- and post-BDNF blood levels under ECT in patients with mood disorders in the acute depressive episode. Results. Eleven studies (n = 221 subjects) were eligible. These studies enrolled subjects with unipolar, bipolar and psychotic depression and varied regarding electrode placement (unipolar vs. bipolar) and previous use of pharmacotherapy. Nonetheless, BDNF significantly increased after ECT (Hedges' g pooled, random-effects model of 0.354; 95% CI = 0.162-0.546). The results were robust according to sensitivity analysis and Begg's funnel plot did not suggest publication bias. Meta-regression results did not show association of the outcome with any clinical and demographic variable, including depression improvement. Conclusions. Our meta-analysis indicates that, similar to pharmacological interventions, peripheral BDNF increases after ECT treatment. The lack of correlation between BDNF increasing and depression improvement suggests that ECT induces neurotrophic effects regardless of clinical response in depression. C1 [Brunoni, Andre R.; Machado-Vieira, Rodrigo; Gattaz, Wagner F.] Univ Sao Paulo, Dept & Inst Psychiat, Lab Neurosci LIM27, Sao Paulo, Brazil. [Brunoni, Andre R.] Univ Sao Paulo, Univ Hosp, Interdisciplinary Ctr Appl Neuromodulat & Clin CI, Sao Paulo, Brazil. [Brunoni, Andre R.] Univ Sao Paulo, Univ Hosp, Epidemiol Res Ctr, Sao Paulo, Brazil. [Brunoni, Andre R.] Univ Sao Paulo, Dept & Inst Psychiat, SIN, Fac Med, Sao Paulo, Brazil. [Baeken, Chris] Univ Ghent, Dept Psychiat & Med Psychol, B-9000 Ghent, Belgium. [Baeken, Chris] Univ Hosp UZBrussel, Dept Psychiat, Brussels, Belgium. [Machado-Vieira, Rodrigo] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Vanderhasselt, Marie-Anne] Univ Ghent, Dept Expt Clin & Hlth Psychol, B-9000 Ghent, Belgium. RP Brunoni, AR (reprint author), Univ Sao Paulo, Dept & Inst Psychiat, R Dr Ovidio Pires de Campos 785,2nd Floor, Sao Paulo, Brazil. EM Brunoni@usp.br RI Gattaz, Wagner/C-4456-2012; Baeken, Chris/E-2074-2013; Brunoni, Andre/H-8394-2012; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI Brunoni, Andre/0000-0002-6310-3571; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Brain & Behavior Research Foundation (NARSAD, YI); Sao Paulo Research State Foundation [FAPESP 2012/20911-5]; National Council for Scientific and Technological Development (CNPq) [455157/2013-8]; Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS); Ghent University Multidisciplinary Research Partnership "The integrative neuroscience of behavioral control" FX MAV (FWO08/PDO/168) is a postdoctoral research fellow of the Research Foundation Flanders (FWO). ARB receives Young Investigator grants from the Brain & Behavior Research Foundation (NARSAD, YI 2013), Sao Paulo Research State Foundation (FAPESP 2012/20911-5) and the National Council for Scientific and Technological Development (CNPq, 455157/2013-8). "The Laboratory of Neurosciences receives financial support from the Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS)". This work was also supported by the Ghent University Multidisciplinary Research Partnership "The integrative neuroscience of behavioral control". NR 44 TC 24 Z9 26 U1 2 U2 18 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1562-2975 EI 1814-1412 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD JUL PY 2014 VL 15 IS 5 BP 411 EP 418 DI 10.3109/15622975.2014.892633 PG 8 WC Psychiatry SC Psychiatry GA AM8HM UT WOS:000340113700008 PM 24628093 ER PT J AU Hwang, SK Baker, AR Young, MR Colburn, NH AF Hwang, Soon-Kyung Baker, Alyson R. Young, Matthew R. Colburn, Nancy H. TI Tumor suppressor PDCD4 inhibits NF-kappa B-dependent transcription in human glioblastoma cells by direct interaction with p65 SO CARCINOGENESIS LA English DT Article ID INITIATION-FACTOR 4A; TRANSFORMATION SUPPRESSOR; MESSENGER-RNA; CANCER-CELLS; PROGRAMMED CELL-DEATH-4; EUKARYOTIC TRANSLATION; STRUCTURAL BASIS; BINDING-PROTEIN; GENE-EXPRESSION; CYCLIN D1 AB PDCD4 is a tumor suppressor induced by apoptotic stimuli that regulates both translation and transcription. Previously, we showed that overexpression of PDCD4 leads to decreased anchorage-independent growth in glioblastoma (GBM)-derived cell lines and decreased tumor growth in a GBM xenograft model. In inflammatory cells, PDCD4 stimulates tumor necrosis factor-induced activation of the transcription factor NF-kappa B, an oncogenic driver in many cancer sites. However, the effect of PDCD4 on NF-kappa B transcriptional activity in most cancers including GBM is still unknown. We studied the effect of PDCD4 on NF-kappa B-dependent transcriptional activity in GBM by stably overexpressing PDCD4 in U251 and LN229 cells. Stable PDCD4 expression inhibits NF-kappa B transcriptional activation measured by a luciferase reporter. The molecular mechanism by which PDCD4 inhibits NF-kappa B transcriptional activation does not involve inhibited expression of NF-kappa B p65 or p50 proteins. PDCD4 does not inhibit pathways upstream of NF-kappa B including the activation of IKK alpha and IKK beta kinases or degradation of I kappa B alpha, events needed for nuclear transport of p65 and p50. PDCD4 overexpression does inhibit localization of p65 but not p50 in the nucleus. PDCD4 protein interacts preferentially with p65 protein as shown by co-immunoprecipitation and confocal imaging. PDCD4 overexpression inhibits the mRNA expression of two NF-kappa B target genes in a p65-dependent manner. These results suggest that PDCD4 can significantly inhibit NF-kappa B activity in GBM cells by a mechanism that involves direct or indirect protein-protein interaction independent of the expected mRNA-selective translational inhibition. These findings offer novel opportunities for NF-kappa B-targeted interventions to prevent or treat cancer. C1 [Hwang, Soon-Kyung; Baker, Alyson R.; Young, Matthew R.; Colburn, Nancy H.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick Natl Lab, Frederick, MD 21702 USA. RP Hwang, SK (reprint author), NCI, Lab Canc Prevent, Ctr Canc Res, Frederick Natl Lab, 1050 Boyles St,Bldg 576,Rm 101, Frederick, MD 21702 USA. EM police042@naver.com FU National Cancer Institute, National Institute of Health [ZIA BC 010026] FX National Cancer Institute, National Institute of Health Intramural Funding (ZIA BC 010026). NR 45 TC 15 Z9 16 U1 0 U2 2 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 JUL PY 2014 VL 35 IS 7 BP 1469 EP 1480 DI 10.1093/carcin/bgu008 PG 12 WC Oncology SC Oncology GA AM4IB UT WOS:000339816100006 PM 24413684 ER PT J AU Cross, AJ Boca, S Freedman, ND Caporaso, NE Huang, WY Sinha, R Sampson, JN Moore, SC AF Cross, Amanda J. Boca, Simina Freedman, Neal D. Caporaso, Neil E. Huang, Wen-Yi Sinha, Rashmi Sampson, Joshua N. Moore, Steven C. TI Metabolites of tobacco smoking and colorectal cancer risk SO CARCINOGENESIS LA English DT Article ID CIGARETTE-SMOKING; PROSPECTIVE COHORT; UNITED-STATES; FOLLOW-UP; MICROSATELLITE INSTABILITY; MASS-SPECTROMETRY; SCREENING TRIAL; LUNG-CANCER; LIFE-STYLE; WOMEN AB Colorectal cancer is not strictly considered a tobacco-related malignancy, but modest associations have emerged from large meta-analyses. Most studies, however, use self-reported data, which are subject to misclassification. Biomarkers of tobacco exposure may reduce misclassification and provide insight into metabolic variability that potentially influences carcinogenesis. Our aim was to identify metabolites that represent smoking habits and individual variation in tobacco metabolism, and investigate their association with colorectal cancer. In a nested case-control study of 255 colorectal cancers and 254 matched controls identified in the Prostate, Lung, Colorectal and Ovarian cancer screening trial, baseline serum was used to identify metabolites by ultra-high-performance liquid-phase chromatography and mass spectrometry, as well as gas chromatography with tandem mass spectrometry. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Self-reported current smoking was associated with serum cotinine, O-cresol sulfate and hydroxycotinine. Self-reported current smoking of any tobacco (OR = 1.90, 95% CI: 1.02-3.54) and current cigarette smoking (OR = 1.51, 95% CI: 0.75-3.04) were associated with elevated colorectal cancer risks, although the latter was not statistically significant. Individuals with detectable levels of hydroxycotinine had an increased colorectal cancer risk compared with those with undetectable levels (OR = 2.68, 95% CI: 1.33-5.40). Although those with detectable levels of cotinine had a suggestive elevated risk of this malignancy (OR = 1.81, 95% CI: 0.98-3.33), those with detectable levels of O-cresol sulfate did not (OR = 1.16, 95% CI: 0.57-2.37). Biomarkers capturing smoking behavior and metabolic variation exhibit stronger associations with colorectal cancer than self-report, providing additional evidence for a role for tobacco in this malignancy. C1 [Cross, Amanda J.; Freedman, Neal D.; Sinha, Rashmi; Moore, Steven C.] NCI, Nutr Epidemiol Branch, NIH, Dept Hlth & Human Serv, Rockville, MD 20850 USA. [Boca, Simina; Sampson, Joshua N.] NCI, Biostat Branch, NIH, Dept Hlth & Human Serv, Rockville, MD 20850 USA. [Caporaso, Neil E.] NCI, Genet Epidemiol Branch, NIH, Dept Hlth & Human Serv, Rockville, MD 20850 USA. [Huang, Wen-Yi] NCI, Occupat & Environm Epidemiol Branch,Div Canc Epid, NIH, Dept Hlth & Human Serv, Rockville, MD 20850 USA. RP Cross, AJ (reprint author), NCI, Dept Hlth & Human Serv, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet,NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM crossa@mail.nih.gov RI Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015; Moore, Steven/D-8760-2016 OI Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098; Moore, Steven/0000-0002-8169-1661 FU National Cancer Institute, National Institutes of Health and Department of Health and Human Services FX Intramural Research Program of the National Cancer Institute, National Institutes of Health and Department of Health and Human Services. NR 52 TC 13 Z9 13 U1 1 U2 13 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 JUL PY 2014 VL 35 IS 7 BP 1516 EP 1522 DI 10.1093/carcin/bgu071 PG 7 WC Oncology SC Oncology GA AM4IB UT WOS:000339816100011 PM 24648381 ER PT J AU Moss, LAS Jensen-Taubman, S Rubinstein, D Viole, G Stetler-Stevenson, WG AF Moss, Laurie A. Shuman Jensen-Taubman, Sandra Rubinstein, Danielle Viole, Gary Stetler-Stevenson, William G. TI Dietary intake of a plant phospholipid/lipid conjugate reduces lung cancer growth and tumor angiogenesis SO CARCINOGENESIS LA English DT Article ID ALPHA-LIPOIC ACID; LONG PENTRAXIN PTX3; BREAST-CANCER; FERULIC ACID; PHYTOSTEROLS; PREVENTION; STEROLS; RISK; PHYTOCHEMICALS; ANTIOXIDANT AB It is well recognized that early detection and cancer prevention are significant armaments in the 'war against cancer'. Changes in lifestyle and diet have significant impact on the global incidence of cancer. For over 30 years, many investigators have studied the concept of chemoprevention. More recently, with the demonstration that antiangiogenic activity reduces tumor growth, the concept of angioprevention has emerged as a novel strategy in the deterrence of cancer development (carcinogenesis). In this study, we utilized a fast growing, highly aggressive murine Lewis lung cancer model to examine the in vivo antitumor effects of a novel, dietary supplement, known as plant phospholipid/lipid conjugate (pPLC). Our goal was to determine if pPLC possessed direct antitumor activity with relatively little toxicity that could be developed as a chemoprevention therapy. We used pPLC directly in this in vivo model due to the lack of aqueous solubility of this novel formulation, which precludes in vitro experimentation. pPLC contains known antioxidants, ferulic acid and lipoic acid, as well as soy sterols, formulated in a unique aqueous-insoluble matrix. The pPLC dietary supplement was shown to suppress in vivo growth of this tumor model by 30%. We also demonstrated a significant decrease in tumor angiogenesis accompanied by increased apoptosis and present preliminary evidence of enhanced expression of the hypoxia-related genes pentraxin-3 and metallothionein-3, by 24.9-fold and 10.9-fold, respectively, compared with vehicle control. These findings lead us to propose using this plant phosolipid/lipid conjugate as a dietary supplement that may be useful in cancer prevention. C1 [Moss, Laurie A. Shuman; Jensen-Taubman, Sandra; Rubinstein, Danielle; Stetler-Stevenson, William G.] NCI, Radiat Oncol Branch, Bethesda, MD 20895 USA. [Rubinstein, Danielle] Gettysburg Coll, Gettysburg, PA 17325 USA. [Viole, Gary] Conjugated Funct Foods, Hackensack, NJ 07601 USA. RP Stetler-Stevenson, WG (reprint author), NCI, Radiat Oncol Branch, Bethesda, MD 20895 USA. EM laurie.shumanmoss@nih.gov; sstevenw@mail.nih.gov RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 FU National Cancer Institute, Center for Cancer Research [ZIA SC009179-23] FX National Cancer Institute, Center for Cancer Research Intramural Program (NCI Intramural Project # ZIA SC009179-23 to W.G.S.-S.). NR 45 TC 3 Z9 3 U1 0 U2 7 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 JUL PY 2014 VL 35 IS 7 BP 1556 EP 1563 DI 10.1093/carcin/bgu039 PG 8 WC Oncology SC Oncology GA AM4IB UT WOS:000339816100016 ER PT J AU Borland, MG Krishnan, P Lee, C Albrecht, PP Shan, WW Bility, MT Marcus, CB Lin, JM Amin, S Gonzalez, FJ Perdew, GH Peters, JM AF Borland, Michael G. Krishnan, Prasad Lee, Christina Albrecht, Prajakta P. Shan, Weiwei Bility, Moses T. Marcus, Craig B. Lin, Jyh M. Amin, Shantu Gonzalez, Frank J. Perdew, Gary H. Peters, Jeffrey M. TI Modulation of aryl hydrocarbon receptor (AHR)-dependent signaling by peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) in keratinocytes SO CARCINOGENESIS LA English DT Article ID INHIBITS CELL-PROLIFERATION; HUMAN HACAT KERATINOCYTES; MOUSE SKIN TUMORS; AH RECEPTOR; LIGAND ACTIVATION; DNA METHYLATION; INITIATION-PROMOTION; OXIDATIVE STRESS; GLUCOCORTICOID-RECEPTOR; DIFFERENTIAL REGULATION AB Whether peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) reduces skin tumorigenesis by altering aryl hydrocarbon receptor (AHR)-dependent activities was examined. Polycyclic aromatic hydrocarbons (PAH) increased expression of cytochrome P4501A1 (CYP1A1), CYP1B1 and phase II xenobiotic metabolizing enzymes in wild-type skin and keratinocytes. Surprisingly, this effect was not found in Ppar beta/delta-null skin and keratinocytes. Ppar beta/delta-null keratinocytes exhibited decreased AHR occupancy and histone acetylation on the Cyp1a1 promoter in response to a PAH compared with wild-type keratinocytes. Bisulfite sequencing of the Cyp1a1 promoter and studies using a DNA methylation inhibitor suggest that PPAR beta/delta promotes demethylation of the Cyp1a1 promoter. Experiments with human HaCaT keratinocytes stably expressing shRNA against PPAR beta/delta also support this conclusion. Consistent with the lower AHR-dependent activities in Ppar beta/delta-null mice compared with wild-type mice, 7,12-dimethylbenz[a] anthracene (DMBA)-induced skin tumorigenesis was inhibited in Ppar beta/delta-null mice compared with wild-type. Results from these studies demonstrate that PPAR beta/delta is required to mediate complete carcinogenesis by DMBA. The mechanisms underlying this PPAR beta/delta-dependent reduction of AHR signaling by PAH are not due to alterations in the expression of AHR auxiliary proteins, ligand binding or AHR nuclear translocation between genotypes, but are likely influenced by PPAR beta/delta-dependent demethylation of AHR target gene promoters including Cyp1a1 that reduces AHR accessibility as shown by reduced promoter occupancy. This PPAR beta/delta/AHR crosstalk is unique to keratinocytes and conserved between mice and humans. C1 [Borland, Michael G.; Krishnan, Prasad; Lee, Christina; Albrecht, Prajakta P.; Shan, Weiwei; Bility, Moses T.; Perdew, Gary H.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Borland, Michael G.; Krishnan, Prasad; Lee, Christina; Albrecht, Prajakta P.; Shan, Weiwei; Bility, Moses T.; Perdew, Gary H.; Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Borland, Michael G.; Perdew, Gary H.; Peters, Jeffrey M.] Penn State Univ, Grad Program Biochem Microbiol & Mol Biol, University Pk, PA 16802 USA. [Marcus, Craig B.] Oregon State Univ, Dept Environm & Mol Toxicol, Corvallis, OR 97331 USA. [Lin, Jyh M.; Amin, Shantu] Penn State Univ, Milton S Hershey Med Ctr, Penn State Canc Inst, Dept Pharmacol, Hershey, PA 17033 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. EM jmp21@psu.edu FU National Institutes of Health [CA141029, CA124533, ES004869, ES019964] FX National Institutes of Health (CA141029, CA124533 to J.M.P); (ES004869, ES019964 to G.H.P.). NR 70 TC 6 Z9 6 U1 0 U2 11 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 JUL PY 2014 VL 35 IS 7 BP 1602 EP 1612 DI 10.1093/carcin/bgu067 PG 11 WC Oncology SC Oncology GA AM4IB UT WOS:000339816100021 PM 24639079 ER PT J AU Nyan, DC Ulitzky, LE Cehan, N Williamson, P Winkelman, V Rios, M Taylor, DR AF Nyan, Dougbeh-Chris Ulitzky, Laura E. Cehan, Nicoleta Williamson, Phillip Winkelman, Valerie Rios, Maria Taylor, Deborah R. TI Rapid Detection of Hepatitis B Virus in Blood Plasma by a Specific and Sensitive Loop-Mediated Isothermal Amplification Assay SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE hepatitis B virus; loop-mediated isothermal amplification; nucleotide; rapid detection; international units per reaction ID STRAND DISPLACEMENT AMPLIFICATION; UNITED-STATES; HBV INFECTION; C VIRUS; DNA; PREVALENCE; TRAVELERS; GENOTYPE; REFUGEES; SEQUENCE AB Background. Hepatitis B virus (HBV) is an important blood-borne pathogen that causes hepatic inflammation and can lead to liver cirrhosis and hepatocellular carcinoma. Conventional methods of HBV detection are time consuming and require highly trained personnel and elaborate equipment. This report describes the development of a rapid, simple, specific, and sensitive loop-mediated isothermal amplification assay (LAMP) for detection of HBV genotypes A, B, C, D, E, and F in blood samples. Methods. HBV standard plasma panels and clinical donor plasma specimens were used for the development and validation of the LAMP assay. Amplification was performed at 60 C for 60 minutes using extracted DNA or heat-treated plasma specimens without DNA extraction. The assay was evaluated for its ability to detect various HBV genotypes and for its sensitivity, specificity, and time-point of detection. Results. The LAMP assay detected HBV genotypes A-F and demonstrated a sensitivity of 10-100 IU per reaction of HBV DNA. The assay also detected 69 of 75 (92%) HBV-positive donor plasma specimens tested and demonstrated a specificity of 100%. Conclusions. These results demonstrate that our HBV-LAMP assay is rapid, sensitive and specific, and capable of detecting the major HBV genotypes. This assay could be used in clinical point-of-care settings, mainly in endemic and resource-limited environments for HBV diagnostics, donor screening, epidemiological studies, and therapeutic monitoring of patients undergoing antiviral treatment. C1 [Nyan, Dougbeh-Chris; Ulitzky, Laura E.; Cehan, Nicoleta; Rios, Maria; Taylor, Deborah R.] US FDA, Lab Emerging Pathogens, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res,Off Blood Res & Review, Bethesda, MD 20892 USA. [Williamson, Phillip; Winkelman, Valerie] Creat Testing Solut, Tempe, AZ USA. RP Taylor, DR (reprint author), US FDA, DETTD, CBER, 8800 Rockville Pike,NIH Bldg 29,Rm 131, Bethesda, MD 20892 USA. EM deborah.taylor@fda.hhs.gov FU Department of Energy; FDA FX This work was supported in part by an appointment to the Research Participation Program at the Center for Biologics Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the Department of Energy and the FDA. NR 43 TC 11 Z9 15 U1 2 U2 20 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2014 VL 59 IS 1 BP 16 EP 23 DI 10.1093/cid/ciu210 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM2FL UT WOS:000339665000005 PM 24704724 ER PT J AU Morgan, MK Whitman, TJ Cohen, JI Pittaluga, S Mitchum, MD Jarell, AD Burgess, TH AF Morgan, Mackenzie K. Whitman, Timothy J. Cohen, Jeffrey I. Pittaluga, Stefania Mitchum, Marsha D. Jarell, Abel D. Burgess, Timothy H. TI A Patient With Fever and Rash SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID EPSTEIN-BARR-VIRUS; GIANOTTI-CROSTI-SYNDROME C1 [Morgan, Mackenzie K.; Whitman, Timothy J.; Burgess, Timothy H.] Walter Reed Natl Mil Med Ctr, Infect Dis Serv, Bethesda, MD 20889 USA. [Cohen, Jeffrey I.] NIH, Infect Dis Lab, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NIH, Pathol Lab, Bethesda, MD 20892 USA. [Mitchum, Marsha D.; Jarell, Abel D.] Walter Reed Natl Mil Med Ctr, Dermatol Serv, Bethesda, MD 20889 USA. RP Burgess, TH (reprint author), Walter Reed Natl Mil Med Ctr, Dept Infect Dis, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM timothy.j.whitman.mil@health.mil NR 7 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2014 VL 59 IS 1 BP 95 EP + DI 10.1093/cid/ciu192 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM2FL UT WOS:000339665000018 PM 25551834 ER PT J AU Kojic, EM Kang, M Cespedes, MS Umbleja, T Godfrey, C Allen, RT Firnhaber, C Grinsztejn, B Palefsky, JM Webster-Cyriaque, JY Saah, A Aberg, JA Cu-Uvin, S AF Kojic, Erna Milunka Kang, Minhee Cespedes, Michelle S. Umbleja, Triin Godfrey, Catherine Allen, Reena T. Firnhaber, Cynthia Grinsztejn, Beatriz Palefsky, Joel M. Webster-Cyriaque, Jennifer Y. Saah, Alfred Aberg, Judith A. Cu-Uvin, Susan TI Immunogenicity and Safety of the Quadrivalent Human Papillomavirus Vaccine in HIV-1-Infected Women SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HPV vaccine; HIV-infected women; immunogenicity; vaccine safety; anogenital disease ID ANAL INTRAEPITHELIAL NEOPLASIA; HIV-INFECTED PERSONS; CERVICAL-CANCER; HPV VACCINE; EFFICACY; RISK; MEN AB Background. Women infected with human immunodeficiency virus (HIV) are disproportionately affected by human papillomavirus (HPV)-related anogenital disease, particularly with increased immunosuppression. AIDS Clinical Trials Group protocol A5240 was a trial of 319 HIV-infected women in the United States, Brazil, and South Africa to determine immunogenicity and safety of the quadrivalent HPV vaccine in 3 strata based on screening CD4 count: >350 (stratum A), 201-350 (stratum B), and <= 200 cells/L (stratum C). Methods. Safety and serostatus of HPV types 6, 11, 16, and 18 were examined. HPV serological testing was performed using competitive Luminex immunoassay (HPV-4 cLIA). HPV type-specific seroconversion analysis was done for participants who were seronegative for the given type at baseline. Results. Median age of patients was 36 years; 11% were white, 56% black, and 31% Hispanic. Median CD4 count was 310 cells/L, and 40% had undetectable HIV-1 load. No safety issues were identified. Seroconversion proportions among women at week 28 for HPV types 6, 11,16, and 18 were 96%, 98%, 99%, and 91%, respectively, for stratum A; 100%, 98%, 98%, and 85%, respectively, for stratum B, and 84%, 92%, 93%, and 75%, respectively, for stratum C. Conclusions. The quadrivalent HPV vaccine targeted at types 6, 11, 16, and 18 was safe and immunogenic in HIV-infected women aged 13-45 years. Women with HIV RNA load > 10 000 copies/mL and/or CD4 count <200 cells/L had lower rates of seroconversion rates. C1 [Kojic, Erna Milunka; Cu-Uvin, Susan] Brown Univ, Dept Infect Dis, Providence, RI 02906 USA. [Kang, Minhee; Umbleja, Triin] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Cespedes, Michelle S.; Aberg, Judith A.] Icahn Sch Med Mt Sinai, Div Infect Dis, New York, NY 10029 USA. [Godfrey, Catherine] NIAID, HIV Res Branch, Therapeut Res Program, Div Aids,NIH, Bethesda, MD 20892 USA. [Allen, Reena T.] AIDS Clin Trials Grp Network Coordinating Ctr, Silver Spring, MD USA. [Firnhaber, Cynthia] Univ Witwatersrand, Dept Internal Med, Fac Hlth Sci, Clin HIV Res Unit, Johannesburg, South Africa. [Grinsztejn, Beatriz] Inst Pesquisa Clin Evandro Chagas Fiocruz, Infect Dis Dept, Rio De Janeiro, Brazil. [Palefsky, Joel M.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Webster-Cyriaque, Jennifer Y.] Univ N Carolina, Oral HIV AIDS Res Alliance OHARA, Chapel Hill, NC USA. [Saah, Alfred] Merck Res Labs, N Wales, PA USA. RP Kojic, EM (reprint author), Brown Univ, 1125 N Main St, Providence, RI 02906 USA. EM ekojic@lifespan.org FU National Institute of Allergy and Infectious Diseases [UM1AI068636]; National Institute of Dental and Craniofacial Research; Statistical and Data Management Center of the ACTG [UM1AI68634]; Harvard Center for AIDS Research [P30 AI060354] FX This work was supported by the National Institute of Allergy and Infectious Diseases (award number UM1AI068636); the National Institute of Dental and Craniofacial Research; and the Statistical and Data Management Center of the ACTG (grant number UM1AI68634). Massachusetts General Hospital receives support from the Harvard Center for AIDS Research (number P30 AI060354). NR 25 TC 27 Z9 27 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2014 VL 59 IS 1 BP 127 EP 135 DI 10.1093/cid/ciu238 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM2FL UT WOS:000339665000023 PM 24723284 ER PT J AU Amico, KR Stirratt, MJ AF Amico, K. Rivet Stirratt, Michael J. TI Adherence to Preexposure Prophylaxis: Current, Emerging, and Anticipated Bases of Evidence SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE study product adherence; PrEP adherence; social science; behavioral science ID INJECTING DRUG-USERS; HIV-INFECTION; INTERIM GUIDANCE; ANTIRETROVIRAL PROPHYLAXIS; CLINICAL CARE; PREVENTION; TRIAL; WOMEN; ACCEPTABILITY; TENOFOVIR AB Despite considerable discussion and debate about adherence to preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV), scant data are available that characterize patterns of adherence to open-label PrEP. The current evidence base is instead dominated by research on adherence to placebo-controlled investigational drug by way of drug detection in active-arm participants of large randomized controlled trials (RCTs). Important differences between the context of blinded RCTs and open-label use suggest caution when generalizing from study product adherence to real-world PrEP use. Evidence specific to open-label PrEP adherence is presently sparse but will expand rapidly over the next few years as roll-out, demonstration projects, and more rigorous research collect and present findings. The current evidence bases established cannot yet predict uptake, adherence, or persistence with open-label effective PrEP. Emerging evidence suggests that some cohorts could execute better adherence in open-label use vs placebo-controlled research. Uptake of PrEP is presently slow in the United States; whether this changes as grassroots and community efforts increase awareness of PrEP as an effective HIV prevention option remains to be determined. As recommended by multiple guidelines for PrEP use, all current demonstration projects offer PrEP education and/or counseling. PrEP support approaches generally fall into community-based, technology, monitoring, and integrated sexual health promotion approaches. Developing and implementing research that moves beyond simple correlates of either study product use or open-label PrEP adherence toward more comprehensive models of sociobehavioral and socioecological adherence determinants would greatly accelerate progress. Intervention research is needed to identify effective models of support for open-label PrEP adherence. C1 [Amico, K. Rivet] Univ Connecticut, Ctr Hlth Intervent & Prevent, Storrs, CT 06269 USA. [Amico, K. Rivet] Appl Hlth Res, Brighton, MI USA. [Stirratt, Michael J.] NIMH, Div AIDS Res, NIH, Bethesda, MD 20892 USA. RP Amico, KR (reprint author), Univ Connecticut, Ctr Hlth Intervent & Prevent, 2006 Hillside Rd Unit 1248, Storrs, CT 06269 USA. EM rivetamico@comcast.net FU International Association of Providers of AIDS Care FX Supplement sponsorship. This article is published as part of a supplement entitled "Controlling the HIV Epidemic With Antiretrovirals," sponsored by the International Association of Providers of AIDS Care. NR 49 TC 27 Z9 27 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2014 VL 59 SU 1 BP S55 EP S60 DI 10.1093/cid/ciu266 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM2FV UT WOS:000339666100013 PM 24926036 ER PT J AU Nguyen, KL Bandettini, WP Shanbhag, S Leung, SW Wilson, JR Arai, AE AF Kim-Lien Nguyen Bandettini, W. Patricia Shanbhag, Sujata Leung, Steve W. Wilson, Joel R. Arai, Andrew E. TI Safety and tolerability of regadenoson CMR SO EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING LA English DT Article DE Cardiovascular MRI; Perfusion imaging; Coronary artery disease; Myocardial perfusion; Vasodilator agents; Regadenoson ID CARDIOVASCULAR MAGNETIC-RESONANCE; HEART-RATE RESPONSE; OBSTRUCTIVE PULMONARY-DISEASE; CORONARY-ARTERY-DISEASE; EMISSION COMPUTED-TOMOGRAPHY; PHARMACOLOGICAL STRESS AGENT; SELECTIVE A(2A) AGONIST; MYOCARDIAL-PERFUSION; VASODILATOR STRESS; DOUBLE-BLIND AB Aims Knowledge of adverse events associated with regadenoson perfusion cardiac magnetic resonance (CMR) and patient tolerability has implications for patient safety and staff training. We sought to assess the safety and tolerability of regadenoson stress CMR. Materials and methods A group of 728 consecutive patients (median age 58, 44% female) and 25 normal volunteers (median age 21, 24% female) were recruited from August 2009 to March 2012 using a prospective, cross-sectional study design. Subjects were stressed using fixed-dose regadenoson and imaged using a 1.5T MRI scanner. Symptoms and adverse events including death, myocardial infarction (MI), ventricular tachycardia (VT)/ventricular fibrillation (VF), hospitalization, arrhythmias, and haemodynamic stability were assessed. Results There were no occurrences of death, MI, VT/VF, high-grade atrioventricular block, or stress-induced atrial fibrillation. Notable adverse events included one case of bronchospasm and one case of heart failure exacerbation resulting in hospitalization. The most common symptoms in patients were dyspnoea (30%, n = 217), chest discomfort (27%, n = 200), and headache (15%, n = 111). There was minimal change between baseline and peak systolic and diastolic blood pressure in both patients and volunteers (P > 0.05). A blunted heart rate response to regadenoson was noted in patients with body mass index (BMI) >= 30 kg/m(2) (P < 0.001), and diabetes (P = 0.001). Conclusions Regadenoson CMR is well tolerated and can be performed safely with few adverse events. C1 [Kim-Lien Nguyen; Bandettini, W. Patricia; Shanbhag, Sujata; Leung, Steve W.; Wilson, Joel R.; Arai, Andrew E.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Kim-Lien Nguyen] Univ Calif Los Angeles, David Geffen Sch Med, Div Cardiol, Los Angeles, CA 90073 USA. [Leung, Steve W.] Univ Kentucky, Div Cardiovasc Med, Lexington, KY 40536 USA. [Wilson, Joel R.] Univ Calif San Diego, Div Cardiovasc Med, San Diego, CA 92103 USA. RP Arai, AE (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, 10 Ctr Dr Bldg 10,Rm B1D416,MSC 1061, Bethesda, MD 20892 USA. EM araia@nih.gov RI Leung, Steve/E-5624-2011; OI Leung, Steve/0000-0003-2832-2258; Nguyen, Kim-Lien/0000-0002-8854-2976 FU Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health [1ZIAHL004607, 1ZIAHL006137, 1ZIEHL006139, 1ZIDHL006140]; Division of Intramural Research of the National Heart, Lung and Blood Institute, National Institutes of Health FX This research was supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (1ZIAHL004607, 1ZIAHL006137, 1ZIEHL006139, 1ZIDHL006140). Funding to pay the Open Access publication charges for this article was provided by the Division of Intramural Research of the National Heart, Lung and Blood Institute, National Institutes of Health. NR 38 TC 7 Z9 7 U1 2 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2047-2404 EI 2047-2412 J9 EUR HEART J-CARD IMG JI Eur. Heart J.-Cardiovasc. Imaging PD JUL PY 2014 VL 15 IS 7 BP 753 EP 760 DI 10.1093/ehjci/jet278 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM5MA UT WOS:000339902000007 PM 24451179 ER PT J AU Navratil, M Ptacek, J Sacha, P Starkova, J Lubkowski, J Barinka, C Konvalinka, J AF Navratil, Michal Ptacek, Jakub Sacha, Pavel Starkova, Jana Lubkowski, Jacek Barinka, Cyril Konvalinka, Jan TI Structural and biochemical characterization of the folyl-poly-gamma-L-glutamate hydrolyzing activity of human glutamate carboxypeptidase II SO FEBS JOURNAL LA English DT Article DE arene-binding site; crystal structure; folate hydrolase 1; H475Y(1561C -> T); polymorphism; zinc metalloprotease ID MEMBRANE ANTIGEN; HOMOCYSTEINE CONCENTRATIONS; REACTION-MECHANISM; PROSTATE-CANCER; AMINO-ACIDS; FOLIC-ACID; FOLATE; CRYSTALLOGRAPHY; POLYMORPHISMS; IDENTIFICATION AB In addition to its well-characterized role in the central nervous system, human glutamate carboxypeptidase II (GCPII; Uniprot ID Q04609) acts as a folate hydrolase in the small intestine, participating in the absorption of dietary polyglutamylated folates (folyl-n-gamma-L-glutamic acid), which are the provitamin form of folic acid (also known as vitamin B-9). Despite the role of GCPII as a folate hydrolase, nothing is known about the processing of polyglutamylated folates by GCPII at the structural or enzymological level. Moreover, many epidemiologic studies on the relationship of the naturally occurring His475Tyr polymorphism to folic acid status suggest that this polymorphism may be associated with several pathologies linked to impaired folate metabolism. In the present study, we report: (a) a series X-ray structures of complexes between a catalytically inactive GCPII mutant (Glu424Ala) and a panel of naturally occurring polyglutamylated folates; (b) the X-ray structure of the His475Tyr variant at a resolution of 1.83 angstrom; (c) the study of the recently identified arene-binding site of GCPII through mutagenesis (Arg463Leu, Arg511Leu and Trp541Ala), inhibitor binding and enzyme kinetics with polyglutamylated folates as substrates; and (d) a comparison of the thermal stabilities and folate-hydrolyzing activities of GCPII wild-type and His475Tyr variants. As a result, the crystallographic data reveal considerable details about the binding mode of polyglutamylated folates to GCPII, especially the engagement of the arene binding site in recognizing the folic acid moiety. Additionally, the combined structural and kinetic data suggest that GCPII wild-type and His475Tyr variant are functionally identical. C1 [Navratil, Michal; Sacha, Pavel; Starkova, Jana; Konvalinka, Jan] Acad Sci Czech Republic, Inst Organ Chem & Biochem, Gilead Sci & IOCB Res Ctr, Prague 16610 6, Czech Republic. [Navratil, Michal; Ptacek, Jakub; Sacha, Pavel; Konvalinka, Jan] Charles Univ Prague, Fac Sci, Dept Biochem, Prague, Czech Republic. [Ptacek, Jakub; Barinka, Cyril] Acad Sci Czech Republic, Inst Biotechnol, Prague 16610 6, Czech Republic. [Lubkowski, Jacek] NCI, Ctr Canc Res, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Konvalinka, J (reprint author), Acad Sci Czech Republic, Inst Organ Chem & Biochem, Gilead Sci & IOCB Res Ctr, Flemingovo 2, Prague 16610 6, Czech Republic. EM konval@uochb.cas.cz RI Sacha, Pavel/G-9729-2014; Ptacek, Jakub/G-8605-2014; Barinka, Cyril/G-9803-2014; OI Sacha, Pavel/0000-0001-6198-9826; Konvalinka, Jan/0000-0003-0695-9266 FU US Department of Energy [W-31-109-Eng38]; Helmholtz-Zentrum Berlin; Bio-Struct-X [283570]; EMBO (Installation grant); IRG [249220]; project 'BI-OCEV - Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University' from the European Regional Development Fund [CZ.1.05/1.1.00/02.0109]; EU OPPC program [CZ.2.16/3.1.00/24016]; Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; Grant Agency of the Czech Republic [P304-12-0847] FX The use of the Advanced Photon Source was supported by the US Department of Energy (Contract number W-31-109-Eng38) and the use of MX 14.2 was in part funded by the Helmholtz-Zentrum Berlin and Bio-Struct-X (grant agreement number 283570). C. B. acknowledges support from the EMBO (Installation grant 1978) and IRG (project number 249220). This publication is supported by the project 'BI-OCEV - Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University' (CZ.1.05/1.1.00/02.0109) from the European Regional Development Fund, in part by EU OPPC program CZ.2.16/3.1.00/24016, by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and by grant P304-12-0847 from the Grant Agency of the Czech Republic. The authors would like to thank Pavlina Rezacova for collecting the diffraction data for the rhGCPII-Glu424Ala-FolGlu2 complex at BESSYII (Berlin, Germany), Barbara Slusher (School of Medicine, John Hopkins University, MD, USA) for her kind gift of the 2-PMPA inhibitor, Hillary Hoffman for language help and Radko Soucek for his excellent technical assistance with the amino acid analysis. NR 39 TC 10 Z9 10 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2014 VL 281 IS 14 BP 3228 EP 3242 DI 10.1111/febs.12857 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM4CU UT WOS:000339800800011 PM 24863754 ER PT J AU Glasgow, RE Phillips, SM Sanchez, MA AF Glasgow, Russell E. Phillips, Siobhan M. Sanchez, Michael A. TI Implementation science approaches for integrating eHealth research into practice and policy SO INTERNATIONAL JOURNAL OF MEDICAL INFORMATICS LA English DT Article DE eHealth; Internet; mHealth; Review; Recommendations; Implementation science; Methodology ID RANDOMIZED CONTROLLED-TRIAL; HEALTH BEHAVIOR-CHANGE; WEIGHT-LOSS; SYSTEMATIC REVIEWS; CLINICAL-TRIALS; RE-AIM; INTERVENTIONS; CARE; MEDICINE; PROGRAM AB Purpose: To summarize key issues in the eHealth field from an implementation science perspective and to highlight illustrative processes, examples and key directions to help more rapidly integrate research, policy and practice. Methods: We present background on implementation science models and emerging principles; discuss implications for eHealth research; provide examples of practical designs, measures and exemplar studies that address key implementation science issues; and make recommendations for ways to more rapidly develop and test eHealth interventions as well as future research, policy and practice. Results: The pace of eHealth research has generally not kept up with technological advances, and many of our designs, methods and funding mechanisms are incapable of providing the types of rapid and relevant information needed. Although there has been substantial eHealth research conducted with positive short-term results, several key implementation and dissemination issues such as representativeness, cost, unintended consequences, impact on health inequities, and sustainability have not been addressed or reported. Examples of studies in several of these areas are summarized to demonstrate this is possible. Conclusions: eHealth research that is intended to translate into policy and practice should be more contextual, report more on setting factors, employ more responsive and pragmatic designs and report results more transparently on issues important to potential adopting patients, clinicians and organizational decision makers. We outline an alternative development and assessment model, summarize implementation science findings that can help focus attention, and call for different types of more rapid and relevant research and funding mechanisms. Published by Elsevier Ireland Ltd. C1 [Glasgow, Russell E.; Phillips, Siobhan M.; Sanchez, Michael A.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6130 Execut Blvd,Room 6144, Rockville, MD 20852 USA. EM glasgowre@mail.nih.gov NR 82 TC 13 Z9 14 U1 3 U2 24 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1386-5056 EI 1872-8243 J9 INT J MED INFORM JI Int. J. Med. Inform. PD JUL PY 2014 VL 83 IS 7 BP E1 EP E11 DI 10.1016/j.ijmedinf.2013.07.002 PG 11 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA AM3EP UT WOS:000339735700001 PM 23910896 ER PT J AU Cheung, GYC Villaruz, AE Joo, HS Duong, AC Yeh, AJ Nguyen, TH Sturdevant, DE Queck, SY Otto, M AF Cheung, Gordon Y. C. Villaruz, Amer E. Joo, Hwang-Soo Duong, Anthony C. Yeh, Anthony J. Nguyen, Thuan H. Sturdevant, Daniel E. Queck, S. Y. Otto, M. TI Genome-wide analysis of the regulatory function mediated by the small regulatory psm-mec RNA of methicillin-resistant Staphylococcus aureus SO INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Article DE Staphylococcus aureus; MRSA; Virulence; Antibiotic resistance ID QUORUM-SENSING SYSTEM; PROTEIN-A; ESCHERICHIA-COLI; VIRULENCE; GENE; EVOLUTION; STRAINS; AGR; EPIDEMIC; MRSA AB Several methicillin resistance (SCCmec) clusters characteristic of hospital-associated methicillin-resistant Staphylococcus aureus (MRSA) strains harbor the psm-mec locus. In addition to encoding the cytolysin, phenol-soluble modulin (PSM)-mec, this locus has been attributed gene regulatory functions. Here we employed genome-wide transcriptional profiling to define the regulatory function of the psm-mec locus. The immune evasion factor protein A emerged as the primary conserved and strongly regulated target of psm-mec, an effect we show is mediated by the psm-mec RNA. Furthermore, the psm-mec locus exerted regulatory effects that were more moderate in extent. For example, expression of PSM-mec limited expression of mecA, thereby decreasing methicillin resistance. Our study shows that the psm-mec locus has a rare dual regulatory RNA and encoded cytolysin function. Furthermore, our findings reveal a specific mechanism underscoring the recently emerging concept that S. aureus strains balance pronounced virulence and high expression of antibiotic resistance. Published by Elsevier GmbH. C1 [Cheung, Gordon Y. C.; Villaruz, Amer E.; Joo, Hwang-Soo; Duong, Anthony C.; Yeh, Anthony J.; Nguyen, Thuan H.; Queck, S. Y.; Otto, M.] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Sturdevant, Daniel E.] NIAID, Genom Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Otto, M (reprint author), 9000 Rockville Pike,Bldg 33 1W10, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115; JOO, HWANG-SOO/0000-0003-4668-3225 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; U.S. National Institutes of Health [ZIA A1000904-12] FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health (grant ZIA A1000904-12). NR 30 TC 8 Z9 8 U1 0 U2 18 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4221 EI 1618-0607 J9 INT J MED MICROBIOL JI Int. J. Med. Microbiol. PD JUL PY 2014 VL 304 IS 5-6 BP 637 EP 644 DI 10.1016/j.ijmm.2014.04.008 PG 8 WC Microbiology; Virology SC Microbiology; Virology GA AM3TL UT WOS:000339775600015 PM 24877726 ER PT J AU Sagar, V Bergmann, R Nerlich, A McMillan, DJ Nitsche-Schmitz, DP Fulde, M Talay, S Geffers, R Hoe, N Kumar, R Rohde, M Chakraborti, A Chhatwal, GS AF Sagar, Vivek Bergmann, Rene Nerlich, Andreas McMillan, David J. Nitsche-Schmitz, D. Patric Fulde, Marcus Talay, Susanne Geffers, Robert Hoe, Nancy Kumar, Rajesh Rohde, Manfred Chakraborti, Anuradha Chhatwal, Gursharan S. TI Differences in virulence repertoire and cell invasive potential of Group A Streptococcus emm1-2 in comparison to emm1 genotype SO INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Article DE Streptococcus pyogenes; Group A streptococcus; emm1-2; emm1; Sfb1-2; Invasion ID FIBRONECTIN-BINDING PROTEIN; COMPARATIVE GENOMIC HYBRIDIZATION; ACUTE RHEUMATIC-FEVER; EPITHELIAL-CELLS; BACTERIAL PATHOGENS; GENETIC DIVERSITY; M1 PROTEIN; PYOGENES; STRAINS; MICROARRAY AB Group A streptococcus (GAS, Streptococcus pyogenes) type emm1 is widely associated with streptococcal invasive disease. This type is prevalent worldwide but is rare in India. Instead, emm1-2 type which is closely related to emm1 but is a distinct type is more prevalent. Although emm1 has been well characterized, information available on emm1-2 is rare. In this study we present a comparative study of both types. DNA microarray analysis showed segregation of emm1 and emm1-2 isolates into two distinct clusters. Out of 229 arrayed genes, 83-87% were present, 6-9% absent and 4-8% genes were ambiguous in emm1 isolates. emm1-2 strains harboured only 68-77%, 11-13% were absent and 10-20% ambiguous genes. Fourteen genes, present in all emm1, were completely absent in the emm1-2 isolates. 4131 is a gene which encodes for Streptococcal fibronectin binding adhesin and invasin which has restricted distribution among different emm types of GAS. A variant of sfb1 (sfb1-2) was the only gene which was present in all emm1-2 isolates, but absent from all emm1 strains. Sfb1 and Sfb1-2 differ in sequences in the aromatic domain and the proline rich repeat region, whereas the fibronectin binding region was conserved and exhibited similar fibronectin binding activity. The presence of Sfb1-2 in emm1-2 strains was concomitant with significantly higher fibronectin-binding and invasion efficiency of HEp-2 cells when compared to emm1 isolates. The role of Sfb1-2 in invasion was confirmed by latex bead assay. emm1-2 isolates follow membrane ruffling mechanism during invasion and intracellularly follow classical endocytic pathway. Further studies are required to understand the correlation between the presence of emm1-2 isolates and the disease pattern in North India. (C) 2014 Elsevier GmbH. All rights reserved. C1 [Sagar, Vivek; Bergmann, Rene; Nerlich, Andreas; Nitsche-Schmitz, D. Patric; Fulde, Marcus; Talay, Susanne; Geffers, Robert; Rohde, Manfred; Chhatwal, Gursharan S.] Helmholtz Ctr Infect Res, D-38124 Braunschweig, Germany. [McMillan, David J.] QIMR Berghofer Med Res Inst, Bacterial Pathogenesis Lab, Brisbane, Qld, Australia. [McMillan, David J.] Univ Sunshine Coast, Sch Hlth & Sport Sci, Inflammat & Healing Res Cluster, Sippy Downs, Qld 4556, Australia. [Sagar, Vivek; Kumar, Rajesh; Chakraborti, Anuradha] Postgrad Inst Med Educ & Res, Chandigarh 160012, India. [Hoe, Nancy] NIH, Hamilton, MT USA. RP Sagar, V (reprint author), Helmholtz Ctr Infect Res, Dept Med Microbiol, Inhoffenstr 7, D-38124 Braunschweig, Germany. EM vivekgenetics@gmail.com RI Nerlich, Andreas/F-9336-2012; McMillan, David/P-5582-2016 OI Nerlich, Andreas/0000-0001-8577-2744; McMillan, David/0000-0002-9339-0639 FU European Commission [INCO-CT-2006-032390-ASSIST] FX This work was supported by the European Commission (INCO-CT-2006-032390-ASSIST). NR 42 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4221 EI 1618-0607 J9 INT J MED MICROBIOL JI Int. J. Med. Microbiol. PD JUL PY 2014 VL 304 IS 5-6 BP 685 EP 695 DI 10.1016/j.ijmm.2014.04.011 PG 11 WC Microbiology; Virology SC Microbiology; Virology GA AM3TL UT WOS:000339775600021 PM 24856243 ER PT J AU Pichard, DC Boyce, AM Collins, MT Cowen, EW AF Pichard, Dominique C. Boyce, Alison M. Collins, Michael T. Cowen, Edward W. TI Oral Pigmentation in McCune-Albright Syndrome SO JAMA DERMATOLOGY LA English DT Article ID PEUTZ-JEGHERS-SYNDROME; CARNEY-COMPLEX; MANIFESTATIONS AB IMPORTANCE The differential diagnosis for oral lentigines includes several syndromes with important associated systemic findings. McCune-Albright syndrome (MAS), a mosaic condition associated with cafe au lait pigmentation, is not typically considered a mucosal lentiginosis syndrome. The clinical phenotype of MAS is variable because of mosaicism, but oral pigmentation developing in mid-childhood to early adulthood should be recognized as a clinical feature of MAS. OBSERVATIONS We present 4 patients with MAS who developed oral mucosal pigmentation during childhood or early adulthood. All patients had other characteristic findings of MAS including hyperfunctioning endocrinopathies, polyostotic fibrous dysplasia, and caf au lait pigmentation. CONCLUSIONS AND RELEVANCE Oral pigmentation is an underrecognized finding in MAS and presents later in development compared with the other mucosal lentiginosis syndromes. The diagnosis of MAS is most commonly a clinical diagnosis because mutational analysis is challenging in mosaic conditions. Expanding the cutaneous phenotype to include oral pigmentation further characterizes the clinical findings in this mosaic condition, broadens the differential diagnosis of syndromes with oral pigmentation, and in some cases may aid in earlier diagnosis of MAS. C1 [Pichard, Dominique C.] Georgetown Univ Hosp, Washington Hosp Ctr, Dept Dermatol, Washington, DC 20007 USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Div Endocrinol & Diabet, Washington, DC 20010 USA. [Boyce, Alison M.] Childrens Natl Med Ctr, Div Orthopaed & Sports Med, Bone Hlth Program, Washington, DC 20010 USA. [Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Cowen, Edward W.] NCI, Ctr Canc Res, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Consultat Serv, Dermatol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU Division of Intramural Research, National Institutes of Dental and Craniofacial Research; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This study was supported in part by the Division of Intramural Research, National Institutes of Dental and Craniofacial Research, and the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 15 TC 3 Z9 4 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD JUL PY 2014 VL 150 IS 7 BP 760 EP 763 DI 10.1001/jamadermatol.2014.184 PG 4 WC Dermatology SC Dermatology GA AM2BF UT WOS:000339652400016 PM 24671640 ER PT J AU Pollack, MM Holubkov, R Funai, T Clark, A Moler, F Shanley, T Meert, K Newth, CJL Carcillo, J Berger, JT Doctor, A Berg, RA Dalton, H Wessel, DL Harrison, RE Dean, JM Jenkins, TL AF Pollack, Murray M. Holubkov, Richard Funai, Tomohiko Clark, Amy Moler, Frank Shanley, Thomas Meert, Kathy Newth, Christopher J. L. Carcillo, Joseph Berger, John T. Doctor, Allan Berg, Robert A. Dalton, Heidi Wessel, David L. Harrison, Rick E. Dean, J. Michael Jenkins, Tammara L. TI Relationship Between the Functional Status Scale and the Pediatric Overall Performance Category and Pediatric Cerebral Performance Category Scales SO JAMA PEDIATRICS LA English DT Article ID INTENSIVE-CARE-UNIT; QUALITY-OF-LIFE; GENERIC CORE SCALES; CHILDREN; VALIDITY; RELIABILITY; OUTCOMES; PEDSQL(TM)-4.0; FEASIBILITY; DISCHARGE AB IMPORTANCE Functional status assessment methods are important as outcome measures for pediatric critical care studies. OBJECTIVE To investigate the relationships between the 2 functional status assessment methods appropriate for large-sample studies, the Functional Status Scale (FSS) and the Pediatric Overall Performance Category and Pediatric Cerebral Performance Category (POPC/PCPC) scales. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study with random patient selection at 7 sites and 8 children's hospitals with general/medical and cardiac/cardiovascular pediatric intensive care units (PICUs) in the Collaborative Pediatric Critical Care Research Network. Participants included all PICU patients younger than 18 years. MAIN OUTCOMES AND MEASURES Functional Status Scale and POPC/PCPC scores determined at PICU admission (baseline) and PICU discharge. We investigated the association between the baseline and PICU discharge POPC/PCPC scores and the baseline and PICU discharge FSS scores, the dispersion of FSS scores within each of the POPC/PCPC ratings, and the relationship between the FSS neurologic components (FSS-CNS) and the PCPC. RESULTS We included 5017 patients. We found a significant (P < .001) difference between FSS scores in each POPC or PCPC interval, with an FSS score increase with each worsening POPC/PCPC rating. The FSS scores for the good and mild disability POPC/PCPC ratings were similar and increased by 2 to 3 points for the POPC/PCPC change from mild to moderate disability, 5 to 6 points for moderate to severe disability, and 8 to 9 points for severe disability to vegetative state or coma. The dispersion of FSS scores within each POPC and PCPC rating was substantial and increased with worsening POPC and PCPC scores. We also found a significant (P < .001) difference between the FSS-CNS scores between each of the PCPC ratings with increases in the FSS-CNS score for each higher PCPC rating. CONCLUSIONS AND RELEVANCE The FSS and POPC/PCPC system are closely associated. Increases in FSS scores occur with each higher POPC and PCPC rating and with greater magnitudes of change as the dysfunction severity increases. However, the dispersion of the FSS scores indicated a lack of precision in the POPC/PCPC system when compared with the more objective and granular FSS. The relationship between the PCPC and the FSS-CNS paralleled the relationship between the FSS and POPC/PCPC system. C1 [Pollack, Murray M.; Dalton, Heidi] Phoenix Childrens Hosp, Dept Crit Care Med, Phoenix, AZ USA. [Pollack, Murray M.; Dalton, Heidi] Univ Arizona, Dept Child Hlth, Coll Med Phoenix, Phoenix, AZ 85016 USA. [Holubkov, Richard; Funai, Tomohiko; Clark, Amy; Dean, J. Michael] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Moler, Frank; Shanley, Thomas] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Meert, Kathy] 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. [Carcillo, Joseph] Childrens Hosp Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15213 USA. [Berger, John T.; Wessel, David L.] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Doctor, Allan] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Doctor, Allan] Washington Univ, Sch Med, Dept Biochem, St Louis, MO 63110 USA. [Berg, Robert A.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Harrison, Rick E.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Jenkins, Tammara L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Pollack, MM (reprint author), Univ Arizona, Coll Med Phoenix, Dept Crit Care Med, Phoenix Childrens Hosp, 1919 E Thomas Rd, Phoenix, AZ 85016 USA. EM mpollack@phoenixchildrens.com OI Doctor, Allan/0000-0002-6096-6400 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Department of Health and Human Services [U10HD050096, U10HD049981, U10HD049983, U10HD050012, U10HD063108, U10HD063106, U10HD063114, U01HD049934] FX This study was supported by cooperative agreements U10HD050096, U10HD049981, U10HD049983, U10HD050012, U10HD063108, U10HD063106, U10HD063114, and U01HD049934 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Department of Health and Human Services. NR 24 TC 23 Z9 23 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD JUL PY 2014 VL 168 IS 7 BP 671 EP 676 DI 10.1001/jamapediatrics.2013.5316 PG 6 WC Pediatrics SC Pediatrics GA AL9VV UT WOS:000339492400017 PM 24862461 ER PT J AU Hu, X Legler, PM Southall, N Maloney, DJ Simeonov, A Jadhav, A AF Hu, Xin Legler, Patricia M. Southall, Noel Maloney, David J. Simeonov, Anton Jadhav, Ajit TI Structural insight into exosite binding and discovery of novel exosite inhibitors of botulinum neurotoxin serotype A through in silico screening SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE Botulinum neurotoxin; Exosite; Synergistic inhibition; Binding free energy calculations; Structure-based drug design; Virtual screening ID SMALL-MOLECULE INHIBITORS; LIGHT-CHAIN; SUBSTRATE RECOGNITION; CLOSTRIDIAL NEUROTOXINS; ACTIVE-SITE; A PROTEASE; IDENTIFICATION; TOXIN; FLEXIBILITY; EFFICIENT AB Botulinum neurotoxin serotype A (BoNT/A) is the most lethal toxin among the Tier 1 Select Agents. Development of potent and selective small molecule inhibitors against BoNT/A zinc metalloprotease remains a challenging problem due to its exceptionally large substrate binding surface and conformational plasticity. The exosites of the catalytic domain of BoNT/A are intriguing alternative sites for small molecule intervention, but their suitability for inhibitor design remains largely unexplored. In this study, we employed two recently identified exosite inhibitors, D-chicoric acid and lomofungin, to probe the structural features of the exosites and molecular mechanisms of synergistic inhibition. The results showed that D-chicoric acid favors binding at the alpha-exosite, whereas lomofungin preferentially binds at the beta-exosite by mimicking the substrate beta-sheet binding interaction. Molecular dynamics simulations and binding interaction analysis of the exosite inhibitors with BoNT/A revealed key elements and hotspots that likely contribute to the inhibitor binding and synergistic inhibition. Finally, we performed database virtual screening for novel inhibitors of BoNT/A targeting the exosites. Hits C1 and C2 showed non-competitive inhibition and likely target the alpha- and beta-exosites, respectively. The identified exosite inhibitors may provide novel candidates for structure-based development of therapeutics against BoNT/A intoxication. C1 [Hu, Xin; Southall, Noel; Maloney, David J.; Simeonov, Anton; Jadhav, Ajit] NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Legler, Patricia M.] Naval Res Labs, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. RP Jadhav, A (reprint author), NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM hux61@mail.nih.gov; ajadhav@mail.nih.gov RI Southall, Noel/H-8991-2012 OI Southall, Noel/0000-0003-4500-880X FU Defense Threat Reduction Agency [CBS.MEDBIO.01.10.WR.001] FX This work was supported by Defense Threat Reduction Agency award CBS.MEDBIO.01.10.WR.001. The opinions or assertions contained herein belong to the authors and are not necessarily the official views of the U.S. Navy or the U. S. Department of Defense. NR 38 TC 8 Z9 8 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X EI 1573-4951 J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD JUL PY 2014 VL 28 IS 7 BP 765 EP 778 DI 10.1007/s10822-014-9758-7 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA AM3AQ UT WOS:000339723800006 PM 24958623 ER PT J AU West, SK Moncada, J Munoz, B Mkocha, H Storey, P Hardick, J Gaydos, CA Quinn, TC Schachter, J AF West, Sheila K. Moncada, Jeanne Munoz, Beatriz Mkocha, Harran Storey, Philip Hardick, Justin Gaydos, Charlotte A. Quinn, Thomas C. Schachter, Julius TI Is There Evidence for Resistance of Ocular Chlamydia trachomatis to Azithromycin After Mass Treatment for Trachoma Control? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE C. trachomatis; trachoma; azithromycin; resistance; mass drug administration ID RISK-FACTORS; RANDOMIZED-TRIAL; TANZANIA; INFECTION; COVERAGE; CHILDREN; GAMBIA AB Background. Trachoma, caused by repeated infections with ocular Chlamydia trachomatis, is targeted for elimination using multiple annual rounds of mass drug administration (MDA) in endemic communities. Infection rates do not decline as expected in some communities, leading to concerns about azithromycin resistance. Methods. After 3 yearly MDAs in 32 communities in Tanzania, 107 children were identified 1 year later with infection. All were provided MDA again, and 90 were seen again at 2 months, of whom 30 had infection. Chlamydia trachomatis isolates were obtained before and after MDA in 15 paired samples and were tested for antimicrobial susceptibility. The infectious load of C. trachomatis before MDA was determined in 30 children who had infection at both times and 60 whose infection cleared. Results. The median load was 8.6 genome copies per polymerase chain reaction in the consistently infected, and 8.4 in those whose infection cleared (P = .86). For the consistently infected, the average minimum inhibitory concentration was 0.26 mu g/mL for azithromycin before and 0.20 mu g/mL after MDA. All isolates had minimum inhibitory concentration <= 0.50 mu g/mL. Conclusions. There is no evidence that continued infection after MDA was due either to resistance to azithromycin or to a heavier load of organism before treatment. Other potential causes of persistent infection need to be evaluated. C1 [West, Sheila K.; Munoz, Beatriz; Storey, Philip] Johns Hopkins Univ, Dana Ctr Prevent Ophthalmol, Baltimore, MD 21218 USA. [Hardick, Justin; Gaydos, Charlotte A.; Quinn, Thomas C.] Johns Hopkins Univ, Div Infect Dis, Baltimore, MD 21218 USA. [Quinn, Thomas C.] NIAID, Div Intramural Res, Bethesda, MD 20892 USA. [Moncada, Jeanne; Schachter, Julius] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Mkocha, Harran] Kongwa Trachoma Project, Kongwa, Tanzania. RP West, SK (reprint author), Wilmer Eye Inst, Room 129,600 N Wolfe St, Baltimore, MD 21287 USA. EM shwest@jhmi.edu OI Storey, Philip/0000-0003-2137-7387 FU Bill and Melinda Gates Foundation FX Financial support. This work was supported by the Bill and Melinda Gates Foundation (grant to S. W.). NR 17 TC 8 Z9 8 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2014 VL 210 IS 1 BP 65 EP 71 DI 10.1093/infdis/jiu046 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM2HI UT WOS:000339670800008 PM 24446528 ER PT J AU Goepfert, PA Elizaga, ML Seaton, K Tomaras, GD Montefiori, DC Sato, A Hural, J DeRosa, SC Kalams, SA McElrath, MJ Keefer, MC Baden, LR Lama, JR Sanchez, J Mulligan, MJ Buchbinder, SP Hammer, SM Koblin, BA Pensiero, M Butler, C Moss, B Robinson, HL AF Goepfert, Paul A. Elizaga, Marnie L. Seaton, Kelly Tomaras, Georgia D. Montefiori, David C. Sato, Alicia Hural, John DeRosa, Stephen C. Kalams, Spyros A. McElrath, M. Juliana Keefer, Michael C. Baden, Lindsey R. Lama, Javier R. Sanchez, Jorge Mulligan, Mark J. Buchbinder, Susan P. Hammer, Scott M. Koblin, Beryl A. Pensiero, Michael Butler, Chris Moss, Bernard Robinson, Harriet L. CA HVTN 205 Study Grp Natl Inst Allergy Infect Dis HIV V TI Specificity and 6-Month Durability of Immune Responses Induced by DNA and Recombinant Modified Vaccinia Ankara Vaccines Expressing HIV-1 Virus-Like Particles SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV/AIDS; vaccines; clinical trial; T cells; antibodies; DNA; recombinant MVA ID T-CELL RESPONSES; EFFICACY TRIAL; VIRAL LOAD; NONNEUTRALIZING ANTIBODIES; NEUTRALIZING ANTIBODY; CONSERVED REGIONS; ENVELOPE PROTEIN; DNA/MVA VACCINE; INNATE IMMUNITY; DOUBLE-BLIND AB Background. Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope glycoprotein (Env) were tested in a phase 2a trial in human immunodeficiency virus (HIV)-uninfected adults for safety, immunogenicity, and 6-month durability of immune responses. Methods. A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the MMM regimen); or placebo injections. Results. At peak response, 93.2% of the DDMM group and 98.4% of the MMM group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gp120) of Env. For both regimens, response rates were higher for CD4(+) T cells (66.4% in the DDMM group and 43.1% in the MMM group) than for CD8(+) T cells (21.8% in the DDMM group and 14.9% in the MMM group). Responding CD4(+) and CD8(+) T cells were biased toward Gag, and >70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon gamma, interleukin 2, tumor necrosis factor alpha, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold. Conclusions. DDMM and MMM vaccinations with virus-like particle-expressing immunogens elicited durable antibody and T-cell responses. C1 [Goepfert, Paul A.] Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. [Elizaga, Marnie L.; Sato, Alicia; Hural, John; DeRosa, Stephen C.; McElrath, M. Juliana] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [DeRosa, Stephen C.; McElrath, M. Juliana] Univ Washington, Seattle, WA 98195 USA. [Seaton, Kelly; Tomaras, Georgia D.; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Lab AIDS Vaccine Res & Dev, Durham, NC 27710 USA. [Kalams, Spyros A.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Keefer, Michael C.] Univ Rochester, Sch Med & Dent, Rochester, NY 14627 USA. [Hammer, Scott M.] Columbia Univ, New York, NY USA. [Koblin, Beryl A.] New York Blood Ctr, New York, NY 10021 USA. [Baden, Lindsey R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Mulligan, Mark J.] Emory Univ, Div Infect Dis, Atlanta, GA 30322 USA. [Robinson, Harriet L.] GeoVax Inc, Smyrna, GA USA. [Buchbinder, Susan P.] San Francisco Dept Publ Hlth, Bridge HIV, San Francisco, CA USA. [Pensiero, Michael; Butler, Chris] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Lama, Javier R.; Sanchez, Jorge] Asociac Civil IMPACTA Salud & Educ, Lima, Peru. RP Goepfert, PA (reprint author), 908 20th St South,CCB 328, Birmingham, AL 35294 USA. EM paulg@uab.edu RI Tomaras, Georgia/J-5041-2016 FU National Institutes of Health (NIH) [AI69452, AI069418, AI06970, AI069511, AI069438, AI069412, AI069439, AI069481, AI069496, AI068614, AI068635, AI068618]; NIH Integrated Preclinical/Clinical AIDS Vaccine Development Program [U19A1074073] FX Financial support. This work was supported by the National Institutes of Health (NIH; grants AI69452 [to the University of Alabama-Birmingham], AI069418 [to Emory University], AI06970 [to the New York Blood Center and Columbia University Medical Center], AI069511 [to the University of Rochester], AI069438 [to the Asociacion Civil Impacta Salud y Educacion], AI069412 [to Brigham and Women's Hospital], AI069439 [to Vanderbilt University], AI069481 [to the Fred Hutchinson Cancer Research Center], AI069496 [to the San Francisco Department of Public Health], AI068614 [to the HVTN Core] AI068635 [to SCHARP], and AI068618 [to the HVTN Laboratory]) and the NIH Integrated Preclinical/Clinical AIDS Vaccine Development Program (grant U19A1074073 to GeoVax for product and preclinical studies). NR 45 TC 21 Z9 23 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2014 VL 210 IS 1 BP 99 EP 110 DI 10.1093/infdis/jiu003 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM2HI UT WOS:000339670800012 PM 24403557 ER PT J AU Nelson, MI Njouom, R Viboud, C Niang, MND Kadjo, H Ampofo, W Adebayo, A Tarnagda, Z Miller, MA Holmes, EC Diop, OM AF Nelson, Martha I. Njouom, Richard Viboud, Cecile Niang, Mbayame N. D. Kadjo, Herve Ampofo, William Adebayo, Adedeji Tarnagda, Zekiba Miller, Mark A. Holmes, Edward C. Diop, Ousmane M. TI Multiyear Persistence of 2 Pandemic A/H1N1 Influenza Virus Lineages in West Africa SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE human influenza A virus; pandemic; phylogenetic analysis; Africa ID SENTINEL SURVEILLANCE; A VIRUS; CIRCULATION; DYNAMICS AB Our understanding of the global ecology of influenza viruses is impeded by historically low levels of viral surveillance in Africa. Increased genetic sequencing of African A/H1N1 pandemic influenza viruses during 2009-2013 revealed multiyear persistence of 2 viral lineages within West Africa, raising questions about the roles of reduced air traffic and the asynchrony of seasonal influenza epidemics among West African countries in the evolution of independent lineages. The potential for novel influenza virus lineages to evolve within Africa warrants intensified influenza surveillance in Africa and other understudied areas. C1 [Nelson, Martha I.; Viboud, Cecile; Miller, Mark A.; Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Njouom, Richard] Ctr Pasteur Cameroun, Natl Influenza Ctr, Yaounde, Cameroon. [Niang, Mbayame N. D.; Diop, Ousmane M.] Inst Pasteur, Dakar, Senegal. [Kadjo, Herve] Inst Pasteur Cote Ivoire, Natl Influenza Ctr, Abidjan, Cote Ivoire. [Ampofo, William] Univ Ghana, Noguchi Mem Inst Med Res, Legon, Accra, Ghana. [Adebayo, Adedeji] Fed Minist Hlth, CDC Nigeria, Abuja, Nigeria. [Tarnagda, Zekiba] Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso. [Holmes, Edward C.] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sch Biol Sci, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. RP Nelson, MI (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 16 Ctr Dr,Room 202, Bethesda, MD 20892 USA. EM nelsonma@mail.nih.gov OI Holmes, Edward/0000-0001-9596-3552 FU Fogarty International Center, National Institutes of Health; Office of Global Affairs at the Department of Health and Human Services; National Health and Medical Research Council (NHMRC) Australia fellowship FX Financial support. This work was supported by the Multinational Influenza Seasonal Mortality Study, an ongoing international collaborative effort to understand influenza epidemiology and evolution, led by the Fogarty International Center, National Institutes of Health, with funding from the Office of Global Affairs at the Department of Health and Human Services (C. V. and M. I. N.). E. C. H. is supported by an National Health and Medical Research Council (NHMRC) Australia fellowship. NR 15 TC 9 Z9 9 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2014 VL 210 IS 1 BP 121 EP 125 DI 10.1093/infdis/jiu047 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM2HI UT WOS:000339670800014 PM 24446525 ER PT J AU Landgren, O Mailankody, S AF Landgren, O. Mailankody, S. TI Update on second primary malignancies in multiple myeloma: a focused review SO LEUKEMIA LA English DT Review DE multiple myeloma; secondary malignancy; treatment; lenalidomide; acute myeloid leukemia; myelodysplastic syndromes ID STEM-CELL TRANSPLANTATION; MYELODYSPLASTIC SYNDROMES; ACUTE-LEUKEMIA; LENALIDOMIDE; THERAPY; MELPHALAN; POMALIDOMIDE; MAINTENANCE; CEREBLON; PROTEIN AB The last decade has seen significant advances in the management of patients with multiple myeloma (MM). With increasingly effective therapies, MM patients are living longer. With improvements in survival, long-term complications including second primary malignancies are becoming new challenges in providing optimal care for MM patients. Three randomized studies have demonstrated possible clinical benefit with maintenance lenalidomide for patients with MM. These same studies have also demonstrated an increased risk of second primary malignancies. In this review, we will update on the current information regarding mechanisms and risk of developing second primary malignancies with a particular focus on disease- and treatment-related factors. C1 [Landgren, O.; Mailankody, S.] NCI, Multiple Myeloma Sect, NIH, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NCI, Multiple Myeloma Sect, Metab Branch, NIH, Bldg 10 Room 13N240,9000 Rockville Pike, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov FU National Cancer Institute of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health. The authors wish to thank Joe Barker and Emily Steplowski at Information Management Systems, Rockville, MD and Dr Lynn Goldin, Division of Cancer Epidemiology & Genetics, NCI for processing of data and for statistical analysis. NR 25 TC 14 Z9 15 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD JUL PY 2014 VL 28 IS 7 BP 1423 EP 1426 DI 10.1038/leu.2014.22 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA AM2UE UT WOS:000339705500006 PM 24418993 ER PT J AU Landgren, O Graubard, BI Katzmann, JA Kyle, RA Ahmadizadeh, I Clark, R Kumar, SK Dispenzieri, A Greenberg, AJ Therneau, TM Melton, LJ Caporaso, N Korde, N Roschewski, M Costello, R McQuillan, GM Rajkumar, SV AF Landgren, O. Graubard, B. I. Katzmann, J. A. Kyle, R. A. Ahmadizadeh, I. Clark, R. Kumar, S. K. Dispenzieri, A. Greenberg, A. J. Therneau, T. M. Melton, L. J., III Caporaso, N. Korde, N. Roschewski, M. Costello, R. McQuillan, G. M. Rajkumar, S. V. TI Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12 482 persons from the National Health and Nutritional Examination Survey SO LEUKEMIA LA English DT Article DE monoclonal gammopathy; prevalence; prognosis; bionnarker; racial disparity ID UNDETERMINED SIGNIFICANCE MGUS; PRECEDES MULTIPLE-MYELOMA; ANTHROPOMETRIC CHARACTERISTICS; RHEUMATOID-ARTHRITIS; SOCIOECONOMIC-STATUS; UNITED-STATES; RISK-FACTOR; CANCER; PATHOGENESIS; WHITE AB Multiple myelonna (MM) incidence is markedly higher in blacks compared with whites, which may be related to a higher prevalence of monoclonal gammopathy of undetermined, significance (MGUS). Our objective was to define the prevalence and risk factors of MGUS in a large cohort representative of the US population. Stored serum samples from the National Health and Nutritional Examination Survey (NHANES) Ill or NHANES 1999-2004 were available for 12 482 individuals of age >= 50 years (2331 'blacks', 2475 Hispanics, 7051 'whites' and 625 'others') on which agarose-gel electrophoresis, serum protein immunofixation, serum-free light-chain assay and M-protein typing were performed. MGUS was identified in 365 participants (2.4%). Adjusted prevalence of MGUS was significantly higher (P<0.001) in blacks (3.7%) compared with whites (2.3%) (P=0.001) or Hispanics (1.8%), as were characteristics that posed a greater risk of progression to MM. The adjusted prevalence of MGUS was 3.1% and 2.1% for the North/Midwest versus South/West regions of the United States, respectively (P=0.052). MGUS is significantly more common in blacks, and more often has features associated with higher risk of progression to MM. A strong geographic disparity in the prevalence of MGUS between the North/Midwest versus the South/West regions of the United States was found, which has etiologic implications. C1 [Landgren, O.; Ahmadizadeh, I.; Korde, N.; Roschewski, M.; Costello, R.] NCI, Multiple Myeloma Sect, Ctr Canc Res, Metab Branch, Rockville, MD USA. [Graubard, B. I.; Caporaso, N.] NCI, Divs Canc Epidemiol & Genet, Biostat Branch, Rockville, MD USA. [Katzmann, J. A.; Clark, R.] Mayo Clin, Dept Lab Med & Pathol, Coll Med, Rochester, MN USA. [Kyle, R. A.; Kumar, S. K.; Dispenzieri, A.; Therneau, T. M.; Rajkumar, S. V.] Mayo Clin, Div Hematol, Dept Med, Coll Med, Rochester, MN USA. [Greenberg, A. J.; Melton, L. J., III] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Coll Med, Rochester, MN USA. [McQuillan, G. M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth & Nutr Examinat Surveys, Hyattsville, MD 20782 USA. RP Landgren, O (reprint author), NCI, Metab Branch, Multiple Myeloma Sect, NIH, 9000 Rockville Pike,Bldg 10,Room 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov RI Kumar, Shaji/A-9853-2008; OI Kumar, Shaji/0000-0001-5392-9284; Dispenzieri, Angela/0000-0001-8780-9512 FU National Cancer Institute [CA 168762, CA 107476, CA 62242, CA 100707, CA 83724]; Intramural Program of the National Cancer Institute; Foundation (Birmingham, United Kingdom); Henry J. Predolin Foundation, USA FX This work was supported in part by National Cancer Institute grants CA 168762, CA 107476, CA 62242, CA 100707, CA 83724; the Intramural Program of the National Cancer Institute; the Jabbs Foundation (Birmingham, United Kingdom); and the Henry J. Predolin Foundation, USA. NR 35 TC 22 Z9 22 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD JUL PY 2014 VL 28 IS 7 BP 1537 EP 1542 DI 10.1038/1eu.2014.34 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA AM2UE UT WOS:000339705500020 PM 24441287 ER PT J AU Baspinar, A Cukuroglu, E Nussinov, R Keskin, O Gursoy, A AF Baspinar, Alper Cukuroglu, Engin Nussinov, Ruth Keskin, Ozlem Gursoy, Attila TI PRISM: a web server and repository for prediction of protein-protein interactions and modeling their 3D complexes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HOT-SPOTS; INTERFACES; SCALE; DOCKING; REFINEMENT; NETWORKS AB The PRISM web server enables fast and accurate prediction of protein-protein interactions (PPIs). The prediction algorithm is knowledge-based. It combines structural similarity and accounts for evolutionary conservation in the template interfaces. The predicted models are stored in its repository. Given two protein structures, PRISM will provide a structural model of their complex if a matching template interface is available. Users can download the complex structure, retrieve the interface residues and visualize the complex model. C1 [Baspinar, Alper; Cukuroglu, Engin; Keskin, Ozlem; Gursoy, Attila] Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey. [Baspinar, Alper; Cukuroglu, Engin; Keskin, Ozlem; Gursoy, Attila] Koc Univ, Coll Engn, TR-34450 Istanbul, Turkey. [Nussinov, Ruth] NCI, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Gursoy, A (reprint author), Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey. EM okeskin@ku.edu.tr; agursoy@ku.edu.tr RI Gursoy, Attila/E-9565-2015 OI Gursoy, Attila/0000-0002-2297-2113 FU National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Scientific and Technological Research Council of Turkey (TUBITAK) [113E164] FX National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E] (whole or in part); Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (in part); Scientific and Technological Research Council of Turkey (TUBITAK) [113E164]. NR 25 TC 26 Z9 26 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 1 PY 2014 VL 42 IS W1 BP W285 EP W289 DI 10.1093/nar/gku397 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM2XN UT WOS:000339715000047 PM 24829450 ER PT J AU Chuang, GY Liou, D Kwong, PD Georgiev, IS AF Chuang, Gwo-Yu Liou, David Kwong, Peter D. Georgiev, Ivelin S. TI NEP: web server for epitope prediction based on antibody neutralization of viral strains with diverse sequences SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HIV-1 GP120; RATIONAL DESIGN; RESIDUES; BROAD; PERFORMANCE; SITES; PG9 AB Delineation of the antigenic site, or epitope, recognized by an antibody can provide clues about functional vulnerabilities and resistance mechanisms, and can therefore guide antibody optimization and epitope-based vaccine design. Previously, we developed an algorithm for antibody-epitope prediction based on antibody neutralization of viral strains with diverse sequences and validated the algorithm on a set of broadly neutralizing HIV-1 antibodies. Here we describe the implementation of this algorithm, NEP (Neutralization-based Epitope Prediction), as a web-based server. The users must supply as input: (i) an alignment of antigen sequences of diverse viral strains; (ii) neutralization data for the antibody of interest against the same set of antigen sequences; and (iii) (optional) a structure of the unbound antigen, for enhanced prediction accuracy. The prediction results can be downloaded or viewed interactively on the antigen structure (if supplied) from the web browser using a JSmol applet. Since neutralization experiments are typically performed as one of the first steps in the characterization of an antibody to determine its breadth and potency, the NEP server can be used to predict antibody-epitope information at no additional experimental costs. C1 [Chuang, Gwo-Yu; Kwong, Peter D.; Georgiev, Ivelin S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Liou, David] NIAID, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Georgiev, IS (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ivelin.georgiev@nih.gov FU Vaccine Research Center's Intramural Research Program; Office of AIDS Research, National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases FX Vaccine Research Center's Intramural Research Program, National Institute of Allergy and Infectious Diseases; Office of AIDS Research, National Institutes of Health (NIH). Funding for open access charge: Vaccine Research Center's Intramural Research Program, National Institute of Allergy and Infectious Diseases; NIH. NR 30 TC 5 Z9 5 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 1 PY 2014 VL 42 IS W1 BP W64 EP W71 DI 10.1093/nar/gku318 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM2XN UT WOS:000339715000012 PM 24782517 ER PT J AU Stamm, M Staritzbichler, R Khafizov, K Forrest, LR AF Stamm, Marcus Staritzbichler, Rene Khafizov, Kamil Forrest, Lucy R. TI AlignMe-a membrane protein sequence alignment web server SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HYDROPATHY PROFILE ALIGNMENT; SECONDARY TRANSPORT PROTEINS; EXPECTED ACCURACY ALIGNMENT; TRANSMEMBRANE PROTEINS; DATA-BANK; STRUCTURE PREDICTION; TOPOLOGY PREDICTION; MULTIPLE ALIGNMENT; HOMOLOGY DETECTION; DRUGGABLE GENOME AB We present a web server for pair-wise alignment of membrane protein sequences, using the program AlignMe. The server makes available two operational modes of AlignMe: (i) sequence to sequence alignment, taking two sequences in fasta format as input, combining information about each sequence from multiple sources and producing a pair-wise alignment (PW mode); and (ii) alignment of two multiple sequence alignments to create family-averaged hydropathy profile alignments (HP mode). For the PW sequence alignment mode, four different optimized parameter sets are provided, each suited to pairs of sequences with a specific similarity level. These settings utilize different types of inputs: (position-specific) substitution matrices, secondary structure predictions and transmembrane propensities from transmembrane predictions or hydrophobicity scales. In the second (HP) mode, each input multiple sequence alignment is converted into a hydrophobicity profile averaged over the provided set of sequence homologs; the two profiles are then aligned. The HP mode enables qualitative comparison of transmembrane topologies (and therefore potentially of 3D folds) of two membrane proteins, which can be useful if the proteins have low sequence similarity. In summary, the AlignMe web server provides user-friendly access to a set of tools for analysis and comparison of membrane protein sequences. C1 [Stamm, Marcus; Staritzbichler, Rene; Khafizov, Kamil; Forrest, Lucy R.] Max Planck Inst Biophys, Computat Struct Biol Grp, D-60438 Frankfurt, Germany. [Staritzbichler, Rene] Johannes Gutenberg Univ Mainz, Transl Oncol TRON, D-6500 Mainz, Germany. [Khafizov, Kamil] Moscow Inst Phys & Technol, Moscow, Russia. [Forrest, Lucy R.] NIH, NINDS, Bethesda, MD 20852 USA. RP Stamm, M (reprint author), Max Planck Inst Biophys, Computat Struct Biol Grp, D-60438 Frankfurt, Germany. EM lucy.forrest@nih.gov RI Khafizov, Kamil/E-5368-2011 FU DFG (German Research Foundation); Collaborative Research Center 807 'Transport and Communication across Biological Membranes'; Max Planck Society; Intramural Research Program of the National Institutes of Health; NINDS FX DFG (German Research Foundation), Collaborative Research Center 807 'Transport and Communication across Biological Membranes'; Max Planck Society; Intramural Research Program of the National Institutes of Health, NINDS. Source of Open Access funding: National Institutes of Health, National Institute of Neurological Disorders and Stroke (NIH-NINDS). NR 38 TC 14 Z9 14 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 1 PY 2014 VL 42 IS W1 BP W246 EP W251 DI 10.1093/nar/gku291 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM2XN UT WOS:000339715000041 PM 24753425 ER PT J AU Tai, CH Paul, R Dukka, KC Shilling, JD Lee, B AF Tai, Chin-Hsien Paul, Rohit Dukka, K. C. Shilling, Jeffery D. Lee, Byungkook TI SymD webserver: a platform for detecting internally symmetric protein structures SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CLASSIFICATION; SCOP; ALIGNMENTS; SEQUENCES; DATABASE AB Internal symmetry of a protein structure is the pseudo-symmetry that a single protein chain sometimes exhibits. This is in contrast to the symmetry with which monomers are arranged in many multimeric protein complexes. SymD is a program that detects proteins with internal symmetry. It proved to be useful for analyzing protein structure, function and modeling. This web-based interactive tool was developed by implementing the SymD algorithm. To the best of our knowledge, SymD webserver is the first tool of its kind with which users can easily study the symmetry of the protein they are interested in by uploading the structure or retrieving it from databases. It uses the Galaxy platform to take advantage of its extensibility and displays the symmetry properties, the symmetry axis and the sequence alignment of the structures before and after the symmetry transformation via an interactive graphical visualization environment in any modern web browser. An Example Run video displays the workflow to help users navigate. C1 [Tai, Chin-Hsien; Dukka, K. C.; Lee, Byungkook] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Paul, Rohit; Shilling, Jeffery D.] NCI, Off Informat Technol, NIH, Rockville, MD 20850 USA. RP Lee, B (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM BK.Lee@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; U.S. National Cancer Institute FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Funding for open access charge: U.S. National Cancer Institute. NR 15 TC 3 Z9 3 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 1 PY 2014 VL 42 IS W1 BP W296 EP W300 DI 10.1093/nar/gku364 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM2XN UT WOS:000339715000049 PM 24799435 ER PT J AU Bailey, JF Fields, AJ Liebenberg, E Mattison, JA Lotz, JC Kramer, PA AF Bailey, J. F. Fields, A. J. Liebenberg, E. Mattison, J. A. Lotz, J. C. Kramer, P. A. TI Comparison of vertebral and intervertebral disc lesions in aging humans and rhesus monkeys SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Spinal osteoarthritis; Intervertebral disc degeneration; Histopathology; Rhesus monkey ID LOW-BACK-PAIN; DIETARY RESTRICTION; PRIMATE MODEL; ANIMAL-MODELS; LUMBAR SPINE; DEGENERATION; OSTEOARTHRITIS; MACAQUES; EPIDEMIOLOGY; DISEASE AB Objective: To compare gross and histologic patterns of age-related degeneration within the intervertebral disc and adjacent vertebra between rhesus monkeys and humans. Materials and methods: We examined age-related patterns of disc degeneration from mid-sagittal sections of the intervertebral disc and adjacent vertebral bodies (VB) among six rhesus monkey thoracolumbar and seven human lumbar spines. Gross morphology and histopathology were assessed via the Thompson grading scheme and other degenerative features of the disc and adjacent bone. Results: Thompson grades ranged from 3 through 5 for rhesus monkey discs (T9-L1) and 2 through 5 for the human discs (T12-S1). In both rhesus monkey and human discs, presence of distinct lesions was positively associated with Thompson grade of the overall segment. Degenerative patterns differed for radial tears, which were more prevalent with advanced disc degeneration in humans only. Additionally, compared to the more uniform anteroposterior disc degeneration patterns of humans, rhesus monkeys showed more severe osteophytosis and degeneration on the anterior border of the vertebral column. Conclusions: Rhesus monkey spines evaluated in the present study appear to develop age-related patterns of disc degeneration similar to humans. One exception is the absence of an association between radial tears and disc degeneration, which could reflect species-specific differences in posture and spinal curvature. Considering rhesus monkeys demonstrate similar patterns of disc degeneration, and age at a faster rate than humans, these findings suggest longitudinal studies of rhesus monkeys may be a valuable model for better understanding the progression of human age-related spinal osteoarthritis (OA) and disc degeneration. (C) 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Bailey, J. F.; Kramer, P. A.] Univ Washington, Dept Anthropol, Seattle, WA 98195 USA. [Bailey, J. F.; Kramer, P. A.] Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. [Fields, A. J.; Liebenberg, E.; Lotz, J. C.] Univ Calif San Francisco, Dept Orthopaed Surg, San Francisco, CA USA. [Mattison, J. A.] NIA, Translat Gerontol Branch, Intramural Res Program, Poolesville, MD USA. RP Bailey, JF (reprint author), Univ Washington, Box 353100, Seattle, WA 98195 USA. EM baileyjf@uw.edu FU NIH [AG021379, AR052811, AR063705] FX This study was funded by NIH grants AG021379, AR052811, and AR063705. The Debs Chair in Orthopaedic Research at the University of Washington, and Relievant Medsystems, Inc. NR 29 TC 3 Z9 3 U1 8 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD JUL PY 2014 VL 22 IS 7 BP 980 EP 985 DI 10.1016/j.joca.2014.04.027 PG 6 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA AM3ST UT WOS:000339773800013 PM 24821664 ER PT J AU Labunskyy, VM Hatfield, DL Gladyshev, VN AF Labunskyy, Vyacheslav M. Hatfield, Dolph L. Gladyshev, Vadim N. TI SELENOPROTEINS: MOLECULAR PATHWAYS AND PHYSIOLOGICAL ROLES SO PHYSIOLOGICAL REVIEWS LA English DT Review ID SELENOCYSTEINE TRANSFER-RNA; HYDROPEROXIDE GLUTATHIONE-PEROXIDASE; METHIONINE SULFOXIDE REDUCTASE; MITOCHONDRIAL THIOREDOXIN REDUCTASE; PHOSPHOSERYL-TRANSFER-RNA; DISULFIDE BOND FORMATION; INSERTION-SEQUENCE-BINDING; THYROID-HORMONE METABOLISM; UNFOLDED PROTEIN RESPONSE; PRESUMED CATALYTIC TRIAD AB Selenium is an essential micronutrient with important functions in human health and relevance to several pathophysiological conditions. The biological effects of selenium are largely mediated by selenium-containing proteins (selenoproteins) that are present in all three domains of life. Although selenoproteins represent diverse molecular pathways and biological functions, all these proteins contain at least one selenocysteine (Sec), a selenium-containing amino acid, and most serve oxidoreductase functions. Sec is cotranslationally inserted into nascent polypeptide chains in response to the UGA codon, whose normal function is to terminate translation. To decode UGA as Sec, organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons in a process requiring a cis-acting Sec insertion sequence (SECIS) element. Although the basic mechanisms of Sec synthesis and insertion into proteins in both prokaryotes and eukaryotes have been studied in great detail, the identity and functions of many selenoproteins remain largely unknown. In the last decade, there has been significant progress in characterizing selenoproteins and selenoproteomes and understanding their physiological functions. We discuss current knowledge about how these unique proteins perform their functions at the molecular level and highlight new insights into the roles that selenoproteins play in human health. C1 Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NCI, Mol Biol Selenium Sect, Mouse Canc Genet Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), New Res Bldg,Rm 435,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM vgladyshev@rics.bwh.harvard.edu FU National Institutes of Health [AG040191, CA080946, GM061603, GM065204] FX This work was supported by National Institutes of Health Grants AG040191 (to V. M. Labunskyy) as well as CA080946, GM061603, and GM065204 (to V. N. Gladyshev). NR 388 TC 88 Z9 89 U1 5 U2 54 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0031-9333 EI 1522-1210 J9 PHYSIOL REV JI Physiol. Rev. PD JUL PY 2014 VL 94 IS 3 BP 739 EP 777 DI 10.1152/physrev.00039.2013 PG 39 WC Physiology SC Physiology GA AM2MR UT WOS:000339685800002 PM 24987004 ER PT J AU Zorov, DB Juhaszova, M Sollott, SJ AF Zorov, Dmitry B. Juhaszova, Magdalena Sollott, Steven J. TI MITOCHONDRIAL REACTIVE OXYGEN SPECIES (ROS) AND ROS-INDUCED ROS RELEASE SO PHYSIOLOGICAL REVIEWS LA English DT Review ID PERMEABILITY TRANSITION PORE; RAT-LIVER MITOCHONDRIA; HYDROGEN-PEROXIDE PRODUCTION; OXIDOREDUCTASE COMPLEX-I; CA-2&-INDUCED MEMBRANE TRANSITION; ALPHA-KETOGLUTARATE DEHYDROGENASE; MYOCARDIAL REPERFUSION INJURY; NADH-Q OXIDOREDUCTASE; T-CELL-ACTIVATION; SUCCINATE-UBIQUINONE OXIDOREDUCTASE AB Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo. C1 [Zorov, Dmitry B.] Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow 119992, Russia. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Zorov, DB (reprint author), Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow 119992, Russia. EM zorov@genebee.msu.su FU Intramural Research Program of the National Institutes of Health; National Institute on Aging; Russian Foundation of Basic Research [14-04-00542]; Russian Science Foundation [14-15-00147, 14-24- 00107] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, Russian Foundation of Basic Research (14-04-00542) and Russian Science Foundation (14-15-00147, 14-24- 00107). The funders had no role in data collection and analysis, decision to publish, or preparation of the manuscript. NR 500 TC 192 Z9 216 U1 17 U2 101 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0031-9333 EI 1522-1210 J9 PHYSIOL REV JI Physiol. Rev. PD JUL PY 2014 VL 94 IS 3 BP 909 EP 950 DI 10.1152/physrev.00026.2013 PG 42 WC Physiology SC Physiology GA AM2MR UT WOS:000339685800006 PM 24987008 ER PT J AU Cragg, G Newman, D AF Cragg, G. Newman, D. TI Natural products and drug discovery and development: A history of success and continuing promise for the future SO PLANTA MEDICA LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Society-of-Pharmacognosy (ASP) CY AUG 02-06, 2014 CL Oxford, MS SP Amer Soc Pharmacognosy C1 [Cragg, G.; Newman, D.] Frederick Natl Lab Canc Res, Nat Prod Branch, Dev Therapeut Program, DCTD, Frederick, MD 21702 USA. NR 0 TC 1 Z9 1 U1 2 U2 29 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2014 VL 80 IS 10 MA IL1 BP 750 EP 750 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AM3VP UT WOS:000339781200003 ER PT J AU Hopp, DC AF Hopp, D. C. TI Research priorities at NCCAM SO PLANTA MEDICA LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Society-of-Pharmacognosy (ASP) CY AUG 02-06, 2014 CL Oxford, MS SP Amer Soc Pharmacognosy C1 [Hopp, D. C.] NIH, Div Extramural Res, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2014 VL 80 IS 10 MA IL35 BP 756 EP 756 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AM3VP UT WOS:000339781200037 ER PT J AU Chan, STS Henrich, CJ O'Keefe, BR McKee, TC McMahon, JB Gustafson, KR AF Chan, S. T. S. Henrich, C. J. O'Keefe, B. R. McKee, T. C. McMahon, J. B. Gustafson, K. R. TI Isolation and identification of biologically active natural products from marine ascidians SO PLANTA MEDICA LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Society-of-Pharmacognosy (ASP) CY AUG 02-06, 2014 CL Oxford, MS SP Amer Soc Pharmacognosy C1 [Chan, S. T. S.; Henrich, C. J.; O'Keefe, B. R.; McKee, T. C.; McMahon, J. B.; Gustafson, K. R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Henrich, C. J.] Leidos Biomed Inc, Basic Res Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2014 VL 80 IS 10 MA PB9 BP 767 EP 767 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AM3VP UT WOS:000339781200087 ER PT J AU Giddings, LA Shipley, S DeLloyd, T Newman, DJ AF Giddings, L. A. Shipley, S. DeLloyd, T. Newman, D. J. TI New cytotoxic agents isolated from various fungal isolates via activity-guided fractionation SO PLANTA MEDICA LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Society-of-Pharmacognosy (ASP) CY AUG 02-06, 2014 CL Oxford, MS SP Amer Soc Pharmacognosy C1 [Giddings, L. A.; Newman, D. J.] Frederick Natl Lab Canc Res, Nat Prod Branch, Frederick, MD 21702 USA. [Shipley, S.; DeLloyd, T.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Nat Prod Support Grp, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2014 VL 80 IS 10 MA PC6 BP 769 EP 770 PG 2 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AM3VP UT WOS:000339781200100 ER PT J AU Thornburg, CC Giddings, LA Shipley, SM DeLloyd, TM Whitt, JA Newman, DJ AF Thornburg, C. C. Giddings, L. A. Shipley, S. M. DeLloyd, T. M. Whitt, J. A. Newman, D. J. TI Fungal biosynthetic gene profiling coupled with the NCI-60 cancer cell line screen for the discovery of cryptic natural products SO PLANTA MEDICA LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Society-of-Pharmacognosy (ASP) CY AUG 02-06, 2014 CL Oxford, MS SP Amer Soc Pharmacognosy C1 [Thornburg, C. C.; Shipley, S. M.; DeLloyd, T. M.; Whitt, J. A.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Nat Prod Support Grp, Frederick, MD 21702 USA. [Giddings, L. A.; Newman, D. J.] Frederick Natl Lab Canc Res, Div Canc Treatment & Diag, Dev Therapeut Program, Nat Prod Branch, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2014 VL 80 IS 10 MA PC16 BP 772 EP 772 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AM3VP UT WOS:000339781200110 ER PT J AU Bokesch, HR Henrich, CJ Ransom, TT Wang, XW McMahon, JB Gustafson, KR AF Bokesch, H. R. Henrich, C. J. Ransom, T. T. Wang, X. W. McMahon, J. B. Gustafson, K. R. TI Isolation and structure elucidation of bioactive leads from terrestrial plants SO PLANTA MEDICA LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Society-of-Pharmacognosy (ASP) CY AUG 02-06, 2014 CL Oxford, MS SP Amer Soc Pharmacognosy C1 [Bokesch, H. R.; Henrich, C. J.] Leidos Biomed Res Inc, Frederick Natl Lab, Basic Res Program, Frederick, MD 21702 USA. [Bokesch, H. R.; Henrich, C. J.; Ransom, T. T.; McMahon, J. B.; Gustafson, K. R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick Natl Lab, Frederick, MD 21702 USA. [Wang, X. W.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2014 VL 80 IS 10 MA PD93 BP 798 EP 798 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AM3VP UT WOS:000339781200226 ER PT J AU da Cunha, MG Rosalen, PL de Alencar, SM Ransom, T Beutler, JA AF da Cunha, M. G. Rosalen, P. L. de Alencar, S. M. Ransom, T. Beutler, J. A. TI Major chemical contituents of geopropolis from Melipona scutellaris SO PLANTA MEDICA LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Society-of-Pharmacognosy (ASP) CY AUG 02-06, 2014 CL Oxford, MS SP Amer Soc Pharmacognosy C1 [da Cunha, M. G.; Rosalen, P. L.] Univ Estadual Campinas, Piracicaba Dent Sch, BR-13414903 Piracicaba, SP, Brazil. [de Alencar, S. M.] Univ Sao Paulo, Luiz de Queiroz Coll Agr, BR-13418900 Piracicaba, SP, Brazil. [da Cunha, M. G.; Ransom, T.; Beutler, J. A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. RI Alencar, Severino/B-7743-2012 OI Alencar, Severino/0000-0002-6637-7973 NR 0 TC 0 Z9 0 U1 2 U2 9 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2014 VL 80 IS 10 BP 810 EP 810 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AM3VP UT WOS:000339781200283 ER PT J AU Bermingham, A Price, E Marchand, C Whitson, E Gustafson, KR McMahon, JB Pommier, Y O'Keefe, BR AF Bermingham, A. Price, E. Marchand, C. Whitson, E. Gustafson, K. R. McMahon, J. B. Pommier, Y. O'Keefe, B. R. TI A screen for the identification of inhibitors of tyrosyl-DNA phosphodiesterase 1 SO PLANTA MEDICA LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Society-of-Pharmacognosy (ASP) CY AUG 02-06, 2014 CL Oxford, MS SP Amer Soc Pharmacognosy C1 [Bermingham, A.; Price, E.; Whitson, E.; Gustafson, K. R.; McMahon, J. B.; O'Keefe, B. R.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Marchand, C.; Pommier, Y.] NCI, Lab Mol Pharmacol, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2014 VL 80 IS 10 MA PQ4 BP 845 EP 845 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AM3VP UT WOS:000339781200448 ER PT J AU Huang, L van Breemen, RB AF Huang, L. van Breemen, R. B. TI UHPLC-MS/MS detection of reactive metabolites trapped as GSH conjugates from plant extracts SO PLANTA MEDICA LA English DT Meeting Abstract CT 55th Annual Meeting of the American-Society-of-Pharmacognosy (ASP) CY AUG 02-06, 2014 CL Oxford, MS SP Amer Soc Pharmacognosy C1 [Huang, L.; van Breemen, R. B.] Univ Illinois, UIC, NIH, Ctr Bot Dietary Supplements Res,Coll Pharm, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD JUL PY 2014 VL 80 IS 10 MA PU5 BP 849 EP 850 PG 2 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA AM3VP UT WOS:000339781200468 ER PT J AU Chowdhury, SA Shackney, SE Heselmeyer-Haddad, K Ried, T Schaffer, AA Schwartz, R AF Chowdhury, Salim Akhter Shackney, Stanley E. Heselmeyer-Haddad, Kerstin Ried, Thomas Schaeffer, Alejandro A. Schwartz, Russell TI Algorithms to Model Single Gene, Single Chromosome, and Whole Genome Copy Number Changes Jointly in Tumor Phylogenetics SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID IN-SITU HYBRIDIZATION; CELL LINEAGE ANALYSIS; BREAST-CANCER; EVOLUTIONARY PATHWAYS; PROGRESSION SCORES; MUTAGENETIC TREES; CLONAL EVOLUTION; CERVICAL-CANCER; HETEROGENEITY; AMPLIFICATION AB We present methods to construct phylogenetic models of tumor progression at the cellular level that include copy number changes at the scale of single genes, entire chromosomes, and the whole genome. The methods are designed for data collected by fluorescence in situ hybridization (FISH), an experimental technique especially well suited to characterizing intratumor heterogeneity using counts of probes to genetic regions frequently gained or lost in tumor development. Here, we develop new provably optimal methods for computing an edit distance between the copy number states of two cells given evolution by copy number changes of single probes, all probes on a chromosome, or all probes in the genome. We then apply this theory to develop a practical heuristic algorithm, implemented in publicly available software, for inferring tumor phylogenies on data from potentially hundreds of single cells by this evolutionary model. We demonstrate and validate the methods on simulated data and published FISH data from cervical cancers and breast cancers. Our computational experiments show that the new model and algorithm lead to more parsimonious trees than prior methods for single-tumor phylogenetics and to improved performance on various classification tasks, such as distinguishing primary tumors from metastases obtained from the same patient population. C1 [Chowdhury, Salim Akhter] Carnegie Mellon Univ, Joint Carnegie Mellon Univ Pittsburgh PhD Program, Pittsburgh, PA 15213 USA. [Chowdhury, Salim Akhter; Schwartz, Russell] Carnegie Mellon Univ, Lane Ctr Computat Biol, Pittsburgh, PA 15213 USA. [Shackney, Stanley E.] Intelligent Oncotherapeut, Pittsburgh, PA USA. [Heselmeyer-Haddad, Kerstin; Ried, Thomas] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Schaeffer, Alejandro A.] NIH, Computat Biol Branch, NCBI, Bethesda, MD 20892 USA. [Schwartz, Russell] Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. RP Chowdhury, SA (reprint author), Carnegie Mellon Univ, Joint Carnegie Mellon Univ Pittsburgh PhD Program, Pittsburgh, PA 15213 USA. EM russells@andrew.cmu.edu RI Schwartz, Russell/A-1998-2016 OI Schwartz, Russell/0000-0002-4970-2252 FU U.S. National Institutes of Health; National Cancer Institute; National Library of Medicine; U.S. National Institutes of Health [1R01CA140214, 1R01AI076318] FX This research was supported in part by the Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, and National Library of Medicine, and by U.S. National Institutes of Health grants 1R01CA140214 (RS and SAC) and 1R01AI076318 (RS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 7 Z9 7 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JUL PY 2014 VL 10 IS 7 AR e1003740 DI 10.1371/journal.pcbi.1003740 PG 19 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA AM5IO UT WOS:000339890900047 PM 25078894 ER PT J AU Miller, BT Singh, RP Schalk, V Pevzner, Y Sun, JJ Miller, CS Boresch, S Ichiye, T Brooks, BR Woodcock, HL AF Miller, Benjamin T. Singh, Rishi P. Schalk, Vinushka Pevzner, Yuri Sun, Jingjun Miller, Carrie S. Boresch, Stefan Ichiye, Toshiko Brooks, Bernard R. Woodcock, H. Lee, III TI Web-Based Computational Chemistry Education with CHARMMing I: Lessons and Tutorial SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID GENERAL FORCE-FIELD; MOLECULAR-DYNAMICS; ENZYMATIC-REACTIONS; PROTEIN; SIMULATIONS; QUANTUM; SYSTEMS; AUTOMATION; RESOLUTION; KINETICS AB This article describes the development, implementation, and use of web-based "lessons'' to introduce students and other newcomers to computer simulations of biological macromolecules. These lessons, i.e., interactive step-by-step instructions for performing common molecular simulation tasks, are integrated into the collaboratively developed CHARMM INterface and Graphics (CHARMMing) web user interface (http://www.charmming.org). Several lessons have already been developed with new ones easily added via a provided Python script. In addition to CHARMMing's new lessons functionality, web-based graphical capabilities have been overhauled and are fully compatible with modern mobile web browsers (e. g., phones and tablets), allowing easy integration of these advanced simulation techniques into course-work. Finally, one of the primary objections to web-based systems like CHARMMing has been that "point and click'' simulation set-up does little to teach the user about the underlying physics, biology, and computational methods being applied. In response to this criticism, we have developed a freely available tutorial to bridge the gap between graphical simulation setup and the technical knowledge necessary to perform simulations without user interface assistance. C1 [Miller, Benjamin T.; Singh, Rishi P.; Sun, Jingjun; Brooks, Bernard R.] NHLBI, Lab Computat Biol, Bethesda, MD 20892 USA. [Schalk, Vinushka] New Coll Florida, Dept Nat Sci, Sarasota, FL USA. [Pevzner, Yuri; Woodcock, H. Lee, III] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. [Miller, Carrie S.; Ichiye, Toshiko] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. [Boresch, Stefan] Univ Vienna, Fac Chem, Dept Computat Biol Chem, Vienna, Austria. RP Miller, BT (reprint author), NHLBI, Lab Computat Biol, Bldg 10, Bethesda, MD 20892 USA. EM btmiller@nhlbi.nih.gov; hlw@usf.edu RI Boresch, Stefan/F-3467-2014; OI Boresch, Stefan/0000-0002-2793-6656; Miller, Benjamin/0000-0003-1647-0122 FU National Heart, Lung, and Blood Institute, NIH; NIH [1K22HL088341-01A1]; University of South Florida; National Science Foundation [CHE-1158267]; McGowan Foundation FX This research was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute, NIH. HLW3 would like to acknowledge NIH (1K22HL088341-01A1) and the University of South Florida (start-up) for funding. TI gratefully acknowledges the support of the National Science Foundation (CHE-1158267) and the McGowan Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 5 Z9 5 U1 0 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JUL PY 2014 VL 10 IS 7 AR e1003719 DI 10.1371/journal.pcbi.1003719 PG 7 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA AM5IO UT WOS:000339890900033 PM 25057988 ER PT J AU Perrin, BS Miller, BT Schalk, V Woodcock, HL Brooks, BR Ichiye, T AF Perrin, B. Scott, Jr. Miller, Benjamin T. Schalk, Vinushka Woodcock, H. Lee Brooks, Bernard R. Ichiye, Toshiko TI Web-Based Computational Chemistry Education with CHARMMing III: Reduction Potentials of Electron Transfer Proteins SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID REDOX POTENTIALS; RUBREDOXIN; DETERMINANTS; SITE AB A module for fast determination of reduction potentials, E degrees, of redox-active proteins has been implemented in the CHARMM INterface and Graphics (CHARMMing) web portal (www.charmming.org). The free energy of reduction, which is proportional to E degrees, is composed of an intrinsic contribution due to the redox site and an environmental contribution due to the protein and solvent. Here, the intrinsic contribution is selected from a library of pre-calculated density functional theory values for each type of redox site and redox couple, while the environmental contribution is calculated from a crystal structure of the protein using Poisson-Boltzmann continuum electrostatics. An accompanying lesson demonstrates a calculation of E degrees. In this lesson, an ionizable residue in a [4Fe-4S]-protein that causes a pH-dependent E degrees is identified, and the E degrees of a mutant that would test the identification is predicted. This demonstration is valuable to both computational chemistry students and researchers interested in predicting sequence determinants of E degrees for mutagenesis. C1 [Perrin, B. Scott, Jr.; Miller, Benjamin T.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Schalk, Vinushka] New Coll Florida, Dept Nat Sci, Sarasota, FL USA. [Woodcock, H. Lee] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. [Ichiye, Toshiko] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. RP Perrin, BS (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM ti9@georgetown.edu OI Miller, Benjamin/0000-0003-1647-0122 FU National Heart, Lung, and Blood Institute, NIH; National Institutes of Health [GM045303]; William G. McGowan Foundation FX This work was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute, NIH, the National Institutes of Health under grant GM045303 (TI), and funds from William G. McGowan Foundation (TI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 4 Z9 4 U1 2 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JUL PY 2014 VL 10 IS 7 AR e1003739 DI 10.1371/journal.pcbi.1003739 PG 6 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA AM5IO UT WOS:000339890900046 PM 25058418 ER PT J AU Pickard, FC Miller, BT Schalk, V Lerner, MG Woodcock, HL Brooks, BR AF Pickard, Frank C. Miller, Benjamin T. Schalk, Vinushka Lerner, Michael G. Woodcock, H. Lee, III Brooks, Bernard R. TI Web-Based Computational Chemistry Education with CHARMMing II: Coarse-Grained Protein Folding SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID MOLECULAR-DYNAMICS; NONNATIVE INTERACTIONS; COMPUTER-SIMULATION; MAXIMUM RATE; FORCE-FIELD; MODELS; KINETICS; THERMODYNAMICS; LANDSCAPES; MECHANISMS AB A lesson utilizing a coarse-grained (CG) Go-like model has been implemented into the CHARMM INterface and Graphics (CHARMMing) web portal (www.charmming.org) to the Chemistry at HARvard Macromolecular Mechanics (CHARMM) molecular simulation package. While widely used to model various biophysical processes, such as protein folding and aggregation, CG models can also serve as an educational tool because they can provide qualitative descriptions of complex biophysical phenomena for a relatively cheap computational cost. As a proof of concept, this lesson demonstrates the construction of a CG model of a small globular protein, its simulation via Langevin dynamics, and the analysis of the resulting data. This lesson makes connections between modern molecular simulation techniques and topics commonly presented in an advanced undergraduate lecture on physical chemistry. It culminates in a straightforward analysis of a short dynamics trajectory of a small fast folding globular protein; we briefly describe the thermodynamic properties that can be calculated from this analysis. The assumptions inherent in the model and the data analysis are laid out in a clear, concise manner, and the techniques used are consistent with those employed by specialists in the field of CG modeling. One of the major tasks in building the Go-like model is determining the relative strength of the nonbonded interactions between coarse-grained sites. New functionality has been added to CHARMMing to facilitate this process. The implementation of these features into CHARMMing helps automate many of the tedious aspects of constructing a CG Go model. The CG model builder and its accompanying lesson should be a valuable tool to chemistry students, teachers, and modelers in the field. C1 [Pickard, Frank C.; Miller, Benjamin T.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Schalk, Vinushka] New Coll Florida, Dept Nat Sci, Sarasota, FL USA. [Lerner, Michael G.] Earlham Coll, Dept Phys & Astron, Richmond, IN USA. [Woodcock, H. Lee, III] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. RP Pickard, FC (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM brb@nih.gov OI Miller, Benjamin/0000-0003-1647-0122 FU National Heart, Lung, and Blood Institute, NIH FX This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, NIH. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 3 Z9 3 U1 0 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JUL PY 2014 VL 10 IS 7 AR e1003738 DI 10.1371/journal.pcbi.1003738 PG 7 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA AM5IO UT WOS:000339890900045 PM 25058338 ER PT J AU Bui, ET Anderson, NK Kassem, L McMahon, FJ AF Bui, Elise T. Anderson, Natalie K. Kassem, Layla McMahon, Francis J. TI Do Participants in Genome Sequencing Studies of Psychiatric Disorders Wish to Be Informed of Their Results? A Survey Study SO PLOS ONE LA English DT Article ID GENETIC RESEARCH; INCIDENTAL FINDINGS; PUBLIC EXPECTATIONS; WORKING GROUP; RETURN; ATTITUDES; RECOMMENDATIONS; PERSPECTIVES; INTENTIONS; AUTONOMY AB Objective: As large-scale genome sequencing technology advances, concerns surrounding the reporting of individual findings to study volunteers have grown and fueled controversy. This is especially true in mental health research, where the clinical importance of sequencing results is particularly unclear. The ethical, legal, and social issues are being widely debated, but less is known about the attitudes of actual study volunteers toward sequencing studies or what they wish to team about their DNA sequence and its health implications. This study provides information on psychiatric research volunteers' attitudes, beliefs, and concerns with respect to participation in DNA sequencing studies and reporting of individual results. Method: We conducted a pilot study using a questionnaire that we developed to assess what information volunteers in an ongoing family study of bipolar disorder would like to receive if they underwent genome sequencing, what they would do with that information, and what concerns they may have. Results: Almost all of the respondents were willing to participate in genome sequencing. Most respondents wished to be informed about all their health-related genetic risks, including risks for diseases without known prevention or treatment. However, few respondents felt well informed about the nature of genome sequencing or its implications for their health, insurability, or offspring. Conclusions: Despite generally positive attitudes toward genome sequencing among study volunteers, most are not fully aware of the special issues raised by genome sequencing. The attitudes of study volunteers should be considered in the debate about the reporting of individual findings from genome sequencing. C1 [Bui, Elise T.; Anderson, Natalie K.; Kassem, Layla; McMahon, Francis J.] NIMH, Human Genet Branch, NIH, Bethesda, MD 20892 USA. RP Kassem, L (reprint author), NIMH, Human Genet Branch, NIH, Bethesda, MD 20892 USA. EM kasseml@mail.nih.gov OI McMahon, Francis/0000-0002-9469-305X FU NIMH Intramural Research Program FX This work was supported by the NIMH Intramural Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 7 Z9 7 U1 1 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 JUL 1 PY 2014 VL 9 IS 7 AR e101111 DI 10.1371/journal.pone.0101111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM1UX UT WOS:000339635000053 PM 24983240 ER PT J AU Catenacci, DVT Liao, WL Thyparambil, S Henderson, L Xu, P Zhao, L Rambo, B Hart, J Xiao, SY Bengali, K Uzzell, J Darfler, M Krizman, DB Cecchi, F Bottaro, DP Karrison, T Veenstra, TD Hembrough, T Burrows, J AF Catenacci, Daniel V. T. Liao, Wei-Li Thyparambil, Sheeno Henderson, Les Xu, Peng Zhao, Lei Rambo, Brittany Hart, John Xiao, Shu-Yuan Bengali, Kathleen Uzzell, Jamar Darfler, Marlene Krizman, David B. Cecchi, Fabiola Bottaro, Donald P. Karrison, Theodore Veenstra, Timothy D. Hembrough, Todd Burrows, Jon TI Absolute Quantitation of Met Using Mass Spectrometry for Clinical Application: Assay Precision, Stability, and Correlation with MET Gene Amplification in FFPE Tumor Tissue SO PLOS ONE LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; STORED PARAFFIN SLIDES; CELL LUNG-CANCER; C-MET; GASTRIC-CANCER; SIGNALING PATHWAY; KINASE INHIBITOR; THERAPEUTIC TARGET; PROTEIN EXPRESSION; ADENOCARCINOMA AB Background: Overexpression of Met tyrosine kinase receptor is associated with poor prognosis. Overexpression, and particularly MET amplification, are predictive of response to Met-specific therapy in preclinical models. Immunohistochemistry (IHC) of formalin-fixed paraffin-embedded (FFPE) tissues is currently used to select for 'high Met' expressing tumors for Met inhibitor trials. IHC suffers from antibody non-specificity, lack of quantitative resolution, and, when quantifying multiple proteins, inefficient use of scarce tissue. Methods: After describing the development of the Liquid-Tissue-Selected Reaction Monitoring-mass spectrometry (LT-SRM-MS) Met assay, we evaluated the expression level of Met in 130 FFPE gastroesophageal cancer (GEC) tissues. We assessed the correlation of SRM Met expression to IHC and mean MET gene copy number (GCN)/nucleus or MET/CEP7 ratio by fluorescence in situ hybridization (FISH). Results: Proteomic mapping of recombinant Met identified (418)TEFTTALQR(426) as the optimal SRM peptide. Limits of detection (LOD) and quantitation (LOQ) for this peptide were 150 and 200 amol/mu g tumor protein, respectively. The assay demonstrated excellent precision and temporal stability of measurements in serial sections analyzed one year apart. Expression levels of 130 GEC tissues ranged (<150 amol/mu g to 4669.5 amol/mu g. High correlation was observed between SRM Met expression and both MET GCN and MET/CEP7 ratio as determined by FISH (n = 30; R-2 = 0.898). IHC did not correlate well with SRM (n = 44; R-2 = 0.537) nor FISH GCN (n = 31; R-2 = 0.509). A Met SRM level of >= 1500 amol/mu g was 100% sensitive (95% CI 0.69-1) and 100% specific (95% CI 0.92-1) for MET amplification. Conclusions: The Met SRM assay measured the absolute Met levels in clinical tissues with high precision. Compared to IHC, SRM provided a quantitative and linear measurement of Met expression, reliably distinguishing between non-amplified and amplified MET tumors. These results demonstrate a novel clinical tool for efficient tumor expression profiling, potentially leading to better informed therapeutic decisions for patients with GEC. C1 [Catenacci, Daniel V. T.; Henderson, Les; Xu, Peng; Rambo, Brittany] Univ Chicago, Dept Med, Sect Hematol & Oncol, Chicago, IL 60637 USA. [Liao, Wei-Li; Thyparambil, Sheeno; Bengali, Kathleen; Uzzell, Jamar; Darfler, Marlene; Krizman, David B.; Veenstra, Timothy D.; Hembrough, Todd; Burrows, Jon] OncoPlex Diagnost Inc, Rockville, MD USA. [Zhao, Lei; Hart, John; Xiao, Shu-Yuan] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Cecchi, Fabiola; Bottaro, Donald P.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Karrison, Theodore] Univ Chicago, Dept Hlth Sci, Chicago, IL 60637 USA. RP Catenacci, DVT (reprint author), Univ Chicago, Dept Med, Sect Hematol & Oncol, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM dcatenac@medicine.bsd.uchicago.edu OI Cecchi, Franco/0000-0002-2035-5621; Bottaro, Donald/0000-0002-5057-5334 FU NIH [CA139160-01A]; CALGB/ALLIANCE YIA Award; Live Like Katie Foundation Award; Oncoplex Dx Research Collaboration; UCCCC (University of Chicago Comprehensive Cancer Center) Award in Precision Oncology (DVTC); NIH, National Cancer Institute, Center for Cancer Research; Oncoplex; University of Chicago; Oncoplex Dx FX This research was supported in part by NIH K12 award (CA139160-01A), CALGB/ALLIANCE YIA Award, Live Like Katie Foundation Award, Oncoplex Dx Research Collaboration, and UCCCC (University of Chicago Comprehensive Cancer Center) Award in Precision Oncology (DVTC); the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (DB). A scientific research collaborative agreement between Oncoplex and University of Chicago allowed funding for reagents, expenses towards tissue acquisition and processing, and salaries of laboratory members. The role of each individual author at Oncoplex is as previously indicated, and as employees they received salaries from Oncoplex Dx. The specific roles of each author is outlined in the author contributions section. NR 50 TC 10 Z9 10 U1 0 U2 4 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 JUL 1 PY 2014 VL 9 IS 7 AR e100586 DI 10.1371/journal.pone.0100586 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM1UX UT WOS:000339635000030 PM 24983965 ER PT J AU Tang, WB Kowgier, M Loth, DW Artigas, MS Joubert, BR Hodge, E Gharib, SA Smith, AV Ruczinski, I Gudnason, V Mathias, RA Harris, TB Hansel, NN Launer, LJ Barnes, KC Hansen, JG Albrecht, E Aldrich, MC Allerhand, M Barr, RG Brusselle, GG Couper, DJ Curjuric, I Davies, G Deary, IJ Dupuis, J Fall, T Foy, M Franceschini, N Gao, W Glaser, S Gu, XJ Hancock, DB Heinrich, J Hofman, A Imboden, M Ingelsson, E James, A Karrasch, S Koch, B Kritchevsky, SB Kumar, A Lahousse, L Li, G Lind, L Lindgren, C Liu, YM Lohman, K Lumley, T McArdle, WL Meibohm, B Morris, AP Morrison, AC Musk, B North, KE Palmer, LJ Probst-Hensch, NM Psaty, BM Rivadeneira, F Rotter, JI Schulz, H Smith, LJ Sood, A Starr, JM Strachan, DP Teumer, A Uitterlinden, AG Volzke, H Voorman, A Wain, LV Wells, MT Wilk, JB Williams, OD Heckbert, SR Stricker, BH London, SJ Fornage, M Tobin, MD O'Connor, GT Hall, IP Cassano, PA AF Tang, Wenbo Kowgier, Matthew Loth, Daan W. Artigas, Maria Soler Joubert, Bonnie R. Hodge, Emily Gharib, Sina A. Smith, Albert V. Ruczinski, Ingo Gudnason, Vilmundur Mathias, Rasika A. Harris, Tamara B. Hansel, Nadia N. Launer, Lenore J. Barnes, Kathleen C. Hansen, Joyanna G. Albrecht, Eva Aldrich, Melinda C. Allerhand, Michael Barr, R. Graham Brusselle, Guy G. Couper, David J. Curjuric, Ivan Davies, Gail Deary, Ian J. Dupuis, Josee Fall, Tove Foy, Millennia Franceschini, Nora Gao, Wei Glaeser, Sven Gu, Xiangjun Hancock, Dana B. Heinrich, Joachim Hofman, Albert Imboden, Medea Ingelsson, Erik James, Alan Karrasch, Stefan Koch, Beate Kritchevsky, Stephen B. Kumar, Ashish Lahousse, Lies Li, Guo Lind, Lars Lindgren, Cecilia Liu, Yongmei Lohman, Kurt Lumley, Thomas McArdle, Wendy L. Meibohm, Bernd Morris, Andrew P. Morrison, Alanna C. Musk, Bill North, Kari E. Palmer, Lyle J. Probst-Hensch, Nicole M. Psaty, Bruce M. Rivadeneira, Fernando Rotter, Jerome I. Schulz, Holger Smith, Lewis J. Sood, Akshay Starr, John M. Strachan, David P. Teumer, Alexander Uitterlinden, Andre G. Voelzke, Henry Voorman, Arend Wain, Louise V. Wells, Martin T. Wilk, Jemma B. Williams, O. Dale Heckbert, Susan R. Stricker, Bruno H. London, Stephanie J. Fornage, Myriam Tobin, Martin D. O'Connor, George T. Hall, Ian P. Cassano, Patricia A. TI Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function SO PLOS ONE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; EPIDERMODYSPLASIA-VERRUCIFORMIS; FUNCTION DECLINE; GLOBAL BURDEN; MALIC ENZYME; HEARING-LOSS; ASTHMA; EXPRESSION; GENE; INTERLEUKIN-16 AB Background: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 x 10(-7)). In addition, meta-analysis using the five cohorts with >= 3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 x 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function. C1 [Tang, Wenbo; Hansen, Joyanna G.; Cassano, Patricia A.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Kowgier, Matthew; Palmer, Lyle J.] Univ Toronto, Ontario Inst Canc Res, Toronto, ON, Canada. [Kowgier, Matthew; Palmer, Lyle J.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Biostat, Toronto, ON, Canada. [Loth, Daan W.; Brusselle, Guy G.; Hofman, Albert; Lahousse, Lies; Stricker, Bruno H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Loth, Daan W.; Stricker, Bruno H.] Netherlands Healthcare Inspectorate, The Hague, Netherlands. [Artigas, Maria Soler; Wain, Louise V.; Tobin, Martin D.] Univ Leicester, Genet Epidemiol Grp, Dept Hlth Sci, Leicester, Leics, England. [Artigas, Maria Soler; Wain, Louise V.; Tobin, Martin D.] Glenfield Gen Hosp, Leicester Resp Biomed Res Unit, NIHR, Leicester LE3 9QP, Leics, England. [Joubert, Bonnie R.; Hancock, Dana B.; London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Hodge, Emily; Hall, Ian P.] Univ Nottingham Hosp, Div Resp Med, Nottingham NG7 2UH, England. [Gharib, Sina A.] Univ Washington, Dept Med, Div Pulm & Crit Care Med, Computat Med Core,Ctr Lung Biol, Seattle, WA USA. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Ruczinski, Ingo] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Mathias, Rasika A.; Hansel, Nadia N.; Barnes, Kathleen C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Albrecht, Eva] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Aldrich, Melinda C.] Vanderbilt Univ, Med Ctr, Dept Thorac Surg, Nashville, TN USA. [Aldrich, Melinda C.] Vanderbilt Univ, Med Ctr, Div Epidemiol, Nashville, TN USA. [Allerhand, Michael; Davies, Gail; Deary, Ian J.; Starr, John M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Barr, R. Graham] Columbia Univ, Coll Phys & Surg, Dept Med, Div Gen Med Pulm Allergy & Crit Care, New York, NY USA. [Barr, R. Graham] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Brusselle, Guy G.; Lahousse, Lies] Ghent Univ Hosp, Dept Resp Med, Ghent, Belgium. [Brusselle, Guy G.] Erasmus MC, Dept Resp Med, Rotterdam, Netherlands. [Brusselle, Guy G.] Univ N Carolina, Dept Biostat 22, Chapel Hill, NC USA. [Curjuric, Ivan; Imboden, Medea; Kumar, Ashish; Probst-Hensch, Nicole M.] Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Curjuric, Ivan; Imboden, Medea; Kumar, Ashish; Probst-Hensch, Nicole M.] Univ Basel, Basel, Switzerland. [Davies, Gail] Univ Edinburgh, Med Genet Sect, Mol Med Ctr, Edinburgh, Midlothian, Scotland. [Davies, Gail] Western Gen Hosp, MRC, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Davies, Gail; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Dupuis, Josee; Gao, Wei] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; Wilk, Jemma B.; O'Connor, George T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fall, Tove; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. [Foy, Millennia; Gu, Xiangjun; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Glaeser, Sven; Koch, Beate] Univ Med Greifswald, Dept Internal Med B, Field Res Pneumol & Pneumol Epidemiol, Greifswald, Germany. [Hancock, Dana B.] Res Triangle Inst, Behav Hlth Epidemiol Program, Res Triangle Pk, NC 27709 USA. [Heinrich, Joachim; Karrasch, Stefan; Schulz, Holger] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Heinrich, Joachim; Schulz, Holger] Comprehens Pneumol Ctr Munich CPC M, Munich, Germany. [Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.] Netherlands Consortium Healthy Aging, Rotterdam, Netherlands. [Ingelsson, Erik; Kumar, Ashish; Lindgren, Cecilia; Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Ingelsson, Erik; Kumar, Ashish; Lindgren, Cecilia; Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England. [James, Alan; Musk, Bill] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Karrasch, Stefan] Univ Munich, Inst & Outpatient Clin Occupat Social & Environm, Munich, Germany. [Karrasch, Stefan] Tech Univ Munich, Klinikum Rechts Isar, Univ Hosp, Inst Gen Practice, D-80290 Munich, Germany. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Li, Guo; Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Lindgren, Cecilia] Broad Inst MIT & Harvard, Cambridge, MA USA. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Lohman, Kurt] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [McArdle, Wendy L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Meibohm, Bernd] Univ Tennessee, Ctr Hlth Sci, Coll Pharm, Memphis, TN 38163 USA. [Morrison, Alanna C.; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Palmer, Lyle J.] Univ Toronto, Toronto, ON, Canada. [Palmer, Lyle J.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Rotter, Jerome I.] Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Smith, Lewis J.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Sood, Akshay] Univ New Mexico, Albuquerque, NM 87131 USA. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Strachan, David P.] Univ London, Div Populat Hlth Sci & Educ, London, England. [Teumer, Alexander] Univ Med Greifswald, Dept Genet & Funct Genom, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Study Hlth Pomerania SHIP Clin Epidemiol Res, Greifswald, Germany. [Voorman, Arend] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Wells, Martin T.] Cornell Univ, Dept Stat Sci, Ithaca, NY USA. [Wilk, Jemma B.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Wilk, Jemma B.] Harvard Univ, Sch Med, Boston, MA USA. [Williams, O. Dale] Florida Int Univ, Miami, FL 33199 USA. [O'Connor, George T.] Boston Univ, Sch Med, Dept Med, Sect Pulm Allergy & Crit Care Med, Boston, MA 02118 USA. [Cassano, Patricia A.] Weill Cornell Med Coll, Dept Hlth Care Policy & Res, Div Biostat & Epidemiol, New York, NY USA. RP Cassano, PA (reprint author), Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. EM pac6@cornell.edu RI Palmer, Lyle/K-3196-2014; Fall, Tove/O-7226-2014; Schulz, Holger/J-5643-2015; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Soler Artigas, Maria/L-6529-2013; Smith, Albert/K-5150-2015; OI Hancock, Dana/0000-0003-2240-3604; Lahousse, Lies/0000-0002-3494-4363; London, Stephanie/0000-0003-4911-5290; Wain, Louise/0000-0003-4951-1867; Hall, Ian/0000-0001-9933-3216; Palmer, Lyle/0000-0002-1628-3055; Schulz, Holger/0000-0002-1157-200X; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Soler Artigas, Maria/0000-0002-3213-1107; Smith, Albert/0000-0003-1942-5845; Smith, Lewis J/0000-0002-4728-1562; Kumar, Ashish/0000-0002-7075-5930 FU NIH; US-EPA; Age UK; BBSRC; Boston University; MSD (Merck); BMBF (German Ministry for Research and Education); Actelion Pharma; Novartis Pharma; GSK; Pfizer; Boehringer Ingelheim; Bayer Pharma; MRC; Medical Research Council, UK; BMBF; German Academic Exchange Service; Research Network for Community Medicine of the University of Greifswald; Division of Intramural Research, NIEHS, NIH, DHHS; Sunovion, Inc.; manufacturer (Zoll LifeCor); Johnson Johnson; Merck Data Safety and Monitoring Board; Medical Research Council [G0902313]; National Institute for Health Research (NIHR), Leicester Respiratory Biomedical Research Unit; FAMRI FX All authors have read the journal's policy, and 57 of the 81 authors have declared that no competing interests exist. The following 24 authors have possible conflicts, as follows: Dr. Aldrich reports grants from NIH, during the conduct of the study; Dr. Barnes reports grants from NIH, during the conduct of the study; Dr. Barr reports grants from NIH and US-EPA, during the conduct of the study; Dr. Couper reports grants from NIH, during the conduct of the study; Dr. Deary reports grants from Age UK, grants from BBSRC, during the conduct of the study; Dr. Dupuis reports grants from Boston University, during the conduct of the study; Dr. Fall reports personal fees from MSD (Merck), outside the submitted work; Dr. Gudnason reports other from NIH, during the conduct of the study; Dr. Glaser reports grants from BMBF (German Ministry for Research and Education), during the conduct of the study; personal fees from Actelion Pharma, personal fees from Novartis Pharma, personal fees from GSK, personal fees from Pfizer, personal fees from Boehringer Ingelheim, personal fees from Bayer Pharma, all those apply outside of the submitted work; Dr. Hall reports grants received from MRC and Pfizer, and Vertex sponsored lecture at ERS, outside the submitted work; Dr. Hodge reports grants from The Medical Research Council, UK, during the conduct of the study; Dr. Koch reports grants from BMBF, during the conduct of the study, travel fees from Actelion Pharma, Pfizer, Bayer Pharma, the German Academic Exchange Service, and the Research Network for Community Medicine of the University of Greifswald, one research prize of the Society of Internal Medicine Mecklenburg-Vorpommern, Germany, outside the submitted work; Dr. Lahousse reports grant from Belgian Society of Pneumology, during the conduct of the study; Dr. London is funded in full by the Division of Intramural Research, NIEHS, NIH, DHHS; Dr. Lumley reports grants from NIH, during the conduct of the study; Dr. Mathias reports grants from NIH, during the conduct of the study; Dr. Meibohm reports grants from NIH, during the conduct of the study; Dr. O'Connor reports personal fees from Sunovion, Inc., outside the submitted work; Dr. Psaty reports grants from NIH, during the conduct of the study, and Dr. Psaty serves on the DSMB for a clinical trial of a device, which is funded by the manufacturer (Zoll LifeCor), and he is on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; Dr. L Smith reports personal fees as member of Merck Data Safety and Monitoring Board, outside the submitted work; Dr. Tobin reports grants from Medical Research Council grant G0902313, grants from National Institute for Health Research (NIHR), Leicester Respiratory Biomedical Research Unit, during the conduct of the study (the views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health), grants from Pfizer for collaborative research project (on rare sequence variants and the smoking resistant lung, Nov. 2010 to Nov 2012), outside the submitted work; Dr. Wain reports grants from Pfizer collaborative research project (onrare sequence variants and the smoking resistant lung, Nov. 2010 to Nov 2012), outside the submitted work; Dr. Wilk reports grants from FAMRI, grants from NIH, during the conduct of the study; personal fees from Pfizer, outside the submitted work. This does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials. NR 35 TC 11 Z9 11 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 1 PY 2014 VL 9 IS 7 AR e100776 DI 10.1371/journal.pone.0100776 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM1UX UT WOS:000339635000039 PM 24983941 ER PT J AU Zhang, YW Calado, R Rao, M Hong, JA Meeker, AK Dumitriu, B Atay, S McCormick, PJ Garfield, SH Wangsa, D Padilla-Nash, HM Burkett, S Zhang, M Kunst, TF Peterson, NR Xi, SC Inchauste, S Altorki, NK Casson, AG Beer, DG Harris, CC Ried, T Young, NS Schrump, DS AF Zhang, Yuwei Calado, Rodrigo Rao, Mahadev Hong, Julie A. Meeker, Alan K. Dumitriu, Bogdan Atay, Scott McCormick, Peter J. Garfield, Susan H. Wangsa, Danny Padilla-Nash, Hesed M. Burkett, Sandra Zhang, Mary Kunst, Tricia F. Peterson, Nathan R. Xi, Sichuan Inchauste, Suzanne Altorki, Nasser K. Casson, Alan G. Beer, David G. Harris, Curtis C. Ried, Thomas Young, Neal S. Schrump, David S. TI Telomerase Variant A279T Induces Telomere Dysfunction and Inhibits Non-Canonical Telomerase Activity in Esophageal Carcinomas SO PLOS ONE LA English DT Article ID BONE-MARROW FAILURE; REVERSE-TRANSCRIPTASE; CANCER-CELLS; APLASTIC-ANEMIA; BETA-CATENIN; MUTATIONS; TERT; BARRETTS; LENGTH; MAINTENANCE AB Background: Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas. Methods: Sequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC) patients. MTS, flow cytometry, time lapse microscopy, and murine xenograft techniques were used to assess proliferation, apoptosis, chemotaxis, and tumorigenicity of EsC cells expressing either wtTERT or TERT variants. Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and beta-catenin, and to assess expression of cytoskeletal proteins, and cell signaling. Fluorescence in-situ hybridization and spectral karyotyping techniques were used to examine telomere length and chromosomal stability. Results: Sequencing analysis revealed one deletion involving TERC (TERC del 341-360), and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous); A1062T (4 heterozygous)]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p<0.01). Relative to wtTERT, A279T decreased telomere length, destabilized TERT-BRG-1-beta-catenin complex, markedly depleted beta-catenin, and down-regulated canonical Wnt signaling in cancer cells; these phenomena coincided with decreased proliferation, depletion of additional cytoskeletal proteins, impaired chemotaxis, increased chemosensitivity, and significantly decreased tumorigenicity of EsC cells. A279T expression significantly increased chromosomal aberrations in mouse embryonic fibroblasts (MEFs) following Zeocin (TM) exposure, as well as Li Fraumeni fibroblasts in the absence of pharmacologically-induced DNA damage. Conclusions: A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal cancer cells. These findings warrant further analysis of A279T expression in esophageal cancers and premalignant esophageal lesions. C1 [Zhang, Yuwei; Rao, Mahadev; Hong, Julie A.; Atay, Scott; Zhang, Mary; Kunst, Tricia F.; Xi, Sichuan; Inchauste, Suzanne; Schrump, David S.] NCI, Thorac Surg Sect, Thorac & GI Oncol Branch, Bethesda, MD 20892 USA. [Calado, Rodrigo; Dumitriu, Bogdan; Peterson, Nathan R.; Young, Neal S.] NHLBI, Bethesda, MD 20892 USA. [Meeker, Alan K.] Johns Hopkins Univ Med, Dept Pathol, Baltimore, MD USA. [Meeker, Alan K.] Johns Hopkins Univ Med, Dept Oncol, Baltimore, MD USA. [McCormick, Peter J.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. [Garfield, Susan H.] NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. [Wangsa, Danny; Padilla-Nash, Hesed M.] NCI, Sect Canc Genom, Bethesda, MD 20892 USA. [Burkett, Sandra] NCI, Comparat Mol Cytogenet Core Facil, Frederick, MD 21701 USA. [Altorki, Nasser K.] Weill Cornell Med Ctr, Dept Thorac Surg, New York, NY USA. [Casson, Alan G.] Univ Saskatchewan, Dept Surg, Saskatoon, SK, Canada. [Beer, David G.] Univ Michigan, Med Ctr, Thorac Surg Sect, Ann Arbor, MI USA. [Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Thorac Surg Sect, Thorac & GI Oncol Branch, Bethesda, MD 20892 USA. EM David_Schrump@nih.gov RI Calado, Rodrigo/G-2619-2011; McCormick, Peter/E-7387-2012 OI McCormick, Peter/0000-0002-2225-5181 FU NIH FX This work was supported by a NIH intramural grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 0 Z9 0 U1 1 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 JUL 1 PY 2014 VL 9 IS 7 AR e101010 DI 10.1371/journal.pone.0101010 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM1UX UT WOS:000339635000046 PM 24983628 ER PT J AU Resnik, DB AF Resnik, David B. TI Paternalistic Food and Beverage Policies: A Response to Conly SO PUBLIC HEALTH ETHICS LA English DT Article ID SUGAR-SWEETENED BEVERAGES; PUBLIC-HEALTH; ETHICS; FREEDOM; TAX AB Sarah Conly defends paternalistic public health policies, such as New York City's soft drink ban, on the grounds that they promote values that people accept but have difficulty realizing, owing to their cognitive biases. In this commentary, I criticize Conly's defense of the soft drink ban and offer my own view of the justification for paternalistic food and beverage policies. I propose that paternalistic government restrictions on food and beverage choices should address a significant health problem pertaining to a specific type or class of food or beverage. There should also be substantial evidence that the restrictions are likely to be effective at dealing with the problem and that alternative ways of dealing with it, which do not involve coercion, are likely to be ineffective. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, 111 Alexander Dr,Box 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov NR 29 TC 3 Z9 3 U1 3 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1754-9973 EI 1754-9981 J9 PUBLIC HEALTH ETH-UK JI Public Health Ethics PD JUL PY 2014 VL 7 IS 2 BP 170 EP 177 DI 10.1093/phe/phu014 PG 8 WC Ethics; Public, Environmental & Occupational Health; Medical Ethics SC Social Sciences - Other Topics; Public, Environmental & Occupational Health; Medical Ethics GA AM4UQ UT WOS:000339851800008 ER PT J AU Floridi, C Radaelli, A Abi-Jaoudeh, N Grass, M De Lin, M Chiaradia, M Geschwind, JF Kobeiter, H Squillaci, E Maleux, G Giovagnoni, A Brunese, L Wood, B Carrafiello, G Rotondo, A AF Floridi, Chiara Radaelli, Alessandro Abi-Jaoudeh, Nadine Grass, Micheal De Lin, Ming Chiaradia, Melanie Geschwind, Jean-Francois Kobeiter, Hishman Squillaci, Ettore Maleux, Geert Giovagnoni, Andrea Brunese, Luca Wood, Bradford Carrafiello, Gianpaolo Rotondo, Antonio TI C-arm cone-beam computed tomography in interventional oncology: technical aspects and clinical applications SO RADIOLOGIA MEDICA LA English DT Article DE Interventional oncology; Cone-beam computed tomography; Imaging guidance; Percutaneous treatments; Embolization; Ablation ID PROSTATIC ARTERIAL EMBOLIZATION; HEPATOCELLULAR-CARCINOMA; Y-90 MICROSPHERES; INITIAL-EXPERIENCE; SOFT-TISSUE; CHEMOEMBOLIZATION; RADIOEMBOLIZATION; ACCURACY; MDCT; ANGIOGRAPHY AB C-arm cone-beam computed tomography (CBCT) is a new imaging technology integrated in modern angiographic systems. Due to its ability to obtain cross-sectional imaging and the possibility to use dedicated planning and navigation software, it provides an informed platform for interventional oncology procedures. In this paper, we highlight the technical aspects and clinical applications of CBCT imaging and navigation in the most common loco-regional oncological treatments. C1 [Floridi, Chiara; Carrafiello, Gianpaolo] Insubria Univ, Dept Radiol, I-21100 Varese, Italy. [Radaelli, Alessandro] Philips Healthcare, Woerden, Netherlands. [Abi-Jaoudeh, Nadine; Wood, Bradford] NIH, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Grass, Micheal; De Lin, Ming] Philips Res North Amer, Briarcliff Manor, NY USA. [Grass, Micheal; De Lin, Ming] Philips Res, Hamburg, Germany. [Chiaradia, Melanie; Kobeiter, Hishman] Henri Mondor Hosp, Dept Radiol & Med Imaging, Creteil, France. [Geschwind, Jean-Francois] Johns Hopkins Univ Hosp, Div Vasc & Intervent Radiol, Baltimore, MD 21287 USA. [Squillaci, Ettore] Univ Roma Tor Vergata, Dept Diagnost & Mol Imaging Intervent Radiol & Ra, Rome, Italy. [Maleux, Geert] Leuven Univ Hosp, Dept Radiol, Louvain, Belgium. [Giovagnoni, Andrea] Univ Ancona, Dept Radiol, Ancona, Italy. [Brunese, Luca] Univ Molise, Dept Radiol, Campobasso, Italy. [Rotondo, Antonio] Univ Naples 2, Dept Radiol, Naples, Italy. RP Floridi, C (reprint author), Insubria Univ, Dept Radiol, Viale Borri 57, I-21100 Varese, Italy. EM chiara.floridi@gmail.com OI Rotondo, Antonio/0000-0003-0088-1779 FU NIH; NIH Center for Interventional Oncology FX This study supported in part by the Intramural Research Program of the NIH and the NIH Center for Interventional Oncology (BJW & NAJ). NIH and Philips Healthcare have a cooperative research and development agreement. NR 48 TC 20 Z9 20 U1 0 U2 3 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 0033-8362 EI 1826-6983 J9 RADIOL MED JI Radiol. Med. PD JUL PY 2014 VL 119 IS 7 SI SI BP 521 EP 532 DI 10.1007/s11547-014-0429-5 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AM4KT UT WOS:000339824100009 PM 25012472 ER PT J AU Pletneva, NV Pletnev, SV Bogdanov, AM Goryacheva, EA Artemyev, IV Suslova, EA Arkhipova, SF Pletnev, VZ AF Pletneva, N. V. Pletnev, S. V. Bogdanov, A. M. Goryacheva, E. A. Artemyev, I. V. Suslova, E. A. Arkhipova, S. F. Pletnev, V. Z. TI Spatial structure of dimeric a genetically engineered variant of green fluorescent protein EGFP-K162Q in the P6(1) crystal space group SO RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY LA English DT Article DE GFP like proteins; EGFP; green fluorescent protein; chromophore; spatial structure; X-ray analysis ID CELLS AB The spatial structure of dimeric green fluorescent protein EGFP-K162Q with MDELYK (EGFPv) C-terminal deletion has been assigned in the P6(1) space group with resolution 1.34 by X-ray diffraction analysis. The results have been compared with X-ray diffraction data of monomeric EGFP (green biomarker with enhanced photophysical properties) assigned in another crystal space group, P2(1)2(1)2(1), with resolution 1.50 and 1.35 . Subunits in the EGFPv dimeric structure are located at 75A degrees angle with the contact area 800 (2). The dimeric framework is stabilized by the six hydrogen bonds and central hydrophobic core of six residues. The root-mean-square deviation value for C-alpha atoms in 3-230 residues of the P6(1) and P2(1)2(1)2(1) crystal structures is 0.55 . The differential characteristics of EGFPv-P6(1) structure, compared to that of P2(1)2(1)2(1), is a noticeably different orientation of the Glu222 side chain, and a new conformation of the 155-159 loop fragment, characterized by deviations among the C-alpha atoms of superimposed structures reaching 4.6 for Lys156 and 5.5 for Lys158. C1 [Pletneva, N. V.; Bogdanov, A. M.; Goryacheva, E. A.; Artemyev, I. V.; Suslova, E. A.; Arkhipova, S. F.; Pletnev, V. Z.] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. [Pletnev, S. V.] NCI, Synchrotron Radiat Res Ctr, Argonne, IL USA. RP Pletneva, NV (reprint author), Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Ul Miklukho Maklaya 16-10,GSP-7, Moscow 117997, Russia. EM nadand@mail.ru; vzpletnev@gmail.com RI Pletneva, Nadya/F-7839-2014; Pletnev, Vladimir/Q-6151-2016; Goryacheva, Ekaterina/Q-6277-2016 FU RFBR Fund [14-04-00004, 11-04-01861a]; Department of Energy, United States [W-31-109-Eng-38]; National Cancer Institute; U.S. National Institutes of Health [HSN261200800001E]; fund "Dinastiya" of Dmitry Zimin FX The study was performed with financial support from the RFBR Fund (14-04-00004, 11-04-01861a) and the fund "Dinastiya" of Dmitry Zimin. Experimental X-ray data were obtained at station (22 ID) of the Synchrotron Center (APS; Argonne, United States). Work in the APS center was supported by the Department of Energy, United States, (contract W-31-109-Eng-38), as well as, in part, by the National Cancer Institute and the U.S. National Institutes of Health under contract HSN261200800001E. NR 20 TC 0 Z9 0 U1 1 U2 5 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 1068-1620 EI 1608-330X J9 RUSS J BIOORG CHEM+ JI Russ. J. Bioorg. Chem. PD JUL PY 2014 VL 40 IS 4 BP 383 EP 389 DI 10.1134/S1068162014040104 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA AM5UB UT WOS:000339925100004 ER PT J AU Jordan, JH Thwin, SS Lash, TL Buist, DSM Field, TS Haque, R Pawloski, PA Petersen, HV Prout, MN Quinn, VP Yood, MU Silliman, RA Geiger, AM AF Jordan, Jennifer H. Thwin, Soe Soe Lash, Timothy L. Buist, Diana S. M. Field, Terry S. Haque, Reina Pawloski, Pamala A. Petersen, Hans V. Prout, Marianne N. Quinn, Virginia P. Yood, Marianne Ulcickas Silliman, Rebecca A. Geiger, Ann M. TI Incident comorbidities and all-cause mortality among 5-year survivors of Stage I and II breast cancer diagnosed at age 65 or older: a prospective-matched cohort study SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Survivorship; Comorbidity; Geriatrics; Managed care; Mortality ID POSTMENOPAUSAL WOMEN; IMPACT; CARE; THERAPY; DISEASE; RISK AB Five-year breast cancer survivors, diagnosed after 65 years of age, may develop more incident comorbidities than similar populations free of cancer. We investigated whether older breast cancer survivors have a similar comorbidity burden 6-15 years after cancer diagnosis to matched women free of breast cancer at start of follow-up and whether incident comorbidities are associated with all-cause mortality. In this prospective cohort study, 1,361 older 5-year early-stage breast cancer survivors diagnosed between 1990 and 1994 and 1,361 age- and health system-matched women were followed for 10 years. Adjudicated medical record review captured prevalent and incident comorbidities during follow-up or until death as collected from the National Death Index. Older 5-year breast cancer survivors did not acquire incident comorbidities more often than matched women free of breast cancer in the subsequent 10 years [hazard ratio (HR) 1.0, 95 % confidence interval (95 % CI) 0.93, 1.1]. Adjusted for cohort membership, women with incident comorbidities had a higher mortality rate than those without incident comorbidities (HR 4.8, 95 % CI 4.1, 5.6). A breast cancer history continued to be a hazard for mortality 6-15 years after diagnosis (HR 1.3, 95 % CI 1.1, 1.4). We found that older breast cancer survivors who developed comorbidities had an increased all-cause mortality rate even after adjusting for age and prevalent comorbidity burden. Additionally, survivors acquire comorbidities at a rate similar to older women free of breast cancer. These results highlight the association between comorbidity burden and long-term mortality risk among older breast cancer survivors and their need for appropriate oncology and primary care follow-up. C1 [Jordan, Jennifer H.] Wake Forest Sch Med, Sect Cardiovasc Med, Dept Internal Med, Winston Salem, NC USA. [Thwin, Soe Soe; Silliman, Rebecca A.] Boston Univ, Sch Med, Boston Med Ctr, Sect Geriatr, Boston, MA 02118 USA. [Thwin, Soe Soe] VA Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Jamaica Plain, MA USA. [Lash, Timothy L.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Buist, Diana S. M.] Grp Hlth Res Inst, Seattle, WA USA. [Field, Terry S.] Meyers Primary Care Inst, Worcester, MA USA. [Haque, Reina; Quinn, Virginia P.] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Pawloski, Pamala A.] HealthPartners Inst Educ & Res, Minneapolis, MN USA. [Petersen, Hans V.] Lovelace Resp Res Inst, Albuquerque, NM USA. [Prout, Marianne N.; Yood, Marianne Ulcickas] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Geiger, Ann M.] NCI, HSEB, ARP, Div Canc Control & Prevent DCCPS, Rockville, MD 20892 USA. RP Geiger, AM (reprint author), NCI, HSEB, ARP, Div Canc Control & Prevent DCCPS, 9609 Med Ctr Dr,MSC 9762, Rockville, MD 20892 USA. EM ann.geiger@nih.gov FU Public Health Service from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services [R01CA093772] FX This study was funded by Public Health Service Grant R01CA093772 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services (PI: RA Silliman). The funding sponsors played no part in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Sponsors had no access to the data and did not perform any of the study analysis. NR 35 TC 9 Z9 9 U1 2 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2014 VL 146 IS 2 BP 401 EP 409 DI 10.1007/s10549-014-3021-8 PG 9 WC Oncology SC Oncology GA AL7QR UT WOS:000339330300018 PM 24939060 ER PT J AU DeSantis, CE Lin, CC Mariotto, AB Siegel, RL Stein, KD Kramer, JL Alteri, R Robbins, AS Jemal, A AF DeSantis, Carol E. Lin, Chun Chieh Mariotto, Angela B. Siegel, Rebecca L. Stein, Kevin D. Kramer, Joan L. Alteri, Rick Robbins, Anthony S. Jemal, Ahmedin TI Cancer Treatment and Survivorship Statistics, 2014 SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Article DE survivorship; statistics; cancer; prevalence; treatment patterns ID ANDROGEN-DEPRIVATION THERAPY; ACUTE-LYMPHOBLASTIC-LEUKEMIA; QUALITY-OF-LIFE; LOCALIZED PROSTATE-CANCER; SELECTIVE BLADDER PRESERVATION; POPULATION-BASED COHORT; LYMPH-NODE DISSECTION; YOUNG-ADULT ONCOLOGY; BREAST-CANCER; CARDIOVASCULAR-DISEASE AB The number of cancer survivors continues to increase due to the aging and growth of the population and improvements in early detection and treatment. In order for the public health community to better serve these survivors, the American Cancer Society and the National Cancer Institute collaborated to estimate the number of current and future cancer survivors using data from the Surveillance, Epidemiology, and End Results (SEER) program registries. In addition, current treatment patterns for the most common cancer types are described based on information in the National Cancer Data Base and the SEER and SEER-Medicare linked databases; treatment-related side effects are also briefly described. Nearly 14.5 million Americans with a history of cancer were alive on January 1, 2014; by January 1, 2024, that number will increase to nearly 19 million. The 3 most common prevalent cancers among males are prostate cancer (43%), colorectal cancer (9%), and melanoma (8%), and those among females are cancers of the breast (41%), uterine corpus (8%), and colon and rectum (8%). The age distribution of survivors varies substantially by cancer type. For example, the majority of prostate cancer survivors (62%) are aged 70 years or older, whereas less than one-third (32%) of melanoma survivors are in this older age group. It is important for clinicians to understand the unique medical and psychosocial needs of cancer survivors and to proactively assess and manage these issues. There are a growing number of resources that can assist patients, caregivers, and health care providers in navigating the various phases of cancer survivorship. (C) 2014 American Cancer Society. C1 [DeSantis, Carol E.; Lin, Chun Chieh; Siegel, Rebecca L.; Robbins, Anthony S.; Jemal, Ahmedin] Amer Canc Soc, Surveillance & Hlth Serv Res, Atlanta, GA 30303 USA. [Mariotto, Angela B.] NCI, Div Canc Control & Populat Sci, Data Modeling Branch, Bethesda, MD 20892 USA. [Stein, Kevin D.] Amer Canc Soc, Behav Res Ctr, Atlanta, GA 30303 USA. [Kramer, Joan L.; Alteri, Rick] Amer Canc Soc, Atlanta, GA 30303 USA. RP DeSantis, CE (reprint author), Amer Canc Soc, Surveillance & Hlth Serv Res, 250 Williams St NW, Atlanta, GA 30303 USA. EM Carol.Desantis@cancer.org NR 108 TC 846 Z9 906 U1 52 U2 306 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-9235 EI 1542-4863 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD JUL-AUG PY 2014 VL 64 IS 4 BP 252 EP 271 DI 10.3322/caac.21235 PG 20 WC Oncology SC Oncology GA AL9QN UT WOS:000339475900004 PM 24890451 ER PT J AU Cheung, GYC Joo, HS Chatterjee, SS Otto, M AF Cheung, Gordon Y. C. Joo, Hwang-Soo Chatterjee, Som S. Otto, Michael TI Phenol-soluble modulins - critical determinants of staphylococcal virulence SO FEMS MICROBIOLOGY REVIEWS LA English DT Review DE Staphylococcus aureus; Staphylococcus epidermidis; phenol-soluble modulin; toxin; virulence; biofilm ID PANTON-VALENTINE LEUKOCIDIN; GENE REGULATOR AGR; AUREUS DELTA-TOXIN; POLYSACCHARIDE INTERCELLULAR ADHESIN; COAGULASE-NEGATIVE STAPHYLOCOCCI; GONOCOCCAL GROWTH INHIBITOR; FORMYL PEPTIDE RECEPTORS; METHICILLIN-RESISTANT; ALPHA-TOXIN; HUMAN NEUTROPHILS AB Phenol-soluble modulins (PSMs) are a recently discovered family of amphipathic, alpha-helical peptides that have multiple roles in staphylococcal pathogenesis and contribute to a large extent to the pathogenic success of virulent staphylococci, such as Staphylococcus aureus. PSMs may cause lysis of many human cell types including leukocytes and erythrocytes, stimulate inflammatory responses, and contribute to biofilm development. PSMs appear to have an original role in the commensal lifestyle of staphylococci, where they facilitate growth and spreading on epithelial surfaces. Aggressive, cytolytic PSMs seem to have evolved from that original role and are mainly expressed in highly virulent S. aureus. Here, we will review the biochemistry, genetics, and role of PSMs in the commensal and pathogenic lifestyles of staphylococci, discuss how diversification of PSMs defines the aggressiveness of staphylococcal species, and evaluate potential avenues to target PSMs for drug development against staphylococcal infections. C1 [Cheung, Gordon Y. C.; Joo, Hwang-Soo; Chatterjee, Som S.; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), 33 North Dr,Bldg 33 1W10, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI JOO, HWANG-SOO/0000-0003-4668-3225; Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH). NR 145 TC 40 Z9 40 U1 3 U2 27 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0168-6445 EI 1574-6976 J9 FEMS MICROBIOL REV JI Fems Microbiol. Rev. PD JUL PY 2014 VL 38 IS 4 BP 698 EP 719 DI 10.1111/1574-6976.12057 PG 22 WC Microbiology SC Microbiology GA AM0RH UT WOS:000339553200005 PM 24372362 ER PT J AU Omsland, A Sixt, BS Horn, M Hackstadt, T AF Omsland, Anders Sixt, Barbara Susanne Horn, Matthias Hackstadt, Ted TI Chlamydial metabolism revisited: interspecies metabolic variability and developmental stage-specific physiologic activities SO FEMS MICROBIOLOGY REVIEWS LA English DT Review DE Chlamydia; Protochlamydia; Parachlamydia; metabolism; genomics; developmental cycle ID FREE-LIVING AMEBAS; TRACHOMATIS INCLUSION MEMBRANE; ABORTED BOVINE FETUS; OBLIGATE INTRACELLULAR BACTERIA; COENZYME-A SYNTHETASE; OUTER-MEMBRANE; WADDLIA-CHONDROPHILA; SIMKANIA-NEGEVENSIS; GENOME SEQUENCE; PARACHLAMYDIA-ACANTHAMOEBAE AB Chlamydiae are a group of obligate intracellular bacteria comprising important human and animal pathogens as well as symbionts of ubiquitous protists. They are characterized by a developmental cycle including two main morphologically and physiologically distinct stages, the replicating reticulate body and the infectious nondividing elementary body. In this review, we reconstruct the history of studies that have led to our current perception of chlamydial physiology, focusing on their energy and central carbon metabolism. We then compare the metabolic capabilities of pathogenic and environmental chlamydiae highlighting interspecies variability among the metabolically more flexible environmental strains. We discuss recent findings suggesting that chlamydiae may not live as energy parasites throughout the developmental cycle and that elementary bodies are not metabolically inert but exhibit metabolic activity under appropriate axenic conditions. The observed host-free metabolic activity of elementary bodies may reflect adequate recapitulation of the intracellular environment, but there is evidence that this activity is biologically relevant and required for extracellular survival and maintenance of infectivity. The recent discoveries call for a reconsideration of chlamydial metabolism and future in-depth analyses to better understand how species-and stage-specific differences in chlamydial physiology may affect virulence, tissue tropism, and host adaptation. C1 [Omsland, Anders; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. [Sixt, Barbara Susanne; Horn, Matthias] Univ Vienna, Dept Microbiol & Ecosyst Sci, Div Microbial Ecol, A-1090 Vienna, Austria. RP Horn, M (reprint author), Univ Vienna, Dept Microbiol & Ecosyst Sci, A-1090 Vienna, Austria. EM horn@microbial-ecology.net; ted_hackstadt@nih.gov RI Horn, Matthias/G-1136-2011 OI Horn, Matthias/0000-0002-8309-5855 FU European Research Council (ERC StG 'EvoChlamy'); Austrian Science Fund [I291-B09]; Intramural Research Program of the NIAID/NIH FX Astrid Collingro is greatly acknowledged for discussions on metabolic features of environmental chlamydiae and for preparing the respective figure. The authors would like to thank Heather Murphy for artwork. Matthias Horn acknowledges support from the European Research Council (ERC StG 'EvoChlamy') and the Austrian Science Fund (I291-B09). Anders Omsland and Ted Hackstadt are supported by the Intramural Research Program of the NIAID/NIH. NR 249 TC 20 Z9 20 U1 3 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0168-6445 EI 1574-6976 J9 FEMS MICROBIOL REV JI Fems Microbiol. Rev. PD JUL PY 2014 VL 38 IS 4 BP 779 EP 801 DI 10.1111/1574-6976.12059 PG 23 WC Microbiology SC Microbiology GA AM0RH UT WOS:000339553200008 PM 24484402 ER PT J AU Ballard, ED Cwik, M Storr, CL Goldstein, M Eaton, WW Wilcox, HC AF Ballard, Elizabeth D. Cwik, Mary Storr, Carla L. Goldstein, Mitchell Eaton, William W. Wilcox, Holly C. TI Recent medical service utilization and health conditions associated with a history of suicide attempts SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Suicide; Emergency department; Depression ID MENTAL-HEALTH; PRIMARY-CARE; EMERGENCY-DEPARTMENT; DEPRESSIVE SYMPTOMS; HELP-SEEKING; IDEATION; RISK; BEHAVIORS; 1ST-GRADE; SETTINGS AB Objectives: Suicide is a leading cause of death; unfortunately most individuals at risk for suicide are not identified, assessed or treated by the mental health system. Investigating medical healthcare utilization among individuals with a history of suicide attempt may identify alternative settings for case finding and brief intervention. Methods: The study sample (n=1422, 58% female, 72% African-American) is from a prospective cohort of adults (27-31 years) who participated in a randomized trial of school-based interventions. Logistic regression evaluated the relationship between lifetime history of suicide attempt with past year medical service utilization and selected self-reported health conditions, controlling for lifetime Major Depressive Disorder (MDD), demographic factors, health insurance status and employment. Results: A suicide attempt history was associated with past year emergency department medical visits [aOR 1.51, 95% CI 1.04-2.18, P=.03], but not primary care visits or inpatient hospitalization, when controlling for MDD and other covariates. Severe headaches and chronic gastrointestinal conditions were also associated with lifetime suicide attempt [aOR 1.50, 95% CI 1.03-2.17 and aOR 1.67, 95% CI 1.06-2.63, respectively]. Conclusions: Suicide prevention, including universal screening and brief intervention, is indicated in emergency department settings. Restricting screening to subgroups, such as those individuals presenting with depression, may miss at-risk individuals with somatic concerns. (C) 2014 Elsevier Inc. All rights reserved. C1 [Cwik, Mary; Wilcox, Holly C.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Cwik, Mary] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Amer Indian Hlth, Baltimore, MD USA. [Storr, Carla L.] Univ Maryland, Sch Nursing, Dept Family & Community Hlth, Baltimore, MD 21201 USA. [Storr, Carla L.; Eaton, William W.; Wilcox, Holly C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Ballard, Elizabeth D.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Goldstein, Mitchell] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. RP Wilcox, HC (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 550 N Broadway,Room 907, Baltimore, MD 21287 USA. EM hwilcox1@jhmi.edu FU National Institute of Mental Health [MH090480, MH42968]; National Institute on Drug Abuse [DA04392, DA09897] FX This research was supported by the National Institute of Mental Health (MH090480 and MH42968) and the National Institute on Drug Abuse (DA04392 and DA09897). The data were presented at the International Association for Suicide Research World Congress in June 2013. NR 43 TC 2 Z9 2 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 EI 1873-7714 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD JUL-AUG PY 2014 VL 36 IS 4 BP 437 EP 441 DI 10.1016/j.genhosppsych.2014.03.004 PG 5 WC Psychiatry SC Psychiatry GA AL7RZ UT WOS:000339333800015 PM 24713329 ER PT J AU Kelly, AC Busby, B Wickner, RB AF Kelly, Amy C. Busby, Ben Wickner, Reed B. TI Effect of Domestication on the Spread of the [PIN plus ] Prion in Saccharomyces cerevisiae SO GENETICS LA English DT Article ID CHRONIC WASTING DISEASE; FALSE DISCOVERY RATE; YEAST PRION; ENVIRONMENTAL-STRESS; POPULATION GENOMICS; INDUSTRIAL YEASTS; GENETIC-VARIATION; DNA POLYMORPHISM; SPECIES BARRIER; WILD YEASTS AB Prions (infectious proteins) cause fatal neurodegenerative diseases in mammals. In the yeast Saccharomyces cerevisiae, many toxic and lethal variants of the [PSI+] and [URE3] prions have been identified in laboratory strains, although some commonly studied variants do not seem to impair cell growth. Phylogenetic analysis has revealed four major clades of S. cerevisiae that share histories of two prion proteins and largely correspond to different ecological niches of yeast. The [PIN+] prion was most prevalent in commercialized niches, infrequent among wine/vineyard strains, and not observed in ancestral isolates. As previously reported, the [PSI+] and [URE3] prions are not found in any of these strains. Patterns of heterozygosity revealed genetic mosaicism and indicated extensive outcrossing among divergent strains in commercialized environments. In contrast, ancestral isolates were all homozygous and wine/vineyard strains were closely related to each other and largely homozygous. Cellular growth patterns were highly variable within and among clades, although ancestral isolates were the most efficient sporulators and domesticated strains showed greater tendencies for flocculation. [PIN+]-infected strains had a significantly higher likelihood of polyploidy, showed a higher propensity for flocculation compared to uninfected strains, and had higher sporulation efficiencies compared to domesticated, uninfected strains. Extensive phenotypic variability among strains from different environments suggests that S. cerevisiae is a niche generalist and that most wild strains are able to switch from asexual to sexual and from unicellular to multicellular growth in response to environmental conditions. Our data suggest that outbreeding and multicellular growth patterns adapted for domesticated environments are ecological risk factors for the [PIN+] prion in wild yeast. C1 [Kelly, Amy C.; Wickner, Reed B.] Natl Inst Diabet Digest & Kidney Dis, Lab Biochem & Genet, Bethesda, MD 20892 USA. [Busby, Ben] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), Natl Inst Diabet Digest & Kidney Dis, Lab Biochem & Genet, NIH, Room 207,8 Ctr Dr, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Intramural Research Program of the National Library of Medicine, National Institutes of Health FX We thank Frank Shewmaker for a thoughtful reading of the manuscript. This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases and in part by the Intramural Research Program of the National Library of Medicine, National Institutes of Health. NR 106 TC 5 Z9 5 U1 1 U2 4 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD JUL PY 2014 VL 197 IS 3 BP 1007 EP + DI 10.1534/genetics.114.165670 PG 28 WC Genetics & Heredity SC Genetics & Heredity GA AL8MA UT WOS:000339391900017 PM 24812307 ER PT J AU Bureau, A Parker, MM Ruczinski, I Taub, MA Marazita, ML Murray, JC Mangold, E Noethen, MM Ludwig, KU Hetmanski, JB Bailey-Wilson, JE Cropp, CD Li, Q Szymczak, S Albacha-Hejazi, H Alqosayer, K Field, LL Wu-Chou, YH Doheny, KF Ling, H Scott, AF Beaty, TH AF Bureau, Alexandre Parker, Margaret M. Ruczinski, Ingo Taub, Margaret A. Marazita, Mary L. Murray, Jeffrey C. Mangold, Elisabeth Noethen, Markus M. Ludwig, Kirsten U. Hetmanski, Jacqueline B. Bailey-Wilson, Joan E. Cropp, Cheryl D. Li, Qing Szymczak, Silke Albacha-Hejazi, Hasan Alqosayer, Khalid Field, L. Leigh Wu-Chou, Yah-Huei Doheny, Kimberly F. Ling, Hua Scott, Alan F. Beaty, Terri H. TI Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts SO GENETICS LA English DT Article ID PALATE; LIP; ASSOCIATION; SCAN; RISK; LOCI; LIP/PALATE; PHENOTYPE; LINKAGE AB A dozen genes/regions have been confirmed as genetic risk factors for oral clefts in human association and linkage studies, and animal models argue even more genes may be involved. Genomic sequencing studies should identify specific causal variants and may reveal additional genes as influencing risk to oral clefts, which have a complex and heterogeneous etiology. We conducted a whole exome sequencing (WES) study to search for potentially causal variants using affected relatives drawn from multiplex cleft families. Two or three affected second, third, and higher degree relatives from 55 multiplex families were sequenced. We examined rare single nucleotide variants (SNVs) shared by affected relatives in 348 recognized candidate genes. Exact probabilities that affected relatives would share these rare variants were calculated, given pedigree structures, and corrected for the number of variants tested. Five novel and potentially damaging SNVs shared by affected distant relatives were found and confirmed by Sanger sequencing. One damaging SNV in CDH1, shared by three affected second cousins from a single family, attained statistical significance (P = 0.02 after correcting for multiple tests). Family-based designs such as the one used in this WES study offer important advantages for identifying genes likely to be causing complex and heterogeneous disorders. C1 [Bureau, Alexandre] Univ Laval, Inst Univ Sante Mentale Quebec, Ctr Rech, Quebec City, PQ G1V 0A6, Canada. [Bureau, Alexandre] Univ Laval, Dept Med Sociale & Prevent, Quebec City, PQ G1V 0A6, Canada. [Parker, Margaret M.; Hetmanski, Jacqueline B.; Beaty, Terri H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Ruczinski, Ingo; Taub, Margaret A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Marazita, Mary L.] Univ Pittsburgh, Sch Dent Med, Dept Oral Biol, Pittsburgh, PA 15219 USA. [Murray, Jeffrey C.] Univ Iowa, Sch Med, Dept Pediat, Iowa City, IA 52242 USA. [Mangold, Elisabeth; Noethen, Markus M.; Ludwig, Kirsten U.] Univ Bonn, Inst Human Genet, D-53111 Bonn, Germany. [Bailey-Wilson, Joan E.; Cropp, Cheryl D.; Li, Qing; Szymczak, Silke] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD 21121 USA. [Albacha-Hejazi, Hasan] Hejazi Clin, Riyadh 11461, Saudi Arabia. [Alqosayer, Khalid] Prime Hlth Clin Jeddah, Riyadh 21511, Saudi Arabia. [Field, L. Leigh] Univ British Columbia, Dept Med Genet, Vancouver, BC V6T 1Z3, Canada. [Wu-Chou, Yah-Huei] Chang Gung Mem Hosp, Lab Human Mol Genet, Taoyuan 333, Taiwan. [Doheny, Kimberly F.; Ling, Hua] Johns Hopkins Sch Med, Ctr Inherited Dis Res, Baltimore, MD 21224 USA. [Scott, Alan F.] Johns Hopkins Sch Med, Inst Med Genet, Baltimore, MD 21224 USA. RP Beaty, TH (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM tbeaty1@jhu.edu OI Bureau, Alexandre/0000-0001-8220-9999; Bailey-Wilson, Joan/0000-0002-9153-2920; Nothen, Markus/0000-0002-8770-2464 FU National Institutes of Health (NIH) [R01-DE-014581, U01-DE-018993, R01-DE-016148, P50-DE-016215]; federal contract from the NIH [X01 HG006177, HHSN268200782096C]; Fonds de Recherche du Quebec - Sante; NIH [R01 GM083084] FX We thank the members of the families who participated in this study and the field and laboratory staff who made this analysis possible. This work was supported by the National Institutes of Health (NIH) (R01-DE-014581 and U01-DE-018993 to T. H. B., R01-DE-016148 to M. L. M., and P50-DE-016215 to J.C.M.), with additional support from X01 HG006177 to T. H. B., M. L. M., and J.C.M. for whole exome sequencing at the Center for Inherited Disease Research, which is funded through a federal contract from the NIH to Johns Hopkins University (contract no. HHSN268200782096C). A.B. is supported by a research fellowship from the Fonds de Recherche du Quebec - Sante. I.R. was further supported by NIH grant R01 GM083084. NR 21 TC 12 Z9 13 U1 0 U2 4 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 EI 1943-2631 J9 GENETICS JI Genetics PD JUL PY 2014 VL 197 IS 3 BP 1039 EP + DI 10.1534/genetics.114.165225 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA AL8MA UT WOS:000339391900019 PM 24793288 ER PT J AU Jelovsek, J AF Jelovsek, J. TI MODELS FOR PREDICTING RECURRENCE AND ADVERSE EVENTS AFTER PELVIC ORGAN PROLAPSE SURGERY SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Meeting Abstract C1 [Jelovsek, J.] NICHD, Pelv Floor Disorders Network, Cleveland, OH USA. NR 0 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-3462 EI 1433-3023 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD JUL PY 2014 VL 25 SU 1 MA PP 52 BP S58 EP S59 PG 2 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA AL7UZ UT WOS:000339342800053 ER PT J AU Rogers, RG AF Rogers, R. G. TI POST-HYSTERECTOMY PATIENTS ARE AS LIKELY AS PATIENTS WITH UTEROVAGINAL PROLAPSE TO HAVE SUCCESSFUL PROLAPSE SURGERY SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Meeting Abstract C1 [Rogers, R. G.] Univ New Mexico, NICHD, Pelv Floor Disorders Network, Albuquerque, NM 87131 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-3462 EI 1433-3023 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD JUL PY 2014 VL 25 SU 1 MA OP 156 BP S235 EP S236 PG 2 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA AL7UZ UT WOS:000339342800227 ER PT J AU Bao, W Tobias, DK Bowers, K Chavarro, J Vaag, A Grunnet, LG Strom, M Mills, J Liu, AY Kiely, M Zhang, CL AF Bao, Wei Tobias, Deirdre K. Bowers, Katherine Chavarro, Jorge Vaag, Allan Grunnet, Louise Groth Strom, Marin Mills, James Liu, Aiyi Kiely, Michele Zhang, Cuilin TI Physical Activity and Sedentary Behaviors Associated With Risk of Progression From Gestational Diabetes Mellitus to Type 2 Diabetes Mellitus A Prospective Cohort Study SO JAMA INTERNAL MEDICINE LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; LIFE-STYLE; WEIGHT-GAIN; WOMEN; VALIDATION; DIET; PREVENTION; OBESITY; POPULATION; VALIDITY AB IMPORTANCE Women with a history of gestational diabetes mellitus (GDM) are at substantially increased risk of type 2 diabetes mellitus (T2DM). The identification of important modifiable factors could help prevent T2DM in this high-risk population. OBJECTIVE To examine the role of physical activity and television watching and other sedentary behaviors, and changes in these behaviors in the progression from GDM to T2DM. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of 4554 women from the Nurses' Health Study II who had a history of GDM, as part of the ongoing Diabetes & Women's Health Study. These women were followed up from 1991 to 2007. EXPOSURES Physical activity and television watching and other sedentary behaviors were assessed in 1991, 1997, 2001, and 2005. MAIN OUTCOMES AND MEASURE Incident T2DM identified through self-report and confirmed by supplemental questionnaires. RESULTS We documented 635 incident T2DM cases during 59 287 person-years of follow-up. Each 5-metabolic equivalent hours per week (MET-h/wk) increment of total physical activity, which is equivalent to 100 minutes per week of moderate-intensity physical activity, was related to a 9% lower risk of T2DM (adjusted relative risk [RR], 0.91; 95% CI, 0.88-0.94); this inverse association remained significant after additional adjustment for body mass index (BMI). Moreover, an increase in physical activity was associated with a lower risk of developing T2DM. Compared with women who maintained their total physical activity levels, women who increased their total physical activity levels by 7.5 MET-h/wk or more (equivalent to 150 minutes per week of moderate-intensity physical activity) had a 47% lower risk of T2DM (RR, 0.53; 95% CI, 0.38-0.75); the association remained significant after additional adjustment for BMI. The multivariable adjusted RRs (95% CIs) for T2DM associated with television watching of 0 to 5, 6 to 10, 11 to 20, and 20 or more hours per week were 1 (reference), 1.28 (1.04-1.59), 1.41 (1.11-1.79), and 1.77 (1.28-2.45), respectively (P value for trend <.001); additional adjustment for BMI attenuated the association. CONCLUSIONS AND RELEVANCE Increasing physical activity may lower the risk of progression from GDM to T2DM. These findings suggest a hopeful message to women with a history of GDM, although they are at exceptionally high risk for T2DM, promoting an active lifestyle may lower the risk. C1 [Bao, Wei; Mills, James; Liu, Aiyi; Kiely, Michele; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Tobias, Deirdre K.; Chavarro, Jorge] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Tobias, Deirdre K.; Chavarro, Jorge] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bowers, Katherine] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Biostat & Res Epidemiol, Cincinnati, OH 45229 USA. [Chavarro, Jorge] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Chavarro, Jorge] Harvard Univ, Sch Med, Boston, MA USA. [Vaag, Allan; Grunnet, Louise Groth] Rigshosp, Dept Endocrinol, DK-2100 Copenhagen, Denmark. [Strom, Marin] Statens Serum Inst, Ctr Fetal Programming, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM zhangcu@mail.nih.gov RI Bowers, Katherine/N-5226-2015; OI Liu, Aiyi/0000-0002-6618-5082; Bao, Wei/0000-0002-7301-5786 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275201000020C]; National Institutes of Health [DK58845, CA50385, P30 DK46200, UM1 CA176726]; American Diabetes Association [7-12-MN-34] FX The 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 (contract No. HHSN275201000020C), and research grants DK58845, CA50385, P30 DK46200, and UM1 CA176726 from the National Institutes of Health. Dr Tobias was supported by a mentored fellowship from the American Diabetes Association (#7-12-MN-34). NR 41 TC 24 Z9 26 U1 1 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2014 VL 174 IS 7 BP 1047 EP 1055 DI 10.1001/jamainternmed.2014.1795 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AL9VS UT WOS:000339491700013 PM 24841449 ER PT J AU Semba, RD Ferrucci, L Bartali, B Urpi-Sarda, M Zamora-Ros, R Sun, K Cherubini, A Bandinelli, S Andres-Lacueva, C AF Semba, Richard D. Ferrucci, Luigi Bartali, Benedetta Urpi-Sarda, Mireia Zamora-Ros, Raul Sun, Kai Cherubini, Antonio Bandinelli, Stefania Andres-Lacueva, Cristina TI Resveratrol Levels and All-Cause Mortality in Older Community-Dwelling Adults SO JAMA INTERNAL MEDICINE LA English DT Article ID CORONARY-ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; GRAPE EXTRACT; PROINFLAMMATORY STATE; PRIMARY PREVENTION; METABOLIC PROFILE; FRENCH PARADOX; CLINICAL-TRIAL; RED WINE; SUPPLEMENTATION AB IMPORTANCE Resveratrol, a polyphenol found in grapes, red wine, chocolate, and certain berries and roots, is considered to have antioxidant, anti-inflammatory, and anticancer effects in humans and is related to longevity in some lower organisms. OBJECTIVE To determine whether resveratrol levels achieved with diet are associated with inflammation, cancer, cardiovascular disease, and mortality in humans. DESIGN Prospective cohort study, the Invecchiare in Chianti (InCHIANTI) Study ("Aging in the Chianti Region"), 1998 to 2009 conducted in 2 villages in the Chianti area in a population-based sample of 783 community-dwelling men and women 65 years or older. EXPOSURES Twenty-four-hour urinary resveratrol metabolites. MAIN OUTCOMES AND MEASURES Primary outcome measure was all-cause mortality. Secondary outcomes were markers of inflammation (serum C-reactive protein [CRP], interleukin [IL]-6, IL-1 beta, and tumor necrosis factor [TNF]) and prevalent and incident cancer and cardiovascular disease. RESULTS Mean (95% CI) log total urinary resveratrol metabolite concentrations were 7.08 (6.69-7.48) nmol/g of creatinine. During 9 years of follow-up, 268 (34.3%) of the participants died. From the lowest to the highest quartile of baseline total urinary resveratrol metabolites, the proportion of participants who died from all causes was 34.4%, 31.6%, 33.5%, and 37.4%, respectively (P = .67). Participants in the lowest quartile had a hazards ratio for mortality of 0.80 (95% CI, 0.54-1.17) compared with those in the highest quartile of total urinary resveratrol in a multivariable Cox proportional hazards model that adjusted for potential confounders. Resveratrol levels were not significantly associated with serum CRP, IL-6, IL-1 beta, TNF, prevalent or incident cardiovascular disease, or cancer. CONCLUSIONS AND RELEVANCE In older community-dwelling adults, total urinary resveratrol metabolite concentration was not associated with inflammatory markers, cardiovascular disease, or cancer or predictive of all-cause mortality. Resveratrol levels achieved with a Western diet did not have a substantial influence on health status and mortality risk of the population in this study. C1 [Semba, Richard D.; Sun, Kai] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21287 USA. [Ferrucci, Luigi] Natl Inst Aging, Longitudinal Studies Sect, Baltimore, MD USA. [Bartali, Benedetta] New England Res Inst, Boston, MA USA. [Urpi-Sarda, Mireia; Zamora-Ros, Raul; Andres-Lacueva, Cristina] Univ Barcelona, Dept Nutr & Food Sci,XaRTA, Food Technol Reference Net & Nutr & Food Safety R, Biomarkers & Nutrimetabol Lab, Barcelona, Spain. [Urpi-Sarda, Mireia; Zamora-Ros, Raul; Andres-Lacueva, Cristina] Catalan Inst Oncol ICO IDIBELL, Unit Nutr Environm & Canc, Canc Epidemiol & Res Program, Barcelona, Spain. [Cherubini, Antonio] Ist Ricovero & Cura Carattere Sci INRCA IRCCS, Ist Nazl Riposo & Cura Anziani VE 2, Geriatr & Geriatr Emergency Dept, Ancona, Italy. [Bandinelli, Stefania] Azienda Sanitaria, Florence, Italy. [Urpi-Sarda, Mireia; Zamora-Ros, Raul; Andres-Lacueva, Cristina] Univ Barcelona, Sch Pharm, INSA, Barcelona, Spain. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Smith Bldg,M015,400 N Broadway, Baltimore, MD 21287 USA. EM rdsemba@jhmi.edu RI Andres-Lacueva, Cristina/J-3377-2012; Urpi-Sarda, Mireia/D-5937-2013; OI Andres-Lacueva, Cristina/0000-0002-8494-4978; Urpi-Sarda, Mireia/0000-0002-4064-5175; Cherubini, Antonio/0000-0003-0261-9897 FU National Institutes of Health (NIH) [R01 AG027012, R01 HL094507]; Italian Ministry of Health [ICS110.1/RF97.71]; Intramural Research Program of the NIA-NIH, Baltimore, Maryland; National Institute on Aging (NIA) [263 MD 9164, 263MD 821336, N01-AG-1-1, N01-AG-1-2111, N01-AG-5-0002]; Spanish Government from INGENIO CONSOLIDER program FUNC-FOOD [CSD2007-00063, AGL2009-13906-C02-01] FX This work was supported by National Institutes of Health (NIH) grants R01 AG027012 and R01 HL094507 (Semba); Italian Ministry of Health grant ICS110.1/RF97.71 (Ferrucci); the Intramural Research Program of the NIA-NIH, Baltimore, Maryland (Ferrucci); National Institute on Aging (NIA) contracts 263 MD 9164 (Ferrucci) and 263MD 821336, N01-AG-1-1, N01-AG-1-2111, and N01-AG-5-0002 (Bandinelli); and the Spanish Government from INGENIO CONSOLIDER program FUNC-FOOD grants CSD2007-00063 and AGL2009-13906-C02-01 (Andres-Lacueva). NR 36 TC 46 Z9 47 U1 2 U2 42 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2014 VL 174 IS 7 BP 1077 EP 1084 DI 10.1001/jamainternmed.2014.1582 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AL9VS UT WOS:000339491700018 PM 24819981 ER PT J AU Marcus, PM AF Marcus, Pamela M. TI Estimating Overdiagnosis in Lung Cancer SO JAMA INTERNAL MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Marcus, PM (reprint author), NCI, 9609 Med Ctr Dr,Room 4E-608, Bethesda, MD 20892 USA. EM marcusp@mail.nih.gov NR 2 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2014 VL 174 IS 7 BP 1198 EP 1198 DI 10.1001/jamainternmed.2014.1546 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AL9VS UT WOS:000339491700049 PM 25003884 ER PT J AU Patz, EF Pinsky, P Kramer, BS AF Patz, Edward F., Jr. Pinsky, Paul Kramer, Barnett S. TI Estimating Overdiagnosis in Lung Cancer Screening Reply SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Patz, Edward F., Jr.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Pinsky, Paul; Kramer, Barnett S.] NCI, Bethesda, MD 20892 USA. RP Patz, EF (reprint author), Duke Univ, Med Ctr, Dept Radiol, POB 3808, Durham, NC 27710 USA. EM patz0002@mc.duke.edu NR 2 TC 2 Z9 2 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2014 VL 174 IS 7 BP 1198 EP 1199 DI 10.1001/jamainternmed.2014.1525 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AL9VS UT WOS:000339491700050 PM 25003885 ER PT J AU Schaal, S Kagan, A Wang, Y Chan, CC Kaplan, HJ AF Schaal, Shlomit Kagan, Aleksandr Wang, Yujuan Chan, Chi-Chao Kaplan, Henry J. TI Acute Retinal Necrosis Associated With Epstein-Barr Virus Immunohistopathologic Confirmation SO JAMA OPHTHALMOLOGY LA English DT Article AB IMPORTANCE Acute retinal necrosis (ARN) is an infectious retinitis primarily caused by the herpesviruses. Although the Epstein-Barr virus (EBV) has been implicated as a cause of ARN, to our knowledge, there has been no histopathologic documentation. We report the clinical history and histopathologic confirmation that EBV can cause ARN. OBSERVATIONS Clinical course and histopathology of a patient diagnosed with ARN caused by infection with EBV confirmed by molecular pathology. CONCLUSIONS AND RELEVANCE Epstein-Barr virus is a recognized cause of intraocular inflammation and has been implicated as a possible cause of ARN. However, to our knowledge, tissue demonstration of EBV in a patient with ARN has not previously been reported. We identified the organism in the necrotic retina of a patient receiving immunosuppression because of idiopathic pulmonary fibrosis. C1 [Schaal, Shlomit; Kagan, Aleksandr; Kaplan, Henry J.] Univ Louisville, Dept Ophthalmol & Visual Sci, Louisville, KY 40202 USA. [Wang, Yujuan; Chan, Chi-Chao] NEI, Immunol Lab, Immunopathol Sect, Bethesda, MD 20892 USA. RP Schaal, S (reprint author), Univ Louisville, Dept Ophthalmol & Visual Sci, 301 E Muhammad Ali Blvd, Louisville, KY 40202 USA. EM s.schaal@louisville.edu RI wang, yujuan/C-8428-2016 FU Research to Prevent Blindness, Inc; Kentucky Research Challenge Trust Fund FX The work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc and Kentucky Research Challenge Trust Fund (Dr Kaplan). NR 6 TC 4 Z9 4 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD JUL PY 2014 VL 132 IS 7 BP 881 EP 882 DI 10.1001/jamaophthalmol.2014.266 PG 2 WC Ophthalmology SC Ophthalmology GA AM1SY UT WOS:000339629800014 PM 24743882 ER PT J AU Chew, EY Clemons, TE AF Chew, Emily Y. Clemons, Traci E. TI Experimental Design Issue for Assessment of Carotenoids Lutein and Zeaxanthin in Age-Related Eye Disease Study 2 Formulation for Age-Related Macular Degeneration Reply SO JAMA OPHTHALMOLOGY LA English DT Letter ID CLINICAL-TRIAL; SUPPLEMENTATION; LUTEIN/ZEAXANTHIN; OLDER C1 [Chew, Emily Y.] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. RP Chew, EY (reprint author), NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, 10 Ctr Dr,MSC 1204,Bldg 10,CRC Room 3-2531, Bethesda, MD 20892 USA. EM echew@nei.nih.gov NR 5 TC 0 Z9 0 U1 2 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD JUL PY 2014 VL 132 IS 7 BP 904 EP 905 DI 10.1001/jamaophthalmol.2014.1783 PG 3 WC Ophthalmology SC Ophthalmology GA AM1SY UT WOS:000339629800027 PM 25010178 ER PT J AU De Ravin, SS Parta, M Sutton, DA Wickes, BL Thompson, EH Wiederhold, NP Nakasone, KK Alimchandani, M OConnell, A Notarangelo, L Kang, E Malech, HL Zelazny, AM AF De Ravin, Suk See Parta, Mark Sutton, Deanna A. Wickes, Brian L. Thompson, Elizabeth H. Wiederhold, Nathan P. Nakasone, Karen K. Alimchandani, Meghna OConnell, Amy Notarangelo, Luigi Kang, Elizabeth Malech, Harry L. Zelazny, Adrian M. TI Paravertebral Mushroom: Identification of a Novel Species of Phellinus as a Human Pathogen in Chronic Granulomatous Disease SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID BASIDIOMYCETOUS FUNGI; TROPICALIS; PATIENT AB We describe a case of paravertebral abscess caused by a Phellinus sp. in a boy with chronic granulomatous disease. Sequence-based identification of this mold, a new agent of disease, suggests a close relation to Phellinus umbrinellus. C1 [De Ravin, Suk See; Kang, Elizabeth; Malech, Harry L.] NIAID, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [Parta, Mark] Leidos Biomed Res Inc, Clin Monitoring Res Program, Frederick, MD USA. [Sutton, Deanna A.; Thompson, Elizabeth H.; Wiederhold, Nathan P.] Univ Texas Hlth Sci Ctr San Antonio, Fungus Testing Lab, Dept Pathol, San Antonio, TX 78229 USA. [Wickes, Brian L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Nakasone, Karen K.] US Forest Serv, Ctr Forest Mycol Res, No Res Stn, Forest Prod Lab,USDA, Madison, WI USA. [Alimchandani, Meghna] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [OConnell, Amy; Notarangelo, Luigi] Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Zelazny, Adrian M.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Zelazny, AM (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM azelazny@mail.nih.gov RI Notarangelo, Luigi/F-9718-2016; OI Notarangelo, Luigi/0000-0002-8335-0262; Malech, Harry/0000-0001-5874-5775; Wiederhold, Nathan/0000-0002-2225-5122 FU NIH Clinical Center FX This research was supported by the Intramural Research Program of the NIH Clinical Center. NR 14 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUL PY 2014 VL 52 IS 7 BP 2726 EP 2729 DI 10.1128/JCM.00667-14 PG 4 WC Microbiology SC Microbiology GA AL6YM UT WOS:000339279700078 PM 24829241 ER PT J AU Doss, M Little, MP Orton, CG AF Doss, Mohan Little, Mark P. Orton, Colin G. TI Point/Counterpoint: Low-dose radiation is beneficial, not harmful SO MEDICAL PHYSICS LA English DT Editorial Material ID ATOMIC-BOMB SURVIVORS; IONIZING-RADIATION; CANCER-RISKS; THRESHOLD; CHILDHOOD; EXPOSURE; CURVATURE; LEUKEMIA; DISEASES; HORMESIS C1 [Doss, Mohan] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Little, Mark P.] NCI, Radiat Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Doss, M (reprint author), Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. EM mohan.doss@fccc.edu; mark.little@nih.gov OI Little, Mark/0000-0003-0980-7567 NR 26 TC 12 Z9 12 U1 2 U2 14 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUL PY 2014 VL 41 IS 7 AR 070601 DI 10.1118/1.4881095 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AL3EW UT WOS:000339009800002 PM 24989368 ER PT J AU Liu, X Shu, S Yu, SH Lee, DY Piszczek, G Gucek, M Wang, GH Korn, ED AF Liu, Xiong Shu, Shi Yu, Shuhua Lee, Duck-Yeon Piszczek, Grzegorz Gucek, Marjan Wang, Guanghui Korn, Edward D. TI Biochemical and biological properties of cortexillin III, a component of Dictyostelium DGAP1-cortexillin complexes SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID F-ACTIN; MYOSIN LOCALIZATION; CLEAVAGE FURROW; LEADING-EDGE; CELL-SHAPE; CYTOKINESIS; PROTEINS; CYTOSKELETON; CHEMOTAXIS; DOMAIN AB Cortexillins I-III are members of the alpha-actinin/spectrin subfamily of Dictyostelium calponin homology proteins. Unlike recombinant cortexillins I and II, which form homodimers as well as heterodimers in vitro, we find that recombinant cortexillin III is an unstable monomer but forms more stable heterodimers when coexpressed in Escherichia coli with cortexillin I or II. Expressed cortexillin III also forms heterodimers with both cortexillin I and II in vivo, and the heterodimers complex in vivo with DGAP1, a Dictyostelium GAP protein. Binding of cortexillin III to DGAP1 requires the presence of either cortexillin I or II; that is, cortexillin III binds to DGAP1 only as a heterodimer, and the heterodimers form in vivo in the absence of DGAP1. Expressed cortexillin III colocalizes with cortexillins I and II in the cortex of vegetative amoebae, the leading edge of motile cells, and the cleavage furrow of dividing cells. Colocalization of cortexillin III and F-actin may require the heterodimer/DGAP1 complex. Functionally, cortexillin III may be a negative regulator of cell growth, cytokinesis, pinocytosis, and phagocytosis, as all are enhanced in cortexillin III-null cells. C1 [Liu, Xiong; Shu, Shi; Yu, Shuhua; Korn, Edward D.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Lee, Duck-Yeon] NHLBI, Biochem Core, NIH, Bethesda, MD 20892 USA. [Piszczek, Grzegorz] NHLBI, Biophys Core, NIH, Bethesda, MD 20892 USA. [Gucek, Marjan; Wang, Guanghui] NHLBI, Prote Core, NIH, Bethesda, MD 20892 USA. RP Korn, ED (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM edk@nih.gov FU Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health FX We thank Richard Firtel (University of California, San Diego, La Jolla, CA), Douglas Robinson (Johns Hopkins University, Baltimore, MD), Jan Faix (Hannover Medical School, Hannover, Germany), the Developmental Studies Hybridoma Bank (Iowa City, IA), and the Dictybase Stock Center (Northwestern University, Chicago, IL) for cell lines, DNA constructs, antibodies, and other reagents; Joseph Brzostowski (Laboratory of Immunogenetics Imaging Facility, National Institute of Allergy and Infectious Diseases) for the analysis of cAMP waves; and Xufeng Wu (National Heart, Lung, and Blood Institute Light Microscopy Core) for help in confocal microscopy. We also thank Jianshe Yan (National Institute of Allergy and Infectious Diseases) and Nathan Kung, Ikuko Fujiwara, Kevin Pridham, Maciej Olszewski, Alan Peterkofsky, and Rodney Levine (National Heart, Lung, and Blood Institute) for their generous assistance. We gratefully acknowledge insightful comments by Hanna Brzeska (National Heart, Lung, and Blood Institute). This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 37 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL 1 PY 2014 VL 25 IS 13 BP 2026 EP 2038 DI 10.1091/mbc.E13-08-0457 PG 13 WC Cell Biology SC Cell Biology GA AM2BK UT WOS:000339652900012 PM 24807902 ER PT J AU Larson, BT Sochacki, KA Kindem, JM Taraska, JW AF Larson, Ben T. Sochacki, Kem A. Kindem, Jonathan M. Taraska, Justin W. TI Systematic spatial mapping of proteins at exocytic and endocytic structures SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CLATHRIN-COATED PIT; MEDIATED ENDOCYTOSIS; REGULATED EXOCYTOSIS; SECRETORY GRANULES; NERVE-TERMINALS; PC12 CELLS; MEMBRANE; DYNAMICS; CARGO; MICROSCOPY AB Vesicular secretion (exocytosis) involves the release and then compensatory recycling of vesicle components through endocytosis. This fundamental cellular process is controlled by the coordinated assembly and interactions of dozens of proteins at the plasma membrane. Understanding the molecular composition of individual exocytic and endocytic structures and their organization across the plasma membrane is critical to understanding the behavior and regulation of these two cellular processes. Here we develop a high-resolution and high-throughput fluorescence imaging-based approach for the unbiased mapping of 78 proteins at single exocytic vesicles and endocytic structures in neuroendocrine PC12 cells. This analysis uses two-color single-frame images to provide a systems-level map of the steady-state distributions of proteins at individual exocytic and endocytic structures in the cell. Along with this quantitative map, we find that both calcium-regulated exocytic vesicles (dense core vesicles) and endocytic structures (clathrin-coated structures) and the proteins associated with these structures exhibit a random spatial distribution in unstimulated neuroendocrine PC12 cells. This approach is broadly applicable for quantitatively mapping the molecular composition and spatial organization of discrete cellular processes with central molecular hubs. C1 [Larson, Ben T.; Sochacki, Kem A.; Kindem, Jonathan M.; Taraska, Justin W.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Taraska, JW (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM justin.taraska@nih.gov RI Taraska, Justin/H-8876-2016 OI Taraska, Justin/0000-0001-5355-9535 FU Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health FX We thank Keir Neuman, Jonathan Silver, John Hammer, and members of the Taraska lab for critical reading of the manuscript. We also thank Paul Whittredge and Shiqin Judy Yu for help with cloning. Additionally, we thank the many labs who contributed plasmids to this study and Alan Hoofring of NIH Medical Arts for design work on Figure 1. J.W.T. is supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 45 TC 7 Z9 7 U1 0 U2 14 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL 1 PY 2014 VL 25 IS 13 BP 2084 EP 2093 DI 10.1091/mbc.E14-02-0771 PG 10 WC Cell Biology SC Cell Biology GA AM2BK UT WOS:000339652900017 PM 24807904 ER PT J AU Lam, TK Rotunno, M Ryan, BM Pesatori, AC Bertazzi, PA Spitz, M Caporaso, NE Landi, MT AF Lam, Tram Kim Rotunno, Melissa Ryan, Brid M. Pesatori, Angela C. Bertazzi, Pier Alberto Spitz, Margaret Caporaso, Neil E. Landi, Maria Teresa TI Heme-Related Gene Expression Signatures of Meat Intakes in Lung Cancer Tissues SO MOLECULAR CARCINOGENESIS LA English DT Article DE gene expression; heme-iron; lung cancer ID UNSATURATED FATTY-ACIDS; MUCIN-DEPLETED FOCI; RED MEAT; COLORECTAL-CANCER; PROCESSED MEAT; RISK; IRON; MUTAGENS; CELLS; COLON AB Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the environment and genetics in lung cancer etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a false discovery rate (FDR) <0.15. We studied whether the identified genes played a role in hemeiron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR 0.12). Sixty-three (similar to 28%) of the 232 identified genes (12 expected by chance, P-value < 0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, and WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, and UCP3) and oxidative stress (e.g., TPO, SGK2, and MTHFR) that may be indirectly related to heme-toxicity. The study's results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer. (C) 2013 Wiley Periodicals, Inc. C1 [Lam, Tram Kim] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Genet Epidemiol Branch,NIH,DHHS, Bethesda, MD 20892 USA. [Lam, Tram Kim; Rotunno, Melissa; Caporaso, Neil E.; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, NIH,DHHS, Bethesda, MD 20892 USA. [Ryan, Brid M.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Pesatori, Angela C.; Bertazzi, Pier Alberto] Univ Milan, Epidemiol Res Ctr, EPOCA, Milan, Italy. [Pesatori, Angela C.; Bertazzi, Pier Alberto] Fdn IRCCS Osped Maggiore Policlin, Epidemiol Unit, Milan, Italy. [Spitz, Margaret] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Landi, MT (reprint author), NCI, 6120 Execut Blvd,MSC 7114, Bethesda, MD 20892 USA. RI bertazzi, pietro alberto/D-5039-2017; OI bertazzi, pietro alberto/0000-0003-3475-2449; Ryan, Brid/0000-0003-0038-131X; pesatori, angela/0000-0002-0261-3252 FU Intramural Research Program of NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX Contract grant sponsor: Intramural Research Program of NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 45 TC 2 Z9 2 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JUL PY 2014 VL 53 IS 7 BP 548 EP 556 DI 10.1002/mc.22006 PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AM0UN UT WOS:000339562500005 PM 23681825 ER PT J AU Patterson, A Fennington, K Bayha, R Wax, D Hirschberg, R Boyd, N Kurilla, M AF Patterson, Amy Fennington, Kelly Bayha, Ryan Wax, Diane Hirschberg, Rona Boyd, Nancy Kurilla, Michael TI Biocontainment laboratory risk assessment: perspectives and considerations SO PATHOGENS AND DISEASE LA English DT Review DE biocontainment laboratory; risk assessment; BSL4 laboratory AB The ability to respond to public health emergencies involving infectious diseases as well as our ability to adequately prepare for as yet unknown or unrecognized emerging infectious diseases requires suitable facilities within which scientific investigations can take place. To ensure the safe conduct of such investigations so that laboratory workers and the general public are protected from potential consequences of accidental or intentional release of high consequence pathogens, special containment facilities have been designed and constructed. Evaluation of the adequacy of containment for these types of investigations requires a risk assessment (RA) as part of the overall construction project for these types of laboratories. A discussion of the RA process along with considerations that impact the design of such studies and the overall results is presented. C1 [Patterson, Amy; Fennington, Kelly; Bayha, Ryan] NIH, Off Sci Policy, Bethesda, MD 20892 USA. [Wax, Diane; Hirschberg, Rona; Boyd, Nancy; Kurilla, Michael] NIAID, NIH, Bethesda, MD 20892 USA. RP Kurilla, M (reprint author), 5601 Fishers Lane, Bethesda, MD 20892 USA. EM mkurilla@niaid.nih.gov NR 7 TC 0 Z9 0 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD JUL PY 2014 VL 71 IS 2 SI SI BP 100 EP 106 DI 10.1111/2049-632X.12162 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM1PV UT WOS:000339620800004 ER PT J AU Milne-Price, S Miazgowicz, KL Munster, VJ AF Milne-Price, Shauna Miazgowicz, Kerri L. Munster, Vincent J. TI The emergence of the Middle East Respiratory Syndrome coronavirus SO PATHOGENS AND DISEASE LA English DT Review DE MERS-CoV; coronavirus; epidemiology; molecular biology; intervention strategies ID RECEPTOR-BINDING DOMAIN; PIPISTRELLUS BAT CORONAVIRUS; GROUP C BETACORONAVIRUS; HEALTH-CARE WORKERS; MERS-COV; SPIKE PROTEIN; NEUTRALIZING ANTIBODIES; SARS-CORONAVIRUS; SAUDI-ARABIA; INTERFERON ANTAGONISTS AB On September 20, 2012, a Saudi Arabian physician reported the isolation of a novel coronavirus from a patient with pneumonia on ProMED-mail. Within a few days, the same virus was detected in a Qatari patient receiving intensive care in a London hospital, a situation reminiscent of the role air travel played in the spread of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002. SARS-CoV originated in China's Guangdong Province and affected more than 8000 patients in 26 countries before it was contained 6 months later. Over a year after the emergence of this novel coronavirus - Middle East respiratory syndrome coronavirus (MERS-CoV) - it has caused 178 laboratory-confirmed cases and 76 deaths. The emergence of a second highly pathogenic coronavirus within a decade highlights the importance of a coordinated global response incorporating reservoir surveillance, high-containment capacity with fundamental and applied research programs, and dependable communication pathways to ensure outbreak containment. Here, we review the current state of knowledge on the epidemiology, ecology, molecular biology, clinical features, and intervention strategies of the novel coronavirus, MERS-CoV. C1 [Milne-Price, Shauna; Miazgowicz, Kerri L.; Munster, Vincent J.] NIAID, Div Intramural Res, Virol Lab, NIH, Hamilton, MT 59840 USA. RP Munster, VJ (reprint author), NIAID, Rocky Mt Labs, 903 South 4th St, Hamilton, MT 59840 USA. EM Vincent.munster@nih.gov OI Munster, Vincent/0000-0002-2288-3196 FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX The authors would like to thank Beth Fisher, Anita Mora, Emmie de Wit, Darryl Falzarano, and Alicia Evangelista for their help with the manuscript. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 143 TC 14 Z9 15 U1 4 U2 41 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD JUL PY 2014 VL 71 IS 2 SI SI BP 119 EP 134 DI 10.1111/2049-632X.12166 PG 16 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM1PV UT WOS:000339620800006 PM 24585737 ER PT J AU Mlera, L Melik, W Bloom, ME AF Mlera, Luwanika Melik, Wessam Bloom, Marshall E. TI The role of viral persistence in flavivirus biology SO PATHOGENS AND DISEASE LA English DT Review DE vector-borne flaviviruses; arboviruses; viral persistence ID WEST-NILE-VIRUS; TICK-BORNE ENCEPHALITIS; TRACT-BINDING-PROTEIN; CULEX-PIPIENS-QUINQUEFASCIATUS; DEPENDENT RNA-POLYMERASE; AMINO-ACID SUBSTITUTION; DOUBLE-STRANDED-RNA; HEPATITIS-C VIRUS; INTERFERON REGULATORY FACTOR-3; HAMSTER MESOCRICETUS-AURATUS AB In nature, vector-borne flaviviruses are persistently cycled between either the tick or mosquito vector and small mammals such as rodents, skunks, and swine. These viruses account for considerable human morbidity and mortality worldwide. Increasing and substantial evidence of viral persistence in humans, which includes the isolation of RNA by RT-PCR and infectious virus by culture, continues to be reported. Viral persistence can also be established in vitro in various human, animal, arachnid, and insect cell lines in culture. Although some research has focused on the potential roles of defective virus particles, evasion of the immune response through the manipulation of autophagy and/or apoptosis, the precise mechanism of flavivirus persistence is still not well understood. We propose additional research for further understanding of how viral persistence is established in different systems. Avenues for additional studies include determining whether the multifunctional flavivirus protein NS5 has a role in viral persistence, the development of relevant animal models of viral persistence, and investigating the host responses that allow vector-borne flavivirus replication without detrimental effects on infected cells. Such studies might shed more light on the viral-host relationships and could be used to unravel the mechanisms for establishment of persistence. C1 [Mlera, Luwanika; Melik, Wessam; Bloom, Marshall E.] NIAID, Rocky Mt Labs, Virol Lab, NIH, Hamilton, MT 59840 USA. RP Bloom, ME (reprint author), NIAID, Rocky Mt Labs, Virol Lab, NIH, 403 South 4th St, Hamilton, MT 59840 USA. EM mbloom@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). We wish to acknowledge the able assistance of Anita Mora and Heather Murphy for graphic support. Danielle Offerdahl and Jennifer Lam provided assistance in manuscript preparation. NR 304 TC 6 Z9 7 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD JUL PY 2014 VL 71 IS 2 SI SI BP 135 EP 161 DI 10.1111/2049-632X.12178 PG 27 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM1PV UT WOS:000339620800007 PM 24737600 ER PT J AU Kindrachuk, J Falcinelli, S Wada, J Kuhn, JH Hensley, LE Jahrling, PB AF Kindrachuk, Jason Falcinelli, Shane Wada, Jiro Kuhn, Jens H. Hensley, Lisa E. Jahrling, Peter B. TI Systems kinomics for characterizing host responses to high-consequence pathogens at the NIH/NIAID Integrated Research Facility-Frederick SO PATHOGENS AND DISEASE LA English DT Review DE kinome; high-consequence pathogens; filovirus; orthopoxvirus; kinase; signaling pathways ID EBOLA HEMORRHAGIC-FEVER; FAMILY TYROSINE KINASES; INFECTED CELLS REVEALS; INNATE IMMUNE-RESPONSE; GENE-EXPRESSION; MONKEYPOX VIRUS; PROTEIN-KINASES; THERAPEUTIC TARGETS; NONHUMAN-PRIMATES; HUMAN MACROPHAGES AB Currently, there is a paucity of information regarding the molecular pathogenesis for many high-consequence pathogens (HCPs) that pose threats to both national and international public health. In spite of this, investigations of the molecular pathogenesis for many HCPs have been limited to gross pathological changes in animal models or global analysis of gene expression. Further, questions remain regarding the ability of animal models of disease to recapitulate human molecular pathogenesis or act as predictors of therapeutic efficacy. Thus, it is likely that medical countermeasure development for HCPs will rely on identifying therapeutic targets that are uniquely modulated during HCP infection. It is also appreciated that many cellular processes can be regulated independently of changes in transcription or translation through phosphorylation events. Cellular kinases, individually or collectively (the kinome), play critical roles in regulating complex biology, underlie various malignancies, and represent high-priority drug targets. The growing interest in kinases in both basic and translational research has driven efforts to develop technologies that enable characterization of phosphorylation-mediated signal transduction. To this end, enhanced technical capabilities at the IRF-Frederick provide the unique capability for characterizing host responses to HCP insult during the course of infection and identify novel targets for therapeutic intervention. C1 [Kindrachuk, Jason; Wada, Jiro; Kuhn, Jens H.; Hensley, Lisa E.; Jahrling, Peter B.] NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, Frederick, MD 21702 USA. [Falcinelli, Shane; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Frederick, MD 21702 USA. RP Kindrachuk, J (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, 8200 Res Plaza, Frederick, MD 21702 USA. EM kindrachuk.kenneth@nih.gov RI Kuhn, Jens H./B-7615-2011; OI Kuhn, Jens H./0000-0002-7800-6045; Kindrachuk, Jason/0000-0002-3305-7084 FU NIAID [HHSN272200700016I] FX The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services or of the institutions and companies affiliated with the authors. JHK performed this work as an employee of Tunnell Governments Services, Inc., a subcontractor to Battelle Memorial Institute; and JK and JW performed this work as employees of Battelle Memorial Institute, all under its prime contract with NIAID, under Contract No. HHSN272200700016I. NR 66 TC 0 Z9 0 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD JUL PY 2014 VL 71 IS 2 SI SI BP 188 EP 196 DI 10.1111/2049-632X.12163 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM1PV UT WOS:000339620800010 ER PT J AU Jahrling, PB Keith, L St Claire, M Johnson, RF Bollinger, L Lackemeyer, MG Hensley, LE Kindrachuk, J Kuhn, JH AF Jahrling, Peter B. Keith, Lauren St Claire, Marisa Johnson, Reed F. Bollinger, Laura Lackemeyer, Matthew G. Hensley, Lisa E. Kindrachuk, Jason Kuhn, Jens H. TI The NIAID Integrated Research Facility at Frederick, Maryland: a unique international resource to facilitate medical countermeasure development for BSL-4 pathogens SO PATHOGENS AND DISEASE LA English DT Review DE BSL-4; countermeasures; medical imaging; viral hemorrhagic fever AB Scientists at the National Institute of Allergy and Infectious Diseases Integrated Research Facility at Fort Detrick, Frederick, Maryland, coordinate and facilitate preclinical research on infectious diseases to develop medical countermeasures for high-consequence pathogens. This facility is unique in that it is the only maximum containment laboratory in the world where conventional and molecular medical imaging equipments are incorporated into the design of the facility. This capability provides investigators with unique tools to dissect disease pathogenesis, evaluate the ability of animal models to recapitulate human disease, and test candidate countermeasures. Importantly, advanced molecular imaging has the potential to provide alternative endpoints to lethality. Using these alternative endpoints, investigators can reduce the number of animals used in experiments and evaluate countermeasures in sublethal models. With the incorporation of medical imaging modalities, a clinical laboratory modeled after those existing in hospitals, and a highly trained veterinary medicine team, IRF-Frederick is uniquely suited to advance our understanding of emerging infectious diseases and to facilitate the development of medical countermeasures and clinical care paradigms previously considered impossible. C1 [Jahrling, Peter B.; Keith, Lauren; St Claire, Marisa; Bollinger, Laura; Lackemeyer, Matthew G.; Hensley, Lisa E.; Kindrachuk, Jason; Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, Frederick, MD 21702 USA. [Jahrling, Peter B.; Johnson, Reed F.] NIAID, Emerging Viral Pathogens Sect, Div Intramural Res, NIH, Frederick, MD 21702 USA. RP Jahrling, PB (reprint author), NIAID, Integrated Res Facil Ft Detrick IRF Frederick, Div Clin Res DCR, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA. EM jahrlingp@niaid.nih.gov RI Kuhn, Jens H./B-7615-2011; OI Kuhn, Jens H./0000-0002-7800-6045; Kindrachuk, Jason/0000-0002-3305-7084 FU NIAID [HHSN272200700016I] FX The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services or of the institutions and companies affiliated with the authors. JHK performed this work as an employee of Tunnell Government Services, Inc.; MGL as an employee of Lovelace Respiratory Research Institute; and JK and LB as employees of Battelle Memorial Institute, all under Battelle Memorial Institute's prime contract with NIAID, Contract No. HHSN272200700016I. LK is an independent contractor for Advanced Health Education Center. MSC, PBJ, and LEH are employees of NIH. NR 8 TC 2 Z9 2 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD JUL PY 2014 VL 71 IS 2 SI SI BP 211 EP 216 DI 10.1111/2049-632X.12171 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM1PV UT WOS:000339620800013 ER PT J AU Kurilla, MG AF Kurilla, Michael G. TI Containing infectious disease SO PATHOGENS AND DISEASE LA English DT Editorial Material ID RESPIRATORY SYNDROME; VIRUS; VACCINE; CORONAVIRUS; EMERGENCE; AMERICA C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Kurilla, MG (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mkurilla@niaid.nih.gov NR 21 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2049-632X J9 PATHOG DIS JI Pathog. Dis. PD JUL PY 2014 VL 71 IS 2 SI SI DI 10.1111/2049-632X.12196 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM1PV UT WOS:000339620800002 ER PT J AU Kwong, P AF Kwong, Peter TI The HIV-1 Viral Spike: Conformational Machine for Entry and Evasion SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 28th Annual Symposium of the Protein-Society CY JUL 27-30, 2014 CL San Diego, CA SP Prot Soc, Bristol Myers Squibb, Lilly, Biochemistry C1 [Kwong, Peter] NAIAD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2014 VL 23 SU 1 MA 06-44 BP 62 EP 62 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM0OU UT WOS:000339545700019 ER PT J AU Weldon, JE Pastan, I AF Weldon, John E. Pastan, Ira TI Rational Design of Thefurin Cleavage Site of an Anti-CD22 Recombinant Immunotoxin Based on Pseudomonas Exotoxin A SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 28th Annual Symposium of the Protein-Society CY JUL 27-30, 2014 CL San Diego, CA SP Prot Soc, Bristol Myers Squibb, Lilly, Biochemistry C1 [Weldon, John E.] Towson Univ, Dept Biol Sci, Towson, MD USA. [Weldon, John E.; Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2014 VL 23 SU 1 MA 10-51 BP 71 EP 71 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM0OU UT WOS:000339545700041 ER PT J AU Jiang, ZP Lee, JC AF Jiang, Zhiping Lee, Jennifer C. TI Lysolipids Modulate Aggregation of the Repeat Domain of a Human Functional Amyloid, Pmel17 SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 28th Annual Symposium of the Protein-Society CY JUL 27-30, 2014 CL San Diego, CA SP Prot Soc, Bristol Myers Squibb, Lilly, Biochemistry C1 [Jiang, Zhiping; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2014 VL 23 SU 1 MA 10-75 BP 84 EP 84 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM0OU UT WOS:000339545700065 ER PT J AU Liu, L Patel, B Ghanem, M Zheng, ZL Bundoc, V Morgan, R Rosenberg, SA Dey, B Berger, EA AF Liu, Li Patel, Bhavik Ghanem, Mustafa Zheng, Zhilli Bundoc, Virgilio Morgan, Richard Rosenberg, Steven A. Dey, Barna Berger, Edward A. TI A Novel CD4-based Chimeric Antigen Receptor for Functional Cure of HIV SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 28th Annual Symposium of the Protein-Society CY JUL 27-30, 2014 CL San Diego, CA SP Prot Soc, Bristol Myers Squibb, Lilly, Biochemistry C1 [Liu, Li; Patel, Bhavik; Ghanem, Mustafa; Bundoc, Virgilio; Dey, Barna; Berger, Edward A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Zheng, Zhilli; Morgan, Richard; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2014 VL 23 SU 1 MA 10-91 BP 93 EP 93 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM0OU UT WOS:000339545700081 ER PT J AU Shastry, S Doyle, S Hoskins, J Wickner, S AF Shastry, Shankar Doyle, Shannon Hoskins, Joel Wickner, Sue TI Mapping the Interactions Between the Molecular Chaperones Hsp70, Hsp104 and Hsp110 SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 28th Annual Symposium of the Protein-Society CY JUL 27-30, 2014 CL San Diego, CA SP Prot Soc, Bristol Myers Squibb, Lilly, Biochemistry C1 [Shastry, Shankar; Doyle, Shannon; Hoskins, Joel; Wickner, Sue] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2014 VL 23 SU 1 MA 11-135 BP 116 EP 116 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM0OU UT WOS:000339545700125 ER PT J AU Hajduczki, A Bundoc, V Berger, EA AF Hajduczki, Agnes Bundoc, Virgilio Berger, Edward A. TI Developing Soluble Co-Receptor Mimetics For The Study Of HIV Env/Receptor Interactions SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 28th Annual Symposium of the Protein-Society CY JUL 27-30, 2014 CL San Diego, CA SP Prot Soc, Bristol Myers Squibb, Lilly, Biochemistry C1 [Hajduczki, Agnes; Bundoc, Virgilio; Berger, Edward A.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2014 VL 23 SU 1 MA 12-161 BP 129 EP 130 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM0OU UT WOS:000339545700151 ER PT J AU Rathore, U Saha, P Kesavardhana, S Kumar, AA Mascola, JR Varadarajan, R AF Rathore, Ujjwal Saha, Piyali Kesavardhana, Sannula Kumar, Aditya A. Mascola, John R. Varadarajan, Raghavan TI N-linked Glycosylation of HIV-1 core gp120 is Not Required for Native Trimer Formation or Viral Infectivity SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 28th Annual Symposium of the Protein-Society CY JUL 27-30, 2014 CL San Diego, CA SP Prot Soc, Bristol Myers Squibb, Lilly, Biochemistry C1 [Rathore, Ujjwal; Saha, Piyali; Kesavardhana, Sannula; Kumar, Aditya A.; Varadarajan, Raghavan] Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. [Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Varadarajan, Raghavan] Indian Inst Sci, Jawaharlal Nehru Ctr Adv Sci Res, Bangalore 560012, Karnataka, India. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2014 VL 23 SU 1 MA 12-165 BP 132 EP 132 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM0OU UT WOS:000339545700155 ER PT J AU Seedorff, J Berger, E AF Seedorff, Jennifer Berger, Edward TI Development Of A Quantitative, Real-Time, Label-Free Assay For Ligands Interacting With The HIV Envelope Glycoprotein In Virus-Like Particles SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 28th Annual Symposium of the Protein-Society CY JUL 27-30, 2014 CL San Diego, CA SP Prot Soc, Bristol Myers Squibb, Lilly, Biochemistry C1 [Seedorff, Jennifer; Berger, Edward] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2014 VL 23 SU 1 MA 06-343 BP 222 EP 223 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM0OU UT WOS:000339545700333 ER PT J AU Hess, SK Lee, JC AF Hess, Sara K. Lee, Jennifer C. TI The Little Lipid That Could: Elucidating the Effects of Small Amounts of Phosphatidic Acid on the alpha-Synuclein Membrane Interaction SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 28th Annual Symposium of the Protein-Society CY JUL 27-30, 2014 CL San Diego, CA SP Prot Soc, Bristol Myers Squibb, Lilly, Biochemistry C1 [Hess, Sara K.; Lee, Jennifer C.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2014 VL 23 SU 1 MA 06-350 BP 226 EP 226 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM0OU UT WOS:000339545700340 ER PT J AU Gruschus, JM AF Gruschus, James M. TI Synuclein and the Coelacanth SO PROTEIN SCIENCE LA English DT Meeting Abstract CT 28th Annual Symposium of the Protein-Society CY JUL 27-30, 2014 CL San Diego, CA SP Prot Soc, Bristol Myers Squibb, Lilly, Biochemistry C1 [Gruschus, James M.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2014 VL 23 SU 1 MA 08-418 BP 261 EP 262 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM0OU UT WOS:000339545700407 ER PT J AU Ford, DW Hartman, TJ Still, C Wood, C Mitchell, D Hsiao, PY Bailey, R Smiciklas-Wright, H Coffman, DL Jensen, GL AF Ford, Dara W. Hartman, Terryl J. Still, Christopher Wood, Craig Mitchell, Diane Hsiao, Pao Ying Bailey, Regan Smiciklas-Wright, Helen Coffman, Donna L. Jensen, Gordon L. TI Diet-related practices and BMI are associated with diet quality in older adults SO PUBLIC HEALTH NUTRITION LA English DT Article DE Diet quality; Ageing; Dietary-related practices ID BODY-MASS INDEX; WEIGHT-LOSS; OF-LIFE; NUTRITION; MORTALITY; PATTERNS; RISK AB Objective: To assess the association of diet-related practices and BMI with diet quality in rural adults aged >= 74 years. Design: Cross-sectional. Dietary quality was assessed by the twenty-five-item Dietary Screening Tool (DST). Diet-related practices were self-reported. Multivariate linear regression models were used to analyse associations of DST scores with BMI and diet-related practices after controlling for gender, age, education, smoking and self- v. proxy reporting. Setting: Geisinger Rural Aging Study (GRAS) in Pennsylvania, USA. Subjects: A total of 4009 (1722 males, 2287 females; mean age 81.5 years) participants aged >= 74 years. Results: Individuals with BMI < 18.5 kg/m(2) had a significantly lower DST score (mean 55.8, 95% CI 52.9, 58.7) than those individuals with BMI = 18.5-24.9 kg/m(2) (mean 60.7, 95% CI 60.1, 61.5; P = 0.001). Older adults with higher, more favourable DST scores were significantly more likely to be food sufficient, report eating breakfast, have no chewing difficulties and report no decline in intake in the previous 6 months. Conclusions: The DST may identify potential targets for improving diet quality in older adults including promotion of healthy BMI, breakfast consumption, improving dentition and identifying strategies to decrease concern about food sufficiency. C1 [Ford, Dara W.; Mitchell, Diane; Hsiao, Pao Ying; Smiciklas-Wright, Helen; Jensen, Gordon L.] Penn State Univ, Dept Nutr Sci, Chandlee Lab 110, University Pk, PA 16802 USA. [Hartman, Terryl J.] Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. [Still, Christopher; Wood, Craig] Geisinger Hlth Syst, Ctr Hlth Res, Danville, PA USA. [Still, Christopher; Wood, Craig] Geisinger Hlth Syst, Obes Inst, Danville, PA USA. [Bailey, Regan] NIH, Off Dietary Supplements, Rockville, MD USA. [Coffman, Donna L.] Penn State Univ, Methodol Ctr, State Coll, PA USA. RP Ford, DW (reprint author), Penn State Univ, Dept Nutr Sci, Chandlee Lab 110, University Pk, PA 16802 USA. EM djw5083@psu.edu FU US Department of Agriculture [1950-51530-010-02G] FX Sources of funding: This work was supported by the US Department of Agriculture (grant #1950-51530-010-02G). NR 19 TC 1 Z9 1 U1 1 U2 2 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD JUL PY 2014 VL 17 IS 7 BP 1565 EP 1569 DI 10.1017/S1368980013001729 PG 5 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA AM1PW UT WOS:000339620900017 PM 23816283 ER PT J AU Brown, JR Wiestner, A AF Brown, Jennifer R. Wiestner, Adrian TI Chronic Lymphocytic Leukemia: Moving Forward-Rapidly SO SEMINARS IN HEMATOLOGY LA English DT Editorial Material C1 [Brown, Jennifer R.] Dana Farber Canc Inst, Cambridge, MA USA. [Brown, Jennifer R.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Wiestner, Adrian] NHLBI, NIH, Bethesda, MD 20892 USA. RP Brown, JR (reprint author), Dana Farber Canc Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2014 VL 51 IS 3 BP 157 EP 157 DI 10.1053/j.seminhematol.2014.05.009 PG 1 WC Hematology SC Hematology GA AM1XE UT WOS:000339641800001 PM 25048779 ER PT J AU Jin, CY Decker, AM Huang, XP Gilmour, BP Blough, BE Roth, BL Hu, Y Gill, JB Zhang, XP AF Jin, Chunyang Decker, Ann M. Huang, Xi-Ping Gilmour, Brian P. Blough, Bruce E. Roth, Bryan L. Hu, Yang Gill, Joseph B. Zhang, X. Peter TI Synthesis, Pharmacological Characterization, and Structure-Activity Relationship Studies of Small Molecular Agonists for the Orphan GPR88 Receptor SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Orphan GPR88; agonists; 2-PCCA ID CENTRAL EXTENDED AMYGDALA; ASYMMETRIC CYCLOPROPANATION; EXPRESSION; COBALT; GENES; PATHWAYS; RADICALS; LIGANDS AB GPR88 is an orphan G-protein-coupled receptor (GPCR) enriched in the striatum. Genetic deletion and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in psychiatric disorders. The signal transduction pathway and receptor functions of GPR88, however, are still largely unknown due to the lack of endogenous and synthetic ligands. In this paper, we report the synthesis of a GPR88 agonist 2-PCCA and its pure diastereomers, which were functionally characterized in both transiently and stably expressing GPR88 HEK293 cells. 2-PCCA inhibited isoproterenol-stimulated cAMP accumulation in a concentration-dependent manner in cells expressing GPR88 but not in the control cells, suggesting that the observed cAMP inhibition is mediated through GPR88 and that GPR88 is coupled to G alpha(i). 2-PCCA did not induce calcium mobilization in GPR88 cells, indicating no G alpha(q)-mediated response. A structure activity relationship (SAR) study of 2-PCCA was also conducted to explore the key structural features for GPR88 agonist activity. C1 [Jin, Chunyang; Decker, Ann M.; Gilmour, Brian P.; Blough, Bruce E.] Res Triangle Inst, Ctr Drug Discovery, Res Triangle Pk, NC 27709 USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, NIMH,Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Hu, Yang; Gill, Joseph B.; Zhang, X. Peter] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. RP Jin, CY (reprint author), Res Triangle Inst, Ctr Drug Discovery, Res Triangle Pk, NC 27709 USA. EM cjin@rti.org RI Zhang, Peter/B-7976-2011; Roth, Bryan/F-3928-2010 OI Zhang, Peter/0000-0001-7574-8409; FU National Institute of Mental Health (NIMH); NSF [CHE-1152767]; NIH [R01-GM098777] FX We thank the National Institute of Mental Health (NIMH) for supporting the research at Psychoactive Drug Screening Program (PDSP). XPZ is grateful for financial support by NSF (CHE-1152767) and NIH (R01-GM098777). NR 25 TC 9 Z9 9 U1 2 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD JUL PY 2014 VL 5 IS 7 BP 576 EP 587 DI 10.1021/cn500082p PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA AL6ET UT WOS:000339226100014 PM 24793972 ER PT J AU Seo, YJ Kang, Y Muench, L Reid, A Caesar, S Jean, L Wagner, F Holson, E Haggarty, SJ Weiss, P King, P Carter, P Volkow, ND Fowler, JS Hooker, JM Kim, SW AF Seo, Young Jun Kang, Yeona Muench, Lisa Reid, Alicia Caesar, Shannon Jean, Logan Wagner, Florence Holson, Edward Haggarty, Stephen J. Weiss, Philipp King, Payton Carter, Pauline Volkow, Nora D. Fowler, Joanna S. Hooker, Jacob M. Kim, Sung Won TI Image-Guided Synthesis Reveals Potent Blood-Brain Barrier Permeable Histone Deacetylase Inhibitors SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Histone deacetylase; positron emission tomography; blood-brain barrier permeability; benzamides ID PSYCHIATRIC-DISORDERS; EPIGENETIC REGULATION; INTERNAL CAVITY; HDAC INHIBITORS; PENETRATION; DRUG; PHARMACOKINETICS; PET; ACETYLDINALINE; VORINOSTAT AB Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addition to low HDAC potency and selectivity observed, poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here we report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compounds based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET imaging in the baboon model and using the imaging derived data on BBB penetration from each compound to feed back into the design process. A total of 17 compounds were evaluated, revealing molecules with both high binding affinity and BBB permeability. A key element conferring BBB penetration in this benzamide series was a basic benzylic amine. These derivatives exhibited 1-100 nM inhibitory activity against recombinant human HDAC1 and HDAC2. Three of the carbon-11 labeled aminomethyl benzamide derivatives showed high BBB penetration (similar to 0.015%ID/cc) and regional binding heterogeneity in the brain (high in thalamus and cerebellum). Taken together this approach has afforded a strategy and a predictive model for developing highly potent and BBB permeable HDAC inhibitors for CNS applications and for the discovery of novel candidate molecules for small molecule probes and drugs. C1 [Seo, Young Jun; Kang, Yeona; Caesar, Shannon; Jean, Logan; King, Payton; Carter, Pauline; Fowler, Joanna S.; Hooker, Jacob M.] Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. [Seo, Young Jun] Chonnam Natl Univ, Dept Chem, Jeonju 561756, South Korea. [Muench, Lisa; Volkow, Nora D.; Kim, Sung Won] NIAAA, Lab Neuroimaging, Upton, NY 11973 USA. [Reid, Alicia] Medgar Evers Coll, Brooklyn, NY 11225 USA. [Wagner, Florence; Holson, Edward] Broad Inst Massachusetts Inst Technol, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Wagner, Florence; Holson, Edward] Harvard Univ, Cambridge, MA 02142 USA. [Haggarty, Stephen J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02142 USA. [Weiss, Philipp] Johannes Gutenberg Univ Mainz, Inst Organ Chem, D-55122 Mainz, Germany. [Hooker, Jacob M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. [Fowler, Joanna S.; Kim, Sung Won] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA. RP Hooker, JM (reprint author), Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. EM hooker@nmr.mgh.harvard.edu; sunny.kim@nih.gov RI Kang, Yeona/M-5305-2016; OI Kang, Yeona/0000-0003-3384-435X; Haggarty, Stephen J./0000-0002-7872-168X FU National Institutes of Health [1R0IDA030321]; National Institute of Alcohol Abuse and Alcoholism; Deutscher Akademischer Austauschdienst (DAAD), Bonn, Germany; U.S. Department of Energy [DE-AC02-98CH10886] FX This work was supported by National Institutes of Health grant 1R0IDA030321 (Y.J.S., J.M.H., S.W.K.), National Institute of Alcohol Abuse and Alcoholism Intramural Program (S.W.K., L.M., N.D.V.), and the Deutscher Akademischer Austauschdienst (DAAD), Bonn, Germany (P.W.). This study was carried out in part at Brookhaven National Laboratory under contract DE-AC02-98CH10886 with the U.S. Department of Energy and with infrastructure support from its Office of Biological and Environmental Research. NR 49 TC 10 Z9 10 U1 4 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD JUL PY 2014 VL 5 IS 7 BP 588 EP 596 DI 10.1021/cn500021p PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA AL6ET UT WOS:000339226100015 PM 24780082 ER PT J AU Ding, HY Zhu, TN Yin, XM Liu, JK Zhang, LZ Bernier, M Zhao, RJ AF Ding, Haiyan Zhu, Tienian Yin, Xiaomei Liu, Jiankun Zhang, Lizhong Bernier, Michel Zhao, Ruijing TI Pyrrolidine dithiocarbamate protects pancreatic beta-cells from oxidative damage through regulation of FoxO1 activity in type 2 diabetes rats SO ACTA BIOCHIMICA ET BIOPHYSICA SINICA LA English DT Article DE pyrrolidine dithiocarbamate (PDTC); diabetes; oxidative damage; FoxO1; PDX-1 ID FACTOR-KAPPA-B; TRANSCRIPTION FACTOR PDX-1; STRESS; ACTIVATION; COMPLICATIONS; TRANSLOCATION; ACETYLATION; PHOSPHORYLATION; ANTIOXIDANTS; RESPONSES AB Pyrrolidine dithiocarbamate (PDTC) can lower the blood glucose level and improve the insulin sensitivity in diabetic rats. However, the mechanisms underlying this effect of PDTC treatment in diabetic rats remained uncertain. In this study, we evaluated the mechanisms by which PDTC conferred protection against oxidative damage to pancreatic islet beta-cells in rats with experimental type 2 diabetes mellitus (DM). DM in the rats was elicited by long-term high-fat diet accompanied with a single intraperitoneal (i.p.) injection of a low dose of streptozotocin. After a 7-day administration of PDTC (50 mg/kg/day i.p.), blood glucose levels were measured and pancreatic tissues were collected for the determination of various biochemical and enzymatic activities using immunohistochemistry, immunofluorescence, and western blot techniques. The percentage of apoptotic pancreatic islet beta-cells was detected by flow cytometry. The results showed that diabetic rats had elevated blood glucose levels and insulin resistance, accompanied with an increase in malondialdehyde content, nitrotyrosine production, and inducible nitric oxide synthase expression. A decrease in superoxide dismutase and glutathione peroxidase activities was also observed in DM rats, culminating with elevated beta-cell apoptosis. PDTC treatment significantly reduced the oxidative damage and the beta-cell apoptosis, and also increased the insulin production through down-regulating FoxO1 acetylation and up-regulating nuclear PDX-1 level. These data suggested that PDTC can protect islet beta-cells from oxidative damage and improve insulin production through regulation of PDX-1 and FoxO1 in a DM rat model. C1 [Ding, Haiyan] Hebei Med Univ, Hosp 4, Dept Endocrinol, Shijiazhuang 050011, Peoples R China. [Zhu, Tienian; Zhao, Ruijing] Hebei Med Univ, Dept Immunol, Key Lab Immune Mech & Intervent Serious Dis Hebei, Shijiazhuang 050017, Peoples R China. [Zhu, Tienian; Yin, Xiaomei; Liu, Jiankun; Zhang, Lizhong] Bethune Int Peace Hosp, Dept Med Oncol, Shijiazhuang 050082, Peoples R China. [Bernier, Michel] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Zhu, TN (reprint author), Hebei Med Univ, Dept Immunol, Key Lab Immune Mech & Intervent Serious Dis Hebei, Shijiazhuang 050017, Peoples R China. EM tienian_zhu@hotmail.com; 6810c@163.com FU Natural Science Foundation of Hebei Province in China [C2009001232]; Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Personnel of China; Department of Science and Technology of Hebei Province [10276105D-66]; Health Bureau of Hebei Province [20090168]; Hebei Education Department in China [2008135]; NIH, National Institute on Aging FX This work was supported by the grants from the Natural Science Foundation of Hebei Province in China (No. C2009001232), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Personnel of China, the Department of Science and Technology of Hebei Province (No. 10276105D-66), the Health Bureau of Hebei Province (No. 20090168), and the Hebei Education Department in China (No. 2008135) and in part, by the Intramural Research Program of the NIH, National Institute on Aging. NR 37 TC 3 Z9 5 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1672-9145 EI 1745-7270 J9 ACTA BIOCH BIOPH SIN JI Acta Biochim. Biophys. Sin. PD JUL PY 2014 VL 46 IS 7 BP 582 EP 589 DI 10.1093/abbs/gmu034 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AL4PS UT WOS:000339115500007 PM 24829401 ER PT J AU Zhou, DW Visessanguan, W Chaikaew, S Benjakul, S Oda, K Wlodawer, A AF Zhou, Dongwen Visessanguan, Wonnop Chaikaew, Siriporn Benjakul, Soottawat Oda, Kohei Wlodawer, Alexander TI Crystallization and preliminary crystallographic analysis of histamine dehydrogenase from Natrinema gari BCC 24369 SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS LA English DT Article ID BRONCHOALVEOLAR LAVAGE; NOCARDIOIDES-SIMPLEX; MAST-CELLS; ALLERGIC ASTHMATICS; ESCHERICHIA-COLI; RHIZOBIUM SP; MILD ASTHMA; FLUID; URTICARIA; RELEASE AB Histamine dehydrogenase (HADH) catalyzes the oxidative deamination of histamine, resulting in the production of imidazole acetaldehyde and an ammonium ion. The enzyme isolated from the newly identified halophilic archaeon Natrinema gari BCC 24369 is significantly different from the previously described protein from Nocardioides simplex. This newly identified HADH comprises three subunits with molecular weights of 49.0, 24.7 and 23.9 kDa, respectively, and is optimally active under high-salt conditions (3.5-5 M NaCl). As a step in the exploration of the unique properties of the protein, the HADH heterotrimer was purified and crystallized. Crystals were obtained using the sitting-drop vapor-diffusion method from a solution composed of 0.2 M calcium chloride dihydrate, 0.1 M HEPES pH 7.5, 28% PEG 400. Diffraction data were collected at -173 degrees C to a resolution limit of 2.4 angstrom on the Southeast Regional Collaborative Access Team (SER-CAT) beamline 22-ID at the Advanced Photon Source, Argonne National Laboratory. The crystals belonged to the monoclinic space group C2, with unit-cell parameters a = 211.9, b = 58.6, c = 135.4 angstrom, beta = 103.0 degrees. The estimated Matthews coefficient is 3.21 angstrom(3) Da(-1), corresponding to 61.7% solvent content. C1 [Zhou, Dongwen; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Visessanguan, Wonnop; Chaikaew, Siriporn] Natl Ctr Genet Engn & Biotechnol BIOTEC, Klongluang 12120, Pathum Thani, Thailand. [Benjakul, Soottawat] Prince Songkla Univ, Fac Agroind, Dept Food Technol, Hat Yai 90112, Songkhla, Thailand. [Oda, Kohei] Kyoto Inst Technol, Sakyo Ku, Kyoto 6068585, Japan. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM wlodawer@nih.gov FU Thailand Research Fund; NIH, National Cancer Institute, Center for Cancer Research FX The authors would like to thank the Thailand Research Fund for financial support under the TRF Senior Research Scholar. This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (DZ and AW). NR 26 TC 2 Z9 2 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1744-3091 J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Commun. PD JUL PY 2014 VL 70 BP 942 EP 945 DI 10.1107/S2053230X14011327 PN 7 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA AL1YQ UT WOS:000338923200019 PM 25005094 ER PT J AU Haynes, R Staplin, N Emberson, J Herrington, WG Tomson, C Agodoa, L Tesar, V Levin, A Lewis, D Reith, C Baigent, C Landray, MJ AF Haynes, Richard Staplin, Natalie Emberson, Jonathan Herrington, William G. Tomson, Charles Agodoa, Lawrence Tesar, Vladimir Levin, Adeera Lewis, David Reith, Christina Baigent, Colin Landray, Martin J. CA SHARP Collaborative Grp TI Evaluating the Contribution of the Cause of Kidney Disease to Prognosis in CKD: Results From the Study of Heart and Renal Protection (SHARP) SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Kidney disease etiology; disease trajectory; end-stage renal disease (ESRD); disease progression; prognosis; cystic kidney disease; risk factor ID COLLABORATIVE METAANALYSIS; POPULATION COHORTS; COMPETING RISK; PROGRESSION; FAILURE; ALBUMINURIA; PROTEINURIA; NEPHROPATHY; CHOLESTEROL; OUTCOMES AB Background: The relevance of the cause of kidney disease to prognosis among patients with chronic kidney disease is uncertain. Study Design: Observational study. Settings & Participants: 6,245 nondialysis participants in the Study of Heart and Renal Protection (SHARP). Predictor: Baseline cause of kidney disease was categorized into 4 groups: cystic kidney disease, diabetic nephropathy, glomerulonephritis, and other recorded diagnoses. Outcomes: End-stage renal disease (ESRD; dialysis or transplantation) and death. Results: During an average 4.7 years' follow-up, 2,080 participants progressed to ESRD, including 454 with cystic kidney disease (23% per year), 378 with glomerulonephritis (10% per year), 309 with diabetic nephropathy (12% per year), and 939 with other recorded diagnoses (8% per year). By comparison with patients with cystic kidney disease, other disease groups had substantially lower adjusted risks of ESRD (relative risks of 0.28 [95% CI, 0.24-0.32], 0.40 [95% CI, 0.34-0.47], and 0.29 [95% CI, 0.25-0.32] for glomerulonephritis, diabetic nephropathy, and other recorded diagnoses, respectively). Albuminuria and baseline estimated glomerular filtration rate were associated more weakly with risk of ESRD in patients with cystic kidney disease than the 3 other diagnostic categories (P for interaction, <0.001 and 0.01, respectively). Death before ESRD was uncommon in patients with cystic kidney disease, but was a major competing risk for participants with diabetic nephropathy, whose adjusted risk of death was 2-fold higher than that of the cystic kidney disease group (relative risk, 2.35 [95% CI, 1.73-3.18]). Limitations: Exclusion of patients with prior myocardial infarction or coronary revascularization. Conclusions: The cause of kidney disease has substantial prognostic implications. Other things being equal, patients with cystic kidney disease are at much higher risk of ESRD (and much lower risk of death before ESRD) than other patients. Patients with diabetic nephropathy are at particularly high risk of death prior to reaching ESRD. (C) 2014 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Haynes, Richard; Staplin, Natalie; Emberson, Jonathan; Herrington, William G.; Lewis, David; Reith, Christina; Baigent, Colin; Landray, Martin J.] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England. [Haynes, Richard; Staplin, Natalie; Emberson, Jonathan; Herrington, William G.; Lewis, David; Reith, Christina; Baigent, Colin; Landray, Martin J.] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford, England. [Tomson, Charles] North Bristol NHS Trust, Bristol, Avon, England. [Agodoa, Lawrence] NIDDK, NIH, Bethesda, MD 20892 USA. [Tesar, Vladimir] Charles Univ Prague, Fac Med 1, Prague, Czech Republic. [Tesar, Vladimir] Charles Univ Prague, Gen Univ Hosp, Prague, Czech Republic. [Levin, Adeera] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. RP Landray, MJ (reprint author), Clin Trial Serv Unit, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England. EM sharpclinical@ctsu.ox.ac.uk RI de Zeeuw, Dick/E-9080-2014; OI de Zeeuw, Dick/0000-0003-3434-7777; Emberson, Jonathan/0000-0001-7792-9422; Herrington, Will/0000-0003-1172-8243; Landray, Martin/0000-0001-6646-827X FU Merck/Schering-Plough Pharmaceuticals (North Wales, PA); Australian National Health Medical Research Council; British Heart Foundation; UK Medical Research Council FX The study was funded by Merck/Schering-Plough Pharmaceuticals (North Wales, PA), with additional support from the Australian National Health Medical Research Council, the British Heart Foundation, and the UK Medical Research Council. SHARP was initiated, conducted, and interpreted independently of the principal study funder (Merck & Co. and Schering Plough Corp, which merged in 2009). The Clinical Trial Service Unit & Epidemiological Studies Unit, which is part of the University of Oxford, has a staff policy of not accepting honoraria or consultancy fees. NR 22 TC 17 Z9 19 U1 0 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2014 VL 64 IS 1 BP 40 EP 48 DI 10.1053/j.ajkd.2013.12.013 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AL2EK UT WOS:000338938500010 PM 24613056 ER PT J AU Chan, JCN Lau, ESH Luk, AOY Cheung, KKT Kong, APS Yu, LWL Choi, KC Chow, FCC Ozaki, R Brown, N Yang, XL Bennett, PH Ma, RCW So, WY AF Chan, Juliana C. N. Lau, Eric S. H. Luk, Andrea O. Y. Cheung, Kitty K. T. Kong, Alice P. S. Yu, Linda W. L. Choi, Kai-Chow Chow, Francis C. C. Ozaki, Risa Brown, Nicola Yang, Xilin Bennett, Peter H. Ma, Ronald C. W. So, Wing-Yee TI Premature Mortality and Comorbidities in Young-onset Diabetes: A 7-Year Prospective Analysis SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Cardiovascular-renal events; Mortality; Young-onset diabetes ID IMPAIRED FASTING GLUCOSE; BETA-CELL FUNCTION; INSULIN SENSITIVITY; JAPANESE SUBJECTS; TYPE-2; DISEASE; YOUTH; COMPLICATIONS; PREVALENCE; MELLITUS AB BACKGROUND: There is an increasing prevalence of young-onset diabetes, especially in developing areas. We compared the clinical outcomes and predictors for cardiovascular-renal events between Chinese patients with type 2 diabetes with young- or late-onset of disease diagnosed before or after the age of 40 years, respectively. METHODS: The Hong Kong Diabetes Registry was established in 1995 as an ongoing quality improvement initiative with consecutive enrollment of diabetic patients from ambulatory settings for documentation of risk factors, microvascular and macrovascular complications, and clinical outcomes using a structured protocol. RESULTS: In 9509 Chinese patients with type 2 diabetes with a median (interquartile range) follow-up period of 7.5 (3.9-10.8) years, 21.3% (n = 2066) had young-onset diabetes. Despite 20 years difference in age, patients with young-onset diabetes (mean age, 41.3 years) had a similar or worse risk profile than those with late-onset disease (mean age, 61.9 years). Compared with the patients with late-onset diabetes, those with young-onset diabetes had lower rates of cardiovascular disease and chronic kidney disease for the same disease duration but a higher cumulative incidence of clinical events at any given age. With the use of stepwise Cox proportional hazard analysis, patients with young-onset diabetes had higher risks for cardiovascular and renal events when adjusted by age, but no difference in risks than in the patients with late-onset diabetes when further adjusted by disease duration. CONCLUSIONS: Patients with young-onset diabetes had a similar or worse metabolic risk profile compared with those with late-onset disease. This group had higher risks for cardiovascular-renal complications at any given age, driven by longer disease duration. (C) 2014 Elsevier Inc. All rights reserved. C1 [Chan, Juliana C. N.; Lau, Eric S. H.; Luk, Andrea O. Y.; Cheung, Kitty K. T.; Kong, Alice P. S.; Chow, Francis C. C.; Ozaki, Risa; Ma, Ronald C. W.; So, Wing-Yee] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China. [Chan, Juliana C. N.; Kong, Alice P. S.; Chow, Francis C. C.; Ozaki, Risa; Ma, Ronald C. W.; So, Wing-Yee] Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China. [Chan, Juliana C. N.] Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China. [Yu, Linda W. L.] Hosp Author Headquarter, Hong Kong, Hong Kong, Peoples R China. [Choi, Kai-Chow] Nethersole Sch Nursing, Tianjin, Peoples R China. [Brown, Nicola] Asia Diabet Fdn, Tianjin, Peoples R China. [Yang, Xilin] Tianjin Med Univ, Coll Publ Hlth, Dept Epidemiol, Tianjin, Peoples R China. [Bennett, Peter H.] NIH, Phoenix, AZ USA. RP Luk, AOY (reprint author), Prince Wales Hosp, Dept Med & Therapeut, Shatin, Hong Kong, Peoples R China. EM andrealuk@cuhk.edu.hk RI Kong, Alice/P-3703-2015; Luk, Andrea/B-5766-2016; Chan, Juliana /B-7918-2016; Ma, Ronald/C-2788-2009 OI Chan, Juliana /0000-0003-1325-1194; Ma, Ronald/0000-0002-1227-803X FU Hong Kong Foundation for Research and Development; Liao Wun Yuk Memorial Diabetes Research Fund of the Chinese University of Hong Kong FX The study is partially supported by the Hong Kong Foundation for Research and Development and Liao Wun Yuk Memorial Diabetes Research Fund of the Chinese University of Hong Kong. NR 30 TC 16 Z9 17 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD JUL PY 2014 VL 127 IS 7 BP 616 EP 624 DI 10.1016/j.amjmed.2014.03.018 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AL2CY UT WOS:000338934700033 PM 24680795 ER PT J AU Yedidi, RS Garimella, H Aoki, M Aoki-Ogata, H Desai, DV Chang, SB Davis, DA Fyvie, WS Kaufman, JD Smith, DW Das, D Wingfield, PT Maeda, K Ghosh, AK Mitsuya, H AF Yedidi, Ravikiran S. Garimella, Harisha Aoki, Manabu Aoki-Ogata, Hiromi Desai, Darshan V. Chang, Simon B. Davis, David A. Fyvie, W. Sean Kaufman, Joshua D. Smith, David W. Das, Debananda Wingfield, Paul T. Maeda, Kenji Ghosh, Arun K. Mitsuya, Hiroaki TI A Conserved Hydrogen-Bonding Network of P2 bis-Tetrahydrofuran-Containing HIV-1 Protease Inhibitors (PIs) with a Protease Active-Site Amino Acid Backbone Aids in Their Activity against PI-Resistant HIV SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; DRUG-RESISTANCE; MOLECULAR-REPLACEMENT; VIRAL INFECTIVITY; DIFFRACTION DATA; IN-VITRO; MUTATIONS; LIGAND; REPLICATION; MATURATION AB In the present study, GRL008, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), and darunavir (DRV), both of which contain a P2-bis-tetrahydrofuranyl urethane (bis-THF) moiety, were found to exert potent antiviral activity (50% effective concentrations [EC(50)s], 0.029 and 0.002 mu M, respectively) against a multidrug-resistant clinical isolate of HIV-1 (HIVA02) compared to ritonavir (RTV; EC50, > 1.0 mu M) and tipranavir (TPV; EC50, 0.364 mu M). Additionally, GRL008 showed potent antiviral activity against an HIV-1 variant selected in the presence of DRV over 20 passages (HIVDRVP20R), with a 2.6-fold increase in its EC50 (0.097 mu M) compared to its corresponding EC50 (0.038 mu M) against wild-type HIV-1(NL4-3) (HIVWT). Based on X-ray crystallographic analysis, both GRL008 and DRV showed strong hydrogen bonds (H-bonds) with the backbone-amide nitrogen/carbonyl oxygen atoms of conserved active-site amino acids G27, D29, D30, and D30' of HIVA02 protease (PRA02) and wild-type PR in their corresponding crystal structures, while TPV lacked H-bonds with G27 and D30' due to an absence of polar groups. The P2' thiazolyl moiety of RTV showed two conformations in the crystal structure of the PRA02-RTV complex, one of which showed loss of contacts in the S2' binding pocket of PRA02, supporting RTV's compromised antiviral activity (EC50, > 1 mu M). Thus, the conserved H-bonding network of P2-bis-THF-containing GRL008 with the backbone of G27, D29, D30, and D30' most likely contributes to its persistently greater antiviral activity against HIVWT, HIVA02, and HIVDRVP20R. C1 [Yedidi, Ravikiran S.; Garimella, Harisha; Desai, Darshan V.; Chang, Simon B.; Das, Debananda; Maeda, Kenji; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Davis, David A.] NCI, Retroviral Dis Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Aoki, Manabu; Aoki-Ogata, Hiromi; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Biomed Sci, Dept Hematol, Kumamoto, Japan. [Aoki, Manabu; Aoki-Ogata, Hiromi; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Biomed Sci, Dept Infect Dis, Kumamoto, Japan. [Aoki, Manabu] Kumamoto Hlth Sci Univ, Dept Med Technol, Kumamoto, Japan. [Fyvie, W. Sean; Ghosh, Arun K.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Fyvie, W. Sean; Ghosh, Arun K.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Kaufman, Joshua D.; Wingfield, Paul T.] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [Smith, David W.] Northwestern Univ, Synchrotron Res Ctr, Life Sci Collaborat Access Team, Argonne, IL USA. RP Mitsuya, H (reprint author), NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. EM mitsuyah@helix.nih.gov OI Yedidi, Ravikiran/0000-0003-2755-1307 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; Ministry of Health, Welfare, and Labor of Japan; Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Re-emerging Infectious Diseases of Monbukagakusho (Kumamoto University) of Monbukagakusho [78]; National Institutes of Health [GM53386]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE AC02 06CH11357, W 31 109 Eng 38]; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor [085P1000817] FX This study was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (H.M.), by a grant for the Global Education and Research Center aiming at the control of AIDS (Global Center of Excellence supported by Monbu-Kagakusho), Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan, by a grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Re-emerging Infectious Diseases (Renkei Jigyo; grant 78, Kumamoto University) of Monbukagakusho (H.M.), and by a grant from the National Institutes of Health (GM53386; A.K.G.).; We thank the Advanced Photon Source (APS) for X-ray diffraction data collection. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract DE AC02 06CH11357 (LS CAT) and contract W 31 109 Eng 38 (SER-CAT). Use of LS CAT sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (grant 085P1000817). Supporting institutions for SER-CAT may be found at www.ser-cat.org/members.html. We thank the NIH AIDS Research and Reference Reagent program for providing IDV, LPV, RTV, SQV, and TPV. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 36 TC 5 Z9 5 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUL PY 2014 VL 58 IS 7 BP 3679 EP 3688 DI 10.1128/AAC.00107-14 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AL0WA UT WOS:000338846500012 PM 24752271 ER PT J AU van Duin, D Perez, F Rudin, SD Cober, E Hanrahan, J Ziegler, J Webber, R Fox, J Mason, P Richter, SS Cline, M Hall, GS Kaye, KS Jacobs, MR Kalayjian, RC Salata, RA Segre, JA Conlan, S Evans, S Fowler, VG Bonomo, RA AF van Duin, David Perez, Federico Rudin, Susan D. Cober, Eric Hanrahan, Jennifer Ziegler, Julie Webber, Raymond Fox, Jacqueline Mason, Pamela Richter, Sandra S. Cline, Marianne Hall, Geraldine S. Kaye, Keith S. Jacobs, Michael R. Kalayjian, Robert C. Salata, Robert A. Segre, Julia A. Conlan, Sean Evans, Scott Fowler, Vance G., Jr. Bonomo, Robert A. TI Surveillance of Carbapenem-Resistant Klebsiella pneumoniae: Tracking Molecular Epidemiology and Outcomes through a Regional Network SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID BLOOD-STREAM INFECTIONS; CARE FACILITIES; ENTEROBACTERIACEAE; EMERGENCE; DISSEMINATION; BACTEREMIA; CRITERIA; THERAPY; ADULTS; NDM-1 AB Carbapenem resistance in Gram-negative bacteria is on the rise in the United States. A regional network was established to study microbiological and genetic determinants of clinical outcomes in hospitalized patients with carbapenem-resistant (CR) Klebsiella pneumoniae in a prospective, multicenter, observational study. To this end, predefined clinical characteristics and outcomes were recorded and K. pneumoniae isolates were analyzed for strain typing and resistance mechanism determination. In a 14-month period, 251 patients were included. While most of the patients were admitted from long-term care settings, 28% of them were admitted from home. Hospitalizations were prolonged and complicated. Nonsusceptibility to colistin and tigecycline occurred in isolates from 7 and 45% of the patients, respectively. Most of the CR K. pneumoniae isolates belonged to repetitive extragenic palindromic PCR (rep-PCR) types A and B (both sequence type 258) and carried either bla(KPC-2) (48%) or bla(KPC-3) (51%). One isolate tested positive for bla(NDM-1), a sentinel discovery in this region. Important differences between strain types were noted; rep-PCR type B strains were associated with bla(KPC-3) (odds ratio [OR], 294; 95% confidence interval [CI], 58 to 2,552; P < 0.001), gentamicin nonsusceptibility (OR, 24; 95% CI, 8.39 to 79.38; P < 0.001), amikacin susceptibility (OR, 11.0; 95% CI, 3.21 to 42.42; P < 0.001), tigecycline nonsusceptibility (OR, 5.34; 95% CI, 1.30 to 36.41; P = 0.018), a shorter length of stay (OR, 0.98; 95% CI, 0.95 to 1.00; P = 0.043), and admission from a skilled-nursing facility (OR, 3.09; 95% CI, 1.26 to 8.08; P = 0.013). Our analysis shows that (i) CR K. pneumoniae is seen primarily in the elderly long-term care population and that (ii) regional monitoring of CR K. pneumoniae reveals insights into molecular characteristics. This work highlights the crucial role of ongoing surveillance of carbapenem resistance determinants. C1 [van Duin, David] Univ N Carolina, Div Infect Dis, Chapel Hill, NC 27514 USA. [Perez, Federico; Rudin, Susan D.; Bonomo, Robert A.] Louis Stokes Cleveland Dept Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA. [Cober, Eric] Cleveland Clin, Dept Infect Dis, Cleveland, OH 44106 USA. [Fox, Jacqueline; Mason, Pamela] Cleveland Clin, Inst Med, Cleveland, OH 44106 USA. [Hanrahan, Jennifer; Ziegler, Julie; Kalayjian, Robert C.] MetroHlth Med Ctr, Dept Med, Cleveland, OH USA. [Perez, Federico; Webber, Raymond; Salata, Robert A.; Bonomo, Robert A.] Case Western Reserve Univ, Sch Med, Dept Med, Div Infect Dis & HIV Med, Cleveland, OH 44106 USA. [Richter, Sandra S.; Cline, Marianne; Hall, Geraldine S.] Cleveland Clin, Dept Microbiol, Cleveland, OH 44106 USA. [Kaye, Keith S.] Wayne State Univ, Detroit Med Ctr, Div Infect Dis, Detroit, MI USA. [Jacobs, Michael R.; Bonomo, Robert A.] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA. [Segre, Julia A.; Conlan, Sean] NHGRI, NIH, Bethesda, MD 20892 USA. [Evans, Scott] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Evans, Scott] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Fowler, Vance G., Jr.] Duke Univ, Med Ctr, Div Infect Dis, Durham, NC USA. [Bonomo, Robert A.] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA. RP van Duin, D (reprint author), Univ N Carolina, Div Infect Dis, Chapel Hill, NC 27514 USA. EM david_vanduin@med.unc.edu; robert.bonomo@va.gov FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [UM1AI104681]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health [UL1TR000439]; NIH Roadmap for Medical Research; Veterans Affairs Merit Review Program; National Institutes of Health [AI072219-05, AI063517-07]; Geriatric Research Education and Clinical Center [VISN 10]; Research Program Committees of the Cleveland Clinic; STERIS Corporation; NHGRI; NIH Director's Challenge Fund FX This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award UM1AI104681 and by funding to D.V.D. and F.P. from the Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health, and NIH Roadmap for Medical Research. In addition, this work was supported in part by the Veterans Affairs Merit Review Program (R.A.B.), the National Institutes of Health (grants AI072219-05 and AI063517-07 to R.A.B.), the Geriatric Research Education and Clinical Center VISN 10 (R.A.B.), the Research Program Committees of the Cleveland Clinic (D.V.D.), an unrestricted research grant from the STERIS Corporation (D.V.D.), NHGRI intramural funding (J.A.S.), and the NIH Director's Challenge Fund (J.A.S.). NR 24 TC 33 Z9 33 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUL PY 2014 VL 58 IS 7 BP 4035 EP 4041 DI 10.1128/AAC.02636-14 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AL0WA UT WOS:000338846500059 PM 24798270 ER PT J AU Chen, L Chavda, KD Findlay, J Peirano, G Hopkins, K Pitout, JDD Bonomo, RA Woodford, N Deleo, FR Kreiswirth, BN AF Chen, Liang Chavda, Kalyan D. Findlay, Jacqueline Peirano, Gisele Hopkins, Katie Pitout, Johann D. D. Bonomo, Robert A. Woodford, Neil Deleo, Frank R. Kreiswirth, Barry N. TI Multiplex PCR for Identification of Two Capsular Types in Epidemic KPC-Producing Klebsiella pneumoniae Sequence Type 258 Strains SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID REAL-TIME PCR; CARBAPENEMASES AB We developed a multiplex PCR assay capable of identifying two capsular polysaccharide synthesis sequence types (sequence type 258 [ST258] cps-1 and cps-2) in epidemic Klebsiella pneumoniae ST258 strains. The assay performed with excellent sensitivity (100%) and specificity (100%) for identifying cps types in 60 ST258 K. pneumoniae sequenced isolates. The screening of 419 ST258 clonal isolates revealed a significant association between cps type and K. pneumoniae carbapenemase (KPC) variant: cps-1 is largely associated with KPC-2, while cps-2 is primarily associated with KPC-3. C1 [Chen, Liang; Chavda, Kalyan D.; Kreiswirth, Barry N.] Rutgers State Univ, New Jersey Med Sch, Publ Hlth Res Inst Ctr, Newark, NJ 07102 USA. [Findlay, Jacqueline; Hopkins, Katie; Woodford, Neil] Publ Hlth England, Antimicrobial Resistance & Healthcare Associated, London, England. [Peirano, Gisele; Pitout, Johann D. D.] Calgary Lab Serv, Div Microbiol, Calgary, AB, Canada. [Peirano, Gisele; Pitout, Johann D. D.] Univ Calgary, Dept Pathol, Calgary, AB, Canada. [Peirano, Gisele; Pitout, Johann D. D.] Univ Calgary, Dept Lab Med, Calgary, AB, Canada. [Pitout, Johann D. D.] Univ Calgary, Dept Microbiol Immunol, Calgary, AB, Canada. [Pitout, Johann D. D.] Univ Calgary, Dept Infect Dis, Calgary, AB, Canada. [Bonomo, Robert A.] Vet Affairs Med Ctr, Louis Stokes Cleveland Dept, Res Serv, Cleveland, OH USA. [Bonomo, Robert A.] Case Western Reserve Univ, Dept Med, Dept Pharmacol, Dept Mol Biol, Cleveland, OH 44106 USA. [Bonomo, Robert A.] Case Western Reserve Univ, Dept Microbiol, Cleveland, OH 44106 USA. [Deleo, Frank R.] NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Kreiswirth, BN (reprint author), Rutgers State Univ, New Jersey Med Sch, Publ Hlth Res Inst Ctr, Newark, NJ 07102 USA. EM kreiswba@njms.rutgers.edu RI Chavda, Kalyan/L-4311-2014; OI DeLeo, Frank/0000-0003-3150-2516; Findlay, Jacqueline/0000-0002-7335-9001 FU National Institutes of Health [1R01AI090155]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Public Health Service from the National Institutes of Health [R01AI072219, R01AI063517]; Cleveland Department of Veterans Affairs; Veterans Affairs Merit Review Program; Geriatric Research Education and Clinical Center [VISN 10] FX This study was supported by a grant (to B.N.K.) from the National Institutes of Health (1R01AI090155) and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. This work was also supported by Public Health Service grants R01AI072219 and R01AI063517 (to R.A.B.) from the National Institutes of Health and funds and/or facilities provided by the Cleveland Department of Veterans Affairs, the Veterans Affairs Merit Review Program, and the Geriatric Research Education and Clinical Center VISN 10 (to R.A.B.). NR 10 TC 11 Z9 11 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUL PY 2014 VL 58 IS 7 BP 4196 EP 4199 DI 10.1128/AAC.02673-14 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AL0WA UT WOS:000338846500079 PM 24733470 ER PT J AU Simino, J Kume, R Kraja, AT Turner, ST Hanis, CL Sheu, WHH Chen, YDI Jaquish, CE Cooper, RS Chakravarti, A Quertermous, T Boerwinkle, E Hunt, SC Rao, DC AF Simino, Jeannette Kume, Rezart Kraja, Aldi T. Turner, Stephen T. Hanis, Craig L. Sheu, Wayne H. -H. Chen, Yii-Der Ida Jaquish, Cashell E. Cooper, Richard S. Chakravarti, Aravinda Quertermous, Thomas Boerwinkle, Eric Hunt, Steven C. Rao, D. C. TI Linkage analysis incorporating gene-age interactions identifies seven novel lipid loci: The Family Blood Pressure Program SO ATHEROSCLEROSIS LA English DT Article DE Lipids; Aging; Genetics; Meta-analysis; Gene-age interactions; Linkage; Triglyceride; Cholesterol ID DENSITY-LIPOPROTEIN-CHOLESTEROL; GENOME-WIDE ASSOCIATION; TRIGLYCERIDE LEVELS; LDL CHOLESTEROL; HDL CHOLESTEROL; HEART-DISEASE; HYPERTENSION; POLYMORPHISM; GENOTYPE; TRAITS AB Objective: To detect novel loci with age-dependent effects on fasting (>= 8 h) levels of total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides using 3600 African Americans, 1283 Asians, 3218 European Americans, and 2026 Mexican Americans from the Family Blood Pressure Program (FBPP). Methods: Within each subgroup (defined by network, race, and sex), we employed stepwise linear regression (retention p <= 0.05) to adjust lipid levels for age, age-squared, age-cubed, body-mass-index, current smoking status, current drinking status, field center, estrogen therapy (females only), as well as antidiabetic, antihypertensive, and antilipidemic medication use. For each trait, we pooled the standardized male and female residuals within each network and race and fit a generalized variance components model that incorporated gene-age interactions. We conducted FBPP-wide and race-specific meta-analyses by combining the p-values of each linkage marker across subgroups using a modified Fisher's method. Results: We identified seven novel loci with age-dependent effects; four total cholesterol loci from the meta-analysis of Mexican Americans (on chromosomes 2q24.1, 4q21.21, 8q22.2, and 12p11.23) and three high-density lipoprotein loci from the meta-analysis of all FBPP subgroups (on chromosomes 1p12, 14q11.2, and 21q21.1). These loci lacked significant genome-wide linkage or association evidence in the literature and had logarithm of odds (LOD) score >= 3 in the meta-analysis with LOD >= 1 in at least two network and race subgroups (exclusively of non-European descent). Conclusion: Incorporating gene-age interactions into the analysis of lipids using multi-ethnic cohorts can enhance gene discovery. These interaction loci can guide the selection of families for sequencing studies of lipid-associated variants. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Simino, Jeannette; Kume, Rezart; Rao, D. C.] Washington Univ, Div Biostat, Sch Med, St Louis, MO 63110 USA. [Kraja, Aldi T.] Washington Univ, Div Stat Genom, Sch Med, St Louis, MO 63110 USA. [Turner, Stephen T.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. [Hanis, Craig L.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Sheu, Wayne H. -H.] Taichung Vet Gen Hosp, Dept Internal Med, Div Endocrinol & Metab, Taichung, Taiwan. [Chen, Yii-Der Ida] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Jaquish, Cashell E.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Cooper, Richard S.] Loyola Univ Chicago, Stritch Sch Med, Dept Prevent Med & Epidemiol, Maywood, IL USA. [Chakravarti, Aravinda] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Quertermous, Thomas] Stanford Univ, Cardiovasc Inst, Div Cardiovasc Med, Stanford, CA 94305 USA. [Hunt, Steven C.] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA. [Rao, D. C.] Washington Univ, Dept Genet, Sch Med, St Louis, MO 63110 USA. [Rao, D. C.] Washington Univ, Dept Psychiat, Sch Med, St Louis, MO 63110 USA. [Rao, D. C.] Washington Univ, Dept Math, Sch Med, St Louis, MO 63110 USA. RP Simino, J (reprint author), Washington Univ, Div Biostat, Sch Med, 660 South Euclid Ave,Campus Box 8067, St Louis, MO 63110 USA. EM jeannette@wubios.wustl.edu FU National Heart, Lung, and Blood Institute [HL54512, HL54481, HL54471, HL54498, HL54473, R21 HL095054, R01HL086694, R01HL055673, R01HL107552, R01HL111249, R01HL118305]; National Institute of General Medical Sciences (NIGMS) [GM 28719] FX This study and the Family Blood Pressure Program were funded by National Heart, Lung, and Blood Institute grants HL54512, HL54481, HL54471, HL54498, HL54473, R21 HL095054, R01HL086694, R01HL055673, R01HL107552, R01HL111249, and R01HL118305; and a methodology grant from the National Institute of General Medical Sciences (NIGMS; GM 28719). NR 48 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JUL PY 2014 VL 235 IS 1 BP 84 EP 93 DI 10.1016/j.atherosclerosis.2014.04.008 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AL8NH UT WOS:000339395500014 PM 24819747 ER PT J AU Kizer, JR Benkeser, D Arnold, AM Ix, JH Mukamal, KJ Djousse, L Tracy, RP Siscovick, DS Psaty, BM Zieman, SJ AF Kizer, Jorge R. Benkeser, David Arnold, Alice M. Ix, Joachim H. Mukamal, Kenneth J. Djousse, Luc Tracy, Russell P. Siscovick, David S. Psaty, Bruce M. Zieman, Susan J. TI Advanced glycation/glycoxidation endproduct carboxymethyl-lysine and incidence of coronary heart disease and stroke in older adults SO ATHEROSCLEROSIS LA English DT Article DE Advanced glycation endproducts; Carboxymethyl-lysine; Aging; Older adults; Coronary heart disease; Stroke ID GLYCATION END-PRODUCTS; CHRONIC KIDNEY-DISEASE; CARDIOVASCULAR-DISEASE; ENDOTHELIAL FUNCTION; OXIDATIVE STRESS; DIABETIC-NEPHROPATHY; SERUM-LEVELS; ALL-CAUSE; MORTALITY; HEALTH AB Background: Advanced glycation/glycoxidation endproducts (AGEs) accumulate in settings of increased oxidative stress - such as diabetes, chronic kidney disease and aging - where they promote vascular stiffness and atherogenesis, but the prospective association between AGEs and cardiovascular events in elders has not been previously examined. Methods: To test the hypothesis that circulating levels of N-epsilon-carboxymethyl-lysine (CML), a major AGE, increase the risk of incident coronary heart disease and stroke in older adults, we measured serum CML by immunoassay in 2111 individuals free of prevalent cardiovascular disease participating in a population-based study of U.S. adults ages 65 and older. Results: During median follow-up of 9.1 years, 625 cardiovascular events occurred. CML was positively associated with incident cardiovascular events after adjustment for age, sex, race, systolic blood pressure, anti-hypertensive treatment, diabetes, smoking status, triglycerides, albumin, and self-reported health status (hazard ratio [HR] per SD [0.99 pmol/l] increase 1.11, 95% confidence interval [CI] 1.03-1.19). This association was not materially attenuated by additional adjustment for C-reactive protein, estimated glomerular filtration rate (eGFR), and urine albumin/creatinine ratio. Findings were similar for the component endpoints of coronary heart disease and stroke. Conclusions: In this large older cohort, CML was associated with an increased risk of cardiovascular events independent of a wide array of potential confounders and mediators. Although the moderate association limits CML's value for risk prediction, these community-based findings provide support for clinical trials to test AGE-lowering therapies for cardiovascular prevention in this population. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Benkeser, David; Arnold, Alice M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Ix, Joachim H.] Dept Med, Div Nephrol, San Diego, CA USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Family & Prevent Med, Div Prevent Med, San Diego, CA 92103 USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Mukamal, Kenneth J.; Djousse, Luc] Harvard Univ, Sch Med, Boston, MA USA. [Djousse, Luc] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Colchester, VT USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Colchester, VT USA. [Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Zieman, Susan J.] Natl Inst Aging, Div Geriatr & Clin Gerontol, NIH, Bethesda, MD USA. RP Kizer, JR (reprint author), Albert Einstein Coll Med, Cardiovasc Clin Res Unit, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM jorge.kizer@einstein.yu.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Institute on Aging (NIA) [AG023629]; National Heart, Lung, and Blood Institute (NHLBI) [HL080295]; [R01 HL094555]; [HHSN268201200036C]; [HHSN268200800007C]; [N01HC55222]; [N01HC85079]; [N01HC85080]; [N01HC85081]; [N01HC85082]; [N01HC85083]; [N01HC85086] FX This research was supported by R01 HL094555, as well as by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/PI.htm. NR 43 TC 10 Z9 10 U1 0 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JUL PY 2014 VL 235 IS 1 BP 116 EP 121 DI 10.1016/j.atherosclerosis.2014.04.013 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AL8NH UT WOS:000339395500018 PM 24825341 ER PT J AU Canepa, M Ameri, P AlGhatrif, M Pestelli, G Milaneschi, Y Strait, JB Giallauria, F Ghigliotti, G Brunelli, C Lakatta, EG Ferrucci, L AF Canepa, Marco Ameri, Pietro AlGhatrif, Majd Pestelli, Gabriele Milaneschi, Yuri Strait, James B. Giallauria, Francesco Ghigliotti, Giorgio Brunelli, Claudio Lakatta, Edward G. Ferrucci, Luigi TI Role of bone mineral density in the inverse relationship between body size and aortic calcification: Results from the Baltimore Longitudinal Study of Aging SO ATHEROSCLEROSIS LA English DT Article DE Aortic calcification; Body mass index; Body size; Bone mineral density; Obesity paradox; Calcification paradox ID CORONARY-ARTERY CALCIFICATION; KAPPA-B LIGAND; VASCULAR CALCIFICATION; OBESITY PARADOX; CARDIOVASCULAR EVENTS; RECEPTOR ACTIVATOR; ABDOMINAL-AORTA; ELDERLY-WOMEN; DISEASE; MORTALITY AB Objective: There is a J-shaped relationship between body mass index (BMI) and cardiovascular outcomes in elderly patients (obesity paradox). Whether low BMI correlates with aortic calcification (AC) and whether this association is accounted for by bone demineralization is uncertain. Methods: Presence of AC was evaluated in 687 community-dwelling individuals (49% male, mean age 67 +/- 13 years) using CT images of the thoracic, upper and lower abdominal aorta, and scored from 0 to 3 according to number of sites that showed any calcification. Whole-body bone mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry. Predictors of AC were assessed by logistic regression, and the role of BMD using mediation analysis. Results: Age and cardiovascular risk factors were positively associated while both BMI (r = -0.11, p < 0.01) and BMD (r = -0.17, p < 0.0001) were negatively associated with AC severity. In multivariate models, lower BMI (OR 0.96, 95%CI 0.92-0.99, p = 0.01), older age, higher systolic blood pressure, use of lipid-lowering drugs and smoking were independent predictors of AC. A nonlinear relationship between BMI and AC was noticed (p = 0.03), with decreased AC severity among overweight participants. After adjusting for BMD, the coefficient relating BMI to AC was reduced by 14% and was no longer significant, whereas BMD remained negatively associated with AC (OR 0.82, 95%CI 0.069-0.96, p = 0.01), with a trend for a stronger relationship in older participants. Conclusion: Low BMI is associated with increased AC, possibly through calcium mobilization from bone, resulting in low BMD. Prevention of weight loss and bone demineralization with aging may help reducing AC. Published by Elsevier Ireland Ltd. C1 [Canepa, Marco; AlGhatrif, Majd; Milaneschi, Yuri; Giallauria, Francesco; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Canepa, Marco; AlGhatrif, Majd; Strait, James B.; Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Human Cardiovasc Studies Unit, NIH, Baltimore, MD 21224 USA. [Canepa, Marco; Ameri, Pietro; Pestelli, Gabriele; Ghigliotti, Giorgio; Brunelli, Claudio] Univ Genoa, Dept Internal Med, I-16132 Genoa, Italy. [AlGhatrif, Majd] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. [Milaneschi, Yuri] Vrije Univ Amsterdam, Med Center, GGZ InGeest, Dept Psychiat, Amsterdam, Netherlands. RP Canepa, M (reprint author), Univ Genoa, IRCCS, AOU San Martino IST, Cardiovasc Unit, Viale Benedetto XV 6, I-16132 Genoa, Italy. EM marco.canepa@unige.it FU Intramural Research Program of the NIH [Z99 AG999999]; National Institute on Aging [Z99 AG999999]; Medstar Research Institute FX This study was supported by the Intramural Research Program of the NIH (Z99 AG999999), National Institute on Aging (Z99 AG999999) and the Medstar Research Institute. NR 49 TC 7 Z9 7 U1 1 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JUL PY 2014 VL 235 IS 1 BP 169 EP 175 DI 10.1016/j.atherosclerosis.2014.04.018 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AL8NH UT WOS:000339395500024 PM 24842457 ER PT J AU Chen, M Lang, A Ying, HS Calabresi, PA Prince, JL Carass, A AF Chen, Min Lang, Andrew Ying, Howard S. Calabresi, Peter A. Prince, Jerry L. Carass, Aaron TI Analysis of macular OCT images using deformable registration SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; MULTIPLE-SCLEROSIS; NONRIGID REGISTRATION; ALZHEIMERS-DISEASE; MOTION CORRECTION; LAYER; BRAIN; SEGMENTATION; THICKNESS; CLASSIFICATION AB Optical coherence tomography (OCT) of the macula has become increasingly important in the investigation of retinal pathology. However, deformable image registration, which is used for aligning subjects for pairwise comparisons, population averaging, and atlas label transfer, has not been well-developed and demonstrated on OCT images. In this paper, we present a deformable image registration approach designed specifically for macular OCT images. The approach begins with an initial translation to align the fovea of each subject, followed by a linear rescaling to align the top and bottom retinal boundaries. Finally, the layers within the retina are aligned by a deformable registration using one-dimensional radial basis functions. The algorithm was validated using manual delineations of retinal layers in OCT images from a cohort consisting of healthy controls and patients diagnosed with multiple sclerosis (MS). We show that the algorithm overcomes the shortcomings of existing generic registration methods, which cannot be readily applied to OCT images. A successful deformable image registration algorithm for macular OCT opens up a variety of population based analysis techniques that are regularly used in other imaging modalities, such as spatial normalization, statistical atlas creation, and voxel based morphometry. Examples of these applications are provided to demonstrate the potential benefits such techniques can have on our understanding of retinal disease. In particular, included is a pilot study of localized volumetric changes between healthy controls and MS patients using the proposed registration algorithm. (C) 2014 Optical Society of America C1 [Chen, Min; Lang, Andrew; Prince, Jerry L.; Carass, Aaron] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Chen, Min] NINDS, Translat Neuroradiol Unit, Bethesda, MD 20892 USA. [Ying, Howard S.] Johns Hopkins Univ, Wilmer Eye Inst, Sch Med, Baltimore, MD 21287 USA. [Calabresi, Peter A.] Johns Hopkins Univ, Dept Neurol, Sch Med, Baltimore, MD 21287 USA. RP Chen, M (reprint author), Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. EM mchen55@jhu.edu OI Carass, Aaron/0000-0003-4939-5085 FU NIH/NEI [R21-EY022150]; NIH/NINDS [R01-NS082347]; NINDS FX This work was supported by the NIH/NEI under grant R21-EY022150, NIH/NINDS R01-NS082347 and the Intramural Research Program of NINDS. NR 57 TC 3 Z9 3 U1 2 U2 12 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD JUL 1 PY 2014 VL 5 IS 7 BP 2196 EP 2214 DI 10.1364/BOE.5.002196 PG 19 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA AL2AV UT WOS:000338929100017 PM 25071959 ER PT J AU Sivina, M Kreitman, RJ Arons, E Ravandi, F Burger, JA AF Sivina, Mariela Kreitman, Robert J. Arons, Evgeny Ravandi, Farhad Burger, Jan A. TI The bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) blocks hairy cell leukaemia survival, proliferation and B cell receptor signalling: a new therapeutic approach SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE hairy cell leukaemia; B cell receptor; microenvironment; bruton tyrosine kinase; ibrutinib ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ANTIGEN RECEPTORS; TUMOR-CELLS; MALIGNANCIES; EXPRESSION; MIGRATION; DIAGNOSIS; LYMPHOMA; MICROENVIRONMENT; CLADRIBINE AB B cell receptor (BCR) signalling plays a critical role in the progression of several B-cell malignancies, but its role in hairy cell leukaemia (HCL) is ambiguous. Bruton tyrosine kinase (BTK), a key player in BCR signalling, as well as B cell migration and adhesion, can be targeted with ibrutinib, a selective, irreversible BTK inhibitor. We analysed BTK expression and function in HCL and analysed the effects of ibrutinib on HCL cells. We demonstrated uniform BTK protein expression in HCL cells. Ibrutinib significantly inhibited HCL proliferation and cell cycle progression. Accordingly, ibrutinib also reduced HCL cell survival after BCR triggering with anti-immunoglobulins and abrogated the activation of kinases downstream of the BCR (PI3K and MAPK). Ibrutinib also inhibited BCR-dependent secretion of the chemokines CCL3 and CCL4 by HCL cells. Interestingly, ibrutinib also inhibited CXCL12-induced signalling, a key pathway for bone marrow homing. Collectively, our data support the clinical development of ibrutinib in patients with HCL. C1 [Sivina, Mariela; Ravandi, Farhad; Burger, Jan A.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77230 USA. [Kreitman, Robert J.; Arons, Evgeny] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Burger, JA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Unit 428,POB 301402, Houston, TX 77230 USA. EM jaburger@mdanderson.org FU CLL Global Research Foundation; Cancer Prevention and Research Institute of Texas (CPRIT) grant; Pharmacyclics Inc. FX This study was supported by grants from the CLL Global Research Foundation (to JAB), a Cancer Prevention and Research Institute of Texas (CPRIT) grant (to JAB) and by Pharmacyclics Inc. NR 43 TC 20 Z9 20 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUL PY 2014 VL 166 IS 2 BP 177 EP 188 DI 10.1111/bjh.12867 PG 12 WC Hematology SC Hematology GA AL7VO UT WOS:000339344700005 PM 24697238 ER PT J AU Gow, RV Hibbeln, JR AF Gow, Rachel V. Hibbeln, Joseph R. TI Omega-3 Fatty Acid and Nutrient Deficits in Adverse Neurodevelopment and Childhood Behaviors SO CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Omega-3 fatty acids; Eicosapentaenoic acid; Docosahexaenoic acid; Arachidonic acid; Child neurodevelopment; Attention-deficit/hyperactivity disorder; Conduct disorder; Learning disorders ID ESSENTIAL FATTY-ACIDS; PLACEBO-CONTROLLED-TRIAL; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CALLOUS-UNEMOTIONAL TRAITS; BRAIN DOCOSAHEXAENOIC ACID; MAJOR DEPRESSIVE DISORDER; CENTRAL-NERVOUS-SYSTEM; DIETARY LINOLEIC-ACID; RANDOMIZED CONTROLLED-TRIALS; YOUNG-ADULT PRISONERS AB Nutritional insufficiencies of omega-3 highly unsaturated fatty acids (HUFAs) may have adverse effects on brain development and neurodevelopmental outcomes. A recent meta-analysis reported a small to modest effect size for the efficacy of omega-3 in youth. Several controlled trials of omega-3 HUFAs combined with micronutrients show sizable reductions in aggressive, antisocial, and violent behavior in youth and young adult prisoners. Studies of HUFAs in youth, however, remain lacking. As the evidence base for omega-3 HUFAs as potential psychiatric treatment develops, dietary adjustments to increase omega-3 and reduce omega-6 HUFA consumption are sensible recommendations based on general health considerations. C1 [Gow, Rachel V.; Hibbeln, Joseph R.] NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20892 USA. RP Hibbeln, JR (reprint author), NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, NIH, 5625 Fishers Lane,Room 3N-01, Rockville, MD 20892 USA. EM jhibbeln@mail.nih.gov FU Intramural NIH HHS [ZIA AA000115-14] NR 172 TC 10 Z9 10 U1 4 U2 33 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1056-4993 EI 1558-0490 J9 CHILD ADOL PSYCH CL JI Child Adolesc. Psychiatr. N. Am. PD JUL PY 2014 VL 23 IS 3 BP 555 EP + DI 10.1016/j.chc.2014.02.002 PG 37 WC Psychiatry SC Psychiatry GA AL8TH UT WOS:000339411900006 PM 24975625 ER PT J AU Mark, DB Anstrom, KJ Clapp-Channing, NE Knight, JD Boineau, R Goertz, C Rozema, TC Liu, DM Nahin, RL Rosenberg, Y Drisko, J Lee, KL Lamas, GA AF Mark, Daniel B. Anstrom, Kevin J. Clapp-Channing, Nancy E. Knight, J. David Boineau, Robin Goertz, Christine Rozema, Theodore C. Liu, Diane M. Nahin, Richard L. Rosenberg, Yves Drisko, Jeanne Lee, Kerry L. Lamas, Gervasio A. CA TACT Investigators TI Quality-of-Life Outcomes With a Disodium EDTA Chelation Regimen for Coronary Disease Results From the Trial to Assess Chelation Therapy Randomized Trial SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE atherosclerosis; coronary disease; quality of life ID INTERMITTENT CLAUDICATION; MYOCARDIAL-INFARCTION; DOUBLE-BLIND; TACT; QUESTIONNAIRE AB Background-The National Institutes of Health-funded Trial to Assess Chelation Therapy (TACT) randomized 1708 stable coronary disease patients aged >= 50 years who were >= 6 months post-myocardial infarction (2003-2010) to 40 infusions of a multicomponent EDTA chelation solution or placebo. Chelation reduced the primary composite end point of mortality, recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina (hazard ratio, 0.82; 95% confidence interval, 0.69-0.99; P=0.035). Methods and Results-In a randomly selected subset of 911 patients, we prospectively collected a battery of quality-of-life (QOL) instruments at baseline and at 6, 12, and 24 months after randomization. The prespecified primary QOL measures were the Duke Activity Status Index (Table I in the Data Supplement) and the Medical Outcomes Study Short-Form 36 Mental Health Inventory-5. All comparisons were by intention to treat. Baseline clinical and QOL variables were well balanced in the 451 patients randomized to chelation and in the 460 patients randomized to placebo. The Duke Activity Status Index improved in both groups during the first 6 months of therapy, but we found no evidence for a treatment-related difference (mean difference [chelation-placebo] during follow-up, 0.9 [95% confidence interval, -0.7 to 2.6; P=0.27]). There was no statistically significant evidence of a treatment-related difference in the Mental Health Inventory-5 during follow-up (mean difference, 1.0; 95% confidence interval, -0.1 to 2.0; P=0.08). None of the secondary QOL measures showed a consistent treatment-related difference. Conclusions-In stable, predominantly asymptomatic coronary disease patients with a history of myocardial infarction, EDTA chelation therapy did not have a detectable effect on QOL during 2 years of follow-up. C1 [Mark, Daniel B.; Anstrom, Kevin J.; Clapp-Channing, Nancy E.; Knight, J. David; Liu, Diane M.] Duke Univ, Med Ctr, Outcomes Res Grp, Durham, NC USA. [Lee, Kerry L.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Boineau, Robin; Nahin, Richard L.; Rosenberg, Yves] NHLBI, Bethesda, MD 20892 USA. [Goertz, Christine] Palmer Ctr Chiropract Res, Davenport, IA USA. [Rozema, Theodore C.] Biogenesis Med Ctr, Landrum, SC USA. [Drisko, Jeanne] Univ Kansas, Med Ctr, Kansas City, KS USA. [Lamas, Gervasio A.] Columbia Univ, Div Cardiol, Mt Sinai Med Ctr, Miami, FL USA. RP Mark, DB (reprint author), Duke Clin Res Inst, 2400 Pratt St,Room 0311, Durham, NC 27705 USA. EM daniel.mark@duke.edu OI Mark, Daniel/0000-0001-6340-8087 FU National Heart, Lung, and Blood Institute [U01 H092607]; National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD [U01 AT001156] FX This work was supported by grants from the National Heart, Lung, and Blood Institute (U01 H092607) and from the National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD (U01 AT001156). NR 13 TC 1 Z9 1 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 EI 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2014 VL 7 IS 4 BP 508 EP 516 DI 10.1161/CIRCOUTCOMES.114.000977 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AL6OJ UT WOS:000339251900003 PM 24987051 ER PT J AU Margulies, KB Anstrom, KJ Hernandez, AF Redfield, MM Shah, MR Braunwald, E Cappola, TP AF Margulies, Kenneth B. Anstrom, Kevin J. Hernandez, Adrian F. Redfield, Margaret M. Shah, Monica R. Braunwald, Eugene Cappola, Thomas P. CA Heart Failure Clinical Res Network TI GLP-1 Agonist Therapy for Advanced Heart Failure With Reduced Ejection Fraction Design and Rationale for the Functional Impact of GLP-1 for Heart Failure Treatment Study SO CIRCULATION-HEART FAILURE LA English DT Article DE clinical trial; glucagon-like peptide-1; heart failure; insulin resistance ID GLUCAGON-LIKE PEPTIDE-1; BRAIN NATRIURETIC PEPTIDE; MYOCARDIAL GLUCOSE-UPTAKE; DILATED CARDIOMYOPATHY; CONSCIOUS DOGS; INSULIN-RESISTANCE; RANDOMIZED-TRIAL; FAILING HEART; VAL-HEFT; DYSFUNCTION C1 [Margulies, Kenneth B.; Cappola, Thomas P.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Anstrom, Kevin J.; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Redfield, Margaret M.] Mayo Clin, Rochester, MN USA. [Shah, Monica R.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Braunwald, Eugene] Harvard Univ, Sch Med, Boston, MA USA. RP Margulies, KB (reprint author), Smilow Ctr Translat Res, Perelman Sch Med, Cardiovasc Inst, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM ken.margulies@uphs.upenn.edu; thomas.cappola@uphs.upenn.edu RI Hernandez, Adrian F./A-7818-2016 OI Hernandez, Adrian F./0000-0003-3387-9616 FU National Heart, Lung, and Blood Institute (co-ordinating center) [U10 HL084904]; National Heart, Lung, and Blood Institute (regional clinical centers) [U10 HL110312, U10 HL110337, U10 HL110342, U10 HL110262, U10 HL110297, U10 HL110302, U10 HL110309, U10 HL110336, U10 HL110338] FX This work was supported by grants from the National Heart, Lung, and Blood Institute (co-ordinating center: U10 HL084904; regional clinical centers: U10 HL110312, U10 HL110337, U10 HL110342, U10 HL110262, U10 HL110297, U10 HL110302, U10 HL110309, U10 HL110336, U10 HL110338). NR 49 TC 15 Z9 15 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2014 VL 7 IS 4 BP 673 EP 679 DI 10.1161/CIRCHEARTFAILURE.114.000346 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AL5KD UT WOS:000339171600017 PM 25028349 ER PT J AU Lu, YC Yao, X Crystal, JS Li, YF El-Gamil, M Gross, C Davis, L Dudley, ME Yang, JC Samuels, Y Rosenberg, SA Robbins, PF AF Lu, Yong-Chen Yao, Xin Crystal, Jessica S. Li, Yong F. El-Gamil, Mona Gross, Colin Davis, Lindy Dudley, Mark E. Yang, James C. Samuels, Yardena Rosenberg, Steven A. Robbins, Paul F. TI Efficient Identification of Mutated Cancer Antigens Recognized by T Cells Associated with Durable Tumor Regressions SO CLINICAL CANCER RESEARCH LA English DT Article ID ADOPTIVE TRANSFER; DNA-REPLICATION; GENE-THERAPY; KINESINS; HUMANS; IMMUNOTHERAPY; LYMPHOCYTES; CATASTROPHE; RESPONSES; MCAK AB Purpose: Cancer immunotherapy with adoptive transfer of tumor-infiltrating lymphocytes (TIL) represents an effective treatment for patients with metastatic melanoma, with the objective regressions in up to 72% of patients in three clinical trials. However, the antigen targets recognized by these effective TILs remain largely unclear. Experimental Design: Melanoma patients 2359 and 2591 both experienced durable complete regressions of metastases ongoing beyond five years following adoptive TIL transfer. Two conventional screening approaches were carried out to identify the antigens recognized by these clinically effective TILs. In addition, a novel approach was developed in this study to identify mutated T-cell antigens by screening a tandem minigene library, which comprised nonsynonymous mutation sequences identified by whole-exome sequencing of autologous tumors. Results: Screening of an autologous melanoma cDNA library using a conventional approach led to the identification of previously undescribed nonmutated targets recognized by TIL 2359 or TIL 2591. In contrast, screening of tandem minigene libraries encoding tumor-specific mutations resulted in the identification of mutated kinesin family member 2C (KIF2C) antigen as a target of TIL 2359, and mutated DNA polymerase alpha subunit B (POLA2) antigen as a target of TIL 2591. Both KIF2C and POLA2 have been found to play important roles in cell proliferation. Conclusions: These findings suggest that the minigene screening approach can facilitate the antigen repertoire analysis of tumor reactive T cells, and lead to the development of new adoptive cell therapies with purified T cells that recognize candidate-mutated antigens derived from genes essential for the carcinogenesis. (C)2014 AACR. C1 [Lu, Yong-Chen; Yao, Xin; Crystal, Jessica S.; Li, Yong F.; El-Gamil, Mona; Gross, Colin; Davis, Lindy; Dudley, Mark E.; Yang, James C.; Rosenberg, Steven A.; Robbins, Paul F.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Samuels, Yardena] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Lu, YC (reprint author), NCI, Surg Branch, NIH, Bldg 10-CRC,Rm 3W-3832,10 Ctr Dr, Bethesda, MD 20892 USA. EM Yong-Chen.Lu@nih.gov; Paul_Robbins@nih.gov RI Lu, Yong-Chen/G-4520-2014 OI Lu, Yong-Chen/0000-0002-0275-9825 FU NCI Director's Innovation Award; Intramural Research Program of NCI; Adelson Medical Research Foundation (AMRF); Milstein Family Foundation; European Research Council [StG-335377] FX This work was supported by the NCI Director's Innovation Award (to Y.-C. Lu), the Intramural Research Program of NCI, Adelson Medical Research Foundation (AMRF), Milstein Family Foundation, and European Research Council (StG-335377; to Y. Samuels). NR 36 TC 71 Z9 73 U1 0 U2 9 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 JUL 1 PY 2014 VL 20 IS 13 BP 3401 EP 3410 DI 10.1158/1078-0432.CCR-14-0433 PG 10 WC Oncology SC Oncology GA AL1XQ UT WOS:000338920100007 PM 24987109 ER PT J AU Ardeshirpour, Y Chernomordik, V Hassan, M Zielinski, R Capala, J Gandjbakhche, A AF Ardeshirpour, Yasaman Chernomordik, Victor Hassan, Moinuddin Zielinski, Rafal Capala, Jacek Gandjbakhche, Amir TI In Vivo Fluorescence Lifetime Imaging for Monitoring the Efficacy of the Cancer Treatment SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN-BREAST-CANCER; AFFIBODY MOLECULES; HER2 EXPRESSION; CONTRAST AGENTS; THERAPY; PET; MOUSE; TRASTUZUMAB; DIAGNOSTICS; SYSTEM AB Purpose: Advances in tumor biology created a foundation for targeted therapy aimed at inactivation of specific molecular mechanisms responsible for cell malignancy. In this paper, we used in vivo fluorescence lifetime imaging with HER2-targeted fluorescent probes as an alternative imaging method to investigate the efficacy of targeted therapy with 17-DMAG (an HSP90 inhibitor) on tumors with high expression of HER2 receptors. Experimental Design: HER2-specific Affibody, conjugated to Alexafluor 750, was injected into nude mice bearing HER2-positive tumor xenograft. The fluorescence lifetime was measured before treatment and monitored after the probe injections at 12 hours after the last treatment dose, when the response to the 17-DMAG therapy was the most pronounced as well as a week after the last treatment when the tumors grew back almost to their pretreatment size. Results: Imaging results showed significant difference between the fluorescence lifetimes at the tumor and the contralateral site (similar to 0.13 ns) in the control group (before treatment) and 7 days after the last treatment when the tumors grew back to their pretreatment dimensions. However, at the time frame that the treatment had its maximum effect (12 hours after the last treatment), the difference between the fluorescence lifetime at the tumor and contralateral site decreased to 0.03 ns. Conclusions: The results showed a good correlation between fluorescence lifetime and the efficacy of the treatment. These findings show that in vivo fluorescence lifetime imaging can be used as a promising molecular imaging tool for monitoring the treatment outcome in preclinical models and potentially in patients. (C)2014 AACR. C1 [Ardeshirpour, Yasaman; Chernomordik, Victor; Hassan, Moinuddin; Gandjbakhche, Amir] NICHHD, NIH, Bethesda, MD 20892 USA. [Hassan, Moinuddin] US FDA, Div Phys, CDRH, Off Sci & Engn Labs, Silver Spring, MD USA. [Zielinski, Rafal; Capala, Jacek] NCI, NIH, Rockville, MD USA. [Zielinski, Rafal] UT MD Anderson Canc Ctr, Houston, TX USA. RP Gandjbakhche, A (reprint author), NICHHD, Sect Analyt & Funct Biophoton, Program Pediat Imaging & Tissue Sci, NIH, Bldg 9,Room 1E-116,9 Mem Dr, Bethesda, MD 20892 USA. EM amir@helix.nih.gov FU National Cancer Institute, NIH; National Institute of Child Health and Human Development, NIH FX This work was supported by the Intramural Research Program of National Cancer Institute, NIH and Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 43 TC 3 Z9 3 U1 3 U2 13 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 JUL 1 PY 2014 VL 20 IS 13 BP 3531 EP 3539 DI 10.1158/1078-0432.CCR-13-1826 PG 9 WC Oncology SC Oncology GA AL1XQ UT WOS:000338920100018 PM 24671949 ER PT J AU Hommer, RE Meyer, A Stoddard, J Connolly, ME Mogg, K Bradley, BP Pine, DS Leibenluft, E Brotman, MA AF Hommer, Rebecca E. Meyer, Allison Stoddard, Joel Connolly, Megan E. Mogg, Karin Bradley, Brendan P. Pine, Daniel S. Leibenluft, Ellen Brotman, Melissa A. TI ATTENTION BIAS TO THREAT FACES IN SEVERE MOOD DYSREGULATION SO DEPRESSION AND ANXIETY LA English DT Article DE child and adolescent; anxiety; mood disorders; biological markers; cognition ID GENERALIZED ANXIETY DISORDER; OPPOSITIONAL DEFIANT DISORDER; PREFRONTAL CORTEX ACTIVATION; BIPOLAR DISORDER; PEDIATRIC ANXIETY; ANGRY FACES; DEVELOPMENTAL PATHWAYS; EMOTIONAL FACES; ADULT OUTCOMES; RATING-SCALE AB Background: We used a dot-probe paradigm to examine attention bias toward threat (i.e., angry) and happy face stimuli in severe mood dysregulation (SMD) versus healthy comparison (HC) youth. The tendency to allocate attention to threat is well established in anxiety and other disorders of negative affect. SMD is characterized by the negative affect of irritability, and longitudinal studies suggest childhood irritability predicts adult anxiety and depression. Therefore, it is important to study pathophysiologic connections between irritability and anxiety disorders. Methods: SMD patients (N = 74) and HC youth (N = 42) completed a visual probe paradigm to assess attention bias to emotional faces. Diagnostic interviews were conducted and measures of irritability and anxiety were obtained in patients. Results: SMD youth differed from HC youth in having a bias toward threatening faces (P < .01). Threat bias was positively correlated with the severity of the SMD syndrome and depressive symptoms; degree of threat bias did not differ between SMD youth with and without co-occurring anxiety disorders or depression. SMD and HC youth did not differ in bias toward or away from happy faces. Conclusions: SMD youth demonstrate an attention bias toward threat, with greater threat bias associated with higher levels of SMD symptom severity. Our findings suggest that irritability may share a pathophysiological link with anxiety and depressive disorders. This finding suggests the value of exploring further whether attention bias modification treatments that are effective for anxiety are also helpful in the treatment of irritability. (C) 2013 Wiley Periodicals, Inc. C1 [Hommer, Rebecca E.; Meyer, Allison; Stoddard, Joel; Connolly, Megan E.; Pine, Daniel S.; Leibenluft, Ellen; Brotman, Melissa A.] NIMH, Emot & Dev Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hommer, Rebecca E.] Yale Univ, Yale Child Study Ctr, Yale Sch Med, New Haven, CT USA. [Connolly, Megan E.] Northwestern Univ, Dept Psychiat & Behav Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Mogg, Karin; Bradley, Brendan P.] Univ Southampton, Dept Psychol, Southampton SO9 5NH, Hants, England. RP Hommer, RE (reprint author), NIMH, Emot & Dev Branch, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM rebecca.hommer@nih.gov RI Brotman, Melissa/H-7409-2013; Mogg, Karin/C-1181-2008; OI Mogg, Karin/0000-0002-2738-7378; Meyer, Allison/0000-0002-7364-6799; Bradley, Brendan/0000-0003-2801-4271 FU Intramural Program of the National Institute of Mental Health (NIMH), National Institutes of Health FX This research was supported by the Intramural Program of the National Institute of Mental Health (NIMH), National Institutes of Health. We would like to thank the children and families who participated in this study, as well as the staff of the Emotion and Development Branch at NIMH. Drs. Hommer, Brotman, Leibenluft, and Pine report no conflicts of interest or outside financial support. Drs. Mogg and Bradley have acted as consultants for GSK for work unrelated to this project; they report no conflicts of interest. Dr. Stoddard reports stock holdings in Pfizer, Inc. NR 51 TC 13 Z9 13 U1 10 U2 37 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JUL PY 2014 VL 31 IS 7 BP 559 EP 565 DI 10.1002/da.22145 PG 7 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA AL3YB UT WOS:000339066900004 PM 23798350 ER PT J AU Stoddard, J Stringaris, A Brotman, MA Montville, D Pine, DS Leibenluft, E AF Stoddard, Joel Stringaris, Argyris Brotman, Melissa A. Montville, Daniel Pine, Daniel S. Leibenluft, Ellen TI IRRITABILITY IN CHILD AND ADOLESCENT ANXIETY DISORDERS SO DEPRESSION AND ANXIETY LA English DT Article DE irritable mood; anxiety disorders; trait anger ID DSM-IV; YOUTH; PSYCHOPATHOLOGY; SPECIFICITY; DIAGNOSIS; SYMPTOMS; SCALE AB Background: Our objective was to compare self-and parent-reported irritability in youths with anxiety disorders, healthy youths, and those with mood disorders characterized by irritability. Irritability is a common but relatively understudied psychiatric symptom in child and adolescent anxiety disorders. In anxious youths, little is known about the severity of irritability, its impact on functioning, or the effect of informant source on reports of irritability. Methods: We compared parent-and self-report forms of the Affective Reactivity Index (ARI), a validated measure of irritability, in youths ages 8-17 years with no psychopathology (healthy comparison, HC; n = 38), anxiety disorders (ANX; n = 42), bipolar disorder (BD; n = 35), or severe mood dysregulation (SMD; n = 61; a phenotype characterized by chronic, severely impairing irritability). Results: Irritability was significantly higher in ANX than HC youths by both parent and self-report (partial eta(2) = 0.24 and 0.22, respectively, P's < 0.001). Informant effects differed among ANX, BD, and SMD. Overall, parent-reported irritability was higher in BD with comorbid anxiety disorders and SMD with or without comorbid anxiety disorders than ANX (P's < 0.007), but self-reported irritability was not significantly different among the three patient groups. Discussion: By both parent and self-report, youths with anxiety disorders exhibit significantly more irritability and associated impairment than healthy subjects. Self-reported irritability in youths with anxiety disorders is comparable to that observed in youths with severe mood disorders, although parental reports of irritability differ among the disorders. Future research should examine the pathophysiology of anxiety-associated irritability, as well as its prognostic and treatment implications. (C) 2013 Wiley Periodicals, Inc. C1 [Stoddard, Joel; Brotman, Melissa A.; Montville, Daniel; Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Stringaris, Argyris] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Emot & Dev Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Stoddard, J (reprint author), NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,Dept Hlth & Human Serv, 9000 Rockville Pike MSC 2670,Bldg 15K, Bethesda, MD 20892 USA. EM joel.stoddard@nih.gov RI Brotman, Melissa/H-7409-2013 FU NIMH; NIH FX Contract grant sponsor: NIMH; NIH. NR 32 TC 12 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JUL PY 2014 VL 31 IS 7 BP 566 EP 573 DI 10.1002/da.22151 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA AL3YB UT WOS:000339066900005 PM 23818321 ER PT J AU Lee, HS Burkhardt, BR McLeod, W Smith, S Eberhard, C Lynch, K Hadley, D Rewers, M Simell, O She, JX Hagopian, B Lernmark, A Akolkar, B Ziegler, AG Krischer, JP AF Lee, Hye-Seung Burkhardt, Brant R. McLeod, Wendy Smith, Susan Eberhard, Chris Lynch, Kristian Hadley, David Rewers, Marian Simell, Olli She, Jin-Xiong Hagopian, Bill Lernmark, Ake Akolkar, Beena Ziegler, Anette G. Krischer, Jeffrey P. CA TEDDY Study Grp TI Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study SO DIABETES-METABOLISM RESEARCH AND REVIEWS LA English DT Article DE batch effects; biomarker discovery; nested case-control design; TEDDY; type 1 diabetes ID COHORT; SELECTION; OPTIONS AB Aims The Environmental Determinants of Diabetes in the Young planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression. Methods This article describes the details of planning The Environmental Determinants of Diabetes in the Young biomarker discovery studies using a nested case-control design that was chosen as an alternative to the full cohort analysis. In the frame of a nested case-control design, it guides the choice of matching factors, selection of controls, preparation of external quality control samples and reduction of batch effects along with proper sample allocation. Results and conclusion Our design is to reduce potential bias and retain study power while reducing the costs by limiting the numbers of samples requiring laboratory analyses. It also covers two primary end points (the occurrence of diabetes-related autoantibodies and the diagnosis of type 1 diabetes). The resulting list of case-control matched samples for each laboratory was augmented with external quality control samples. Copyright (C) 2013 John Wiley & Sons, Ltd. C1 [Lee, Hye-Seung; McLeod, Wendy; Smith, Susan; Eberhard, Chris; Lynch, Kristian; Hadley, David; Krischer, Jeffrey P.] Univ S Florida, Dept Pediat, Pediat Epidemiol Ctr, Tampa, FL 33620 USA. [Burkhardt, Brant R.] Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL 33620 USA. [Rewers, Marian] Univ Colorado Denver, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Simell, Olli] Turku Univ, Cent Hosp, Dept Pediat, Turku, Finland. [She, Jin-Xiong] Georgia Regents Univ, Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA USA. [Hagopian, Bill] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Lernmark, Ake] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Akolkar, Beena] NIDDK, Bethesda, MD USA. [Ziegler, Anette G.] Helmholtz Zentrum Munchen, Inst Diabet Res, Munich, Germany. [Ziegler, Anette G.] Tech Univ Munich, Klinikum Rechts Isar, D-80290 Munich, Germany. [Ziegler, Anette G.] Forschergrp Diabet eV Neuherberg, Neuherberg, Germany. RP Krischer, JP (reprint author), Univ S Florida, Dept Pediat, Pediat Epidemiol Ctr, Tampa, FL 33620 USA. EM Jeffrey.Krischer@epi.usf.edu RI Ziegler, Anette-Gabriele/M-4614-2014; Bonifacio, Ezio/E-7700-2010; OI Ziegler, Anette-Gabriele/0000-0002-6290-5548; Bonifacio, Ezio/0000-0002-8704-4713; Elding Larsson, Helena/0000-0003-3306-1742; Warncke, Katharina/0000-0003-1758-7656; Little, Randie/0000-0001-6450-8012 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, HHSN267200700014C]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Child Health and Human Development (NICHD); National Institute of Environmental Health Sciences (NIEHS); Juvenile Diabetes Research Foundation (JDRF); Centers for Disease Control and Prevention (CDC) FX Funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836 and UC4 DK95300 and contract no. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF) and Centers for Disease Control and Prevention (CDC). NR 25 TC 6 Z9 6 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1520-7560 J9 DIABETES-METAB RES JI Diabetes-Metab. Res. Rev. PD JUL PY 2014 VL 30 IS 5 BP 424 EP 434 DI 10.1002/dmrr.2510 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AL8VD UT WOS:000339416900009 PM 24339168 ER PT J AU Rais-Bahrami, S Turkbey, B Rastinehad, AR Walton-Diaz, A Hoang, AN Siddiqui, MM Stamatakis, L Truong, H Nix, JW Vourganti, S Grant, KB Merino, MJ Wood, BJ Choyke, PL Pinto, PA AF Rais-Bahrami, Soroush Tuerkbey, Baris Rastinehad, Ardeshir R. Walton-Diaz, Annerleim Hoang, Anthony N. Siddiqui, M. Minhaj Stamatakis, Lambros Truong, Hong Nix, Jeffrey W. Vourganti, Srinivas Grant, Kinzya B. Merino, Maria J. Wood, Bradford J. Choyke, Peter L. Pinto, Peter A. TI Natural history of small index lesions suspicious for prostate cancer on multiparametric MRI: recommendations for interval imaging follow-up SO DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY LA English DT Article ID TUMOR VOLUME; RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; SPECIMENS; PREDICT AB PURPOSE We aimed to determine the natural history of small index lesions identified on multiparametric-magnetic resonance imaging (MP-MRI) of the prostate by evaluating lesion-specific pathology and growth on serial MP-MRI. MATERIALS AND METHODS We performed a retrospective review of 153 patients who underwent a minimum of two MP-MRI sessions, on an institutional review board-approved protocol. Index lesion is defined as the lesion(s) with the highest cancer suspicion score based on initial MP-MRI of a patient, irrespective of size. Two study cohorts were identified: (1) patients with no index lesion or index lesion(s) <= 7 mm and (2) a subset with no index lesion or index lesion(s) <= 5 mm. Pathological analysis of the index lesions was performed following magnetic resonance/ultrasound fusion-guided biopsy. Growth rate of the lesions was calculated based on MP-MRI follow-up. RESULTS Patients with small index lesions measuring <= 7 mm (n=42) or a subset with lesions <= 5 mm (n=20) demonstrated either benign findings (86.2% and 87.5%, respectively) or low grade Gleason 6 prostate cancer (13.8% and 12.5%, respectively) on lesion-specific targeted biopsies. These lesions demonstrated no significant change in size (P = 0.93 and P = 0.36) over a mean imaging period of 2.31 +/- 1.56 years and 2.40 +/- 1.77 years for <= 7 mm and <= 5 mm index lesion thresholds, respectively. These findings held true on subset analyses of patients who had a minimum of two-year interval follow-up with MP-MRI. CONCLUSION Small index lesions of the prostate are pathologically benign lesions or occasionally low-grade cancers. Slow growth rate of these small index lesions on serial MP-MRI suggests a surveillance interval of at least two years without significant change. C1 [Rais-Bahrami, Soroush; Rastinehad, Ardeshir R.; Walton-Diaz, Annerleim; Hoang, Anthony N.; Siddiqui, M. Minhaj; Stamatakis, Lambros; Truong, Hong; Nix, Jeffrey W.; Vourganti, Srinivas; Pinto, Peter A.] NCI, NIH, Bethesda, MD 20892 USA. [Tuerkbey, Baris; Grant, Kinzya B.; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. RP Rais-Bahrami, S (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM bahrami@nih.gov OI Rais-Bahrami, Soroush/0000-0001-9466-9925 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research; Center for Interventional Oncology; NIH; Pfizer Inc; Leona M. and Harry B. Helmsley Charitable Trust; Howard Hughes Medical Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the Center for Interventional Oncology. NIH and Philips Healthcare have a cooperative research and development agreement. NIH and Philips share intellectual property in the field.; This research was also made possible through the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc, The Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at http://www.fnih. org/work/programs-development/medical-research-scholars-program. NR 22 TC 21 Z9 21 U1 0 U2 2 PU TURKISH SOC RADIOLOGY PI ANKARA PA HOSDERE CAD, GUZELKENT SOK, CANKAYA EVLERI, F-2, ANKARA, 06540, TURKEY SN 1305-3825 EI 1305-3612 J9 DIAGN INTERV RADIOL JI Diagn. Interv. Radiol. PD JUL PY 2014 VL 20 IS 4 BP 293 EP 298 DI 10.5152/dir.2014.13319 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AL2HH UT WOS:000338946100001 PM 24808435 ER PT J AU Blackstone, C AF Blackstone, Craig TI Huntington's disease: from disease mechanisms to therapies SO DRUG DISCOVERY TODAY LA English DT Editorial Material ID REPEAT; MICE; GENE C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Blackstone, C (reprint author), NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 14 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 EI 1878-5832 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD JUL PY 2014 VL 19 IS 7 BP 949 EP 950 DI 10.1016/j.drudis.2014.04.013 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AL5BO UT WOS:000339148700018 PM 24792720 ER PT J AU Elliott, KC Resnik, DB AF Elliott, Kevin C. Resnik, David B. TI Science, Policy, and the Transparency of Values SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID PRECAUTIONARY PRINCIPLE; COMMON-SENSE; TOXICOLOGY; INDUSTRY; SOCIETY; ETHICS; GIFTS AB Background: Opposing groups of scientists have recently engaged in a heated dispute over a preliminary European Commission (EC) report on its regulatory policy for endocrine-disrupting chemicals. In addition to the scientific issues at stake, a central question has been how scientists can maintain their objectivity when informing policy makers. Objectives: Drawing from current ethical, conceptual, and empirical studies of objectivity and conflicts of interest in scientific research, we propose guiding principles for communicating scientific findings in a manner that promotes objectivity, public trust, and policy relevance. Discussion: Both conceptual and empirical studies of scientific reasoning have shown that it is unrealistic to prevent policy-relevant scientific research from being influenced by value judgments. Conceptually, the current dispute over the EC report illustrates how scientists are forced to make value judgments about appropriate standards of evidence when informing public policy. Empirical studies provide further evidence that scientists are unavoidably influenced by a variety of potentially subconscious financial, social, political, and personal interests and values. Conclusions: When scientific evidence is inconclusive and major regulatory decisions are at stake, it is unrealistic to think that values can be excluded from scientific reasoning. Thus, efforts to suppress or hide interests or values may actually damage scientific objectivity and public trust, whereas a willingness to bring implicit interests and values into the open may be the best path to promoting good science and policy. C1 [Elliott, Kevin C.] Michigan State Univ, Dept Fisheries & Wildlife, Lyman Briggs Coll, E Lansing, MI 48825 USA. [Elliott, Kevin C.] Michigan State Univ, Dept Philosophy, E Lansing, MI 48825 USA. [Resnik, David B.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Elliott, KC (reprint author), Michigan State Univ, 35 East Holmes Hall,919 E Shaw Lane, E Lansing, MI 48825 USA. EM kce@msu.edu NR 35 TC 16 Z9 17 U1 2 U2 27 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2014 VL 122 IS 7 BP 647 EP 650 DI 10.1289/ehp.1408107 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AL2AK UT WOS:000338928000012 PM 24667564 ER PT J AU Vlaanderen, J Straif, K Ruder, A Blair, A Hansen, J Lynge, E Charbotel, B Loomis, D Kauppinen, T Kyyronen, P Pukkala, E Weiderpass, E Guha, N AF Vlaanderen, Jelle Straif, Kurt Ruder, Avima Blair, Aaron Hansen, Johnni Lynge, Elsebeth Charbotel, Barbara Loomis, Dana Kauppinen, Timo Kyyronen, Pentti Pukkala, Eero Weiderpass, Elisabete Guha, Neela TI Tetrachloroethylene Exposure and Bladder Cancer Risk: A Meta-Analysis of Dry-Cleaning-Worker Studies SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review ID UNITED-STATES; FOLLOW-UP; OCCUPATIONAL EXPOSURES; CHLORINATED SOLVENTS; NORDIC COUNTRIES; MORTALITY; TRICHLOROETHYLENE; CARCINOGENS; CLEANERS; MEN AB Background: In 2012, the International Agency for Research on Cancer classified tetrachloroethylene, used in the production of chemicals and the primary solvent used in dry cleaning, as "probably carcinogenic to humans" based on limited evidence of an increased risk of bladder cancer in dry cleaners. Objectives: We assessed the epidemiological evidence for the association between tetrachloroethylene exposure and bladder cancer from published studies estimating occupational exposure to tetrachloroethylene or in workers in the dry-cleaning industry. Methods: Random-effects meta-analyses were carried out separately for occupational exposure to tetrachloroethylene and employment as a dry cleaner. We qualitatively summarized exposure-response data because of the limited number of studies available. Results: The meta-relative risk (mRR) among tetrachloroethylene-exposed workers was 1.08 (95% CI: 0.82, 1.42; three studies; 463 exposed cases). For employment as a dry cleaner, the overall mRR was 1.47 (95% CI: 1.16, 1.85; seven studies; 139 exposed cases), and for smoking-adjusted studies, the mRR was 1.50 (95% CI: 0.80, 2.84; 4 case-control studies). Conclusions: Our meta-analysis demonstrates an increased risk of bladder cancer in dry cleaners, reported in both cohort and case-control studies, and some evidence for an exposure-response relationship. Although dry cleaners incur mixed exposures, tetrachloroethylene could be responsible for the excess risk of bladder cancer because it is the primary solvent used and it is the only chemical commonly used by dry cleaners that is currently identified as a potential bladder carcinogen. Relatively crude approaches in exposure assessment in the studies of "tetrachloroethylene-exposed workers" may have attenuated the relative risks. C1 [Vlaanderen, Jelle] Int Agcy Res Canc, Sect Environm & Radiat, F-69372 Lyon 08, France. [Straif, Kurt; Loomis, Dana; Guha, Neela] Int Agcy Res Canc, Sect IARC Monog, F-69372 Lyon 08, France. [Ruder, Avima] NIOSH, Ctr Dis Control & Prevent, Cincinnati, OH 45226 USA. [Blair, Aaron] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. [Hansen, Johnni] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Lynge, Elsebeth] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Charbotel, Barbara] Univ Lyon, Unite Mixte Rech, Epidemiol & Surveillance Transport Travail Enviro, Lyon, France. [Kauppinen, Timo] Finnish Inst Occupat Hlth, Helsinki, Finland. [Kyyronen, Pentti; Pukkala, Eero] Finnish Canc Registry, Inst Stat & Epidemiol Canc Res, FIN-00170 Helsinki, Finland. [Pukkala, Eero] Univ Tampere, Sch Hlth Sci, FIN-33101 Tampere, Finland. [Weiderpass, Elisabete] Canc Registry Norway, Oslo, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Arctic Univ Norway, Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Samfundet Folkhalsan, Folkhalsan Res Ctr, Helsinki, Finland. RP Guha, N (reprint author), Int Agcy Res Canc, Sect IARC Monog, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM Guhan@iarc.fr RI Weiderpass, Elisabete/M-4029-2016; OI Weiderpass, Elisabete/0000-0003-2237-0128; Lynge, Elsebeth/0000-0003-4785-5236 FU Nordic Cancer Union; International Agency for Research on Cancer (IARC); European commission FP7 Marie Curie Actions-People-Cofunding of regional, national, and international programmes (COFUND) FX This work was financially supported by the Nordic Cancer Union. Part of the work reported in this article was undertaken during the tenure of a postdoctoral fellowship (J.V.) from the International Agency for Research on Cancer (IARC), partially supported by the European commission FP7 Marie Curie Actions-People-Cofunding of regional, national, and international programmes (COFUND). NR 39 TC 10 Z9 10 U1 3 U2 19 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2014 VL 122 IS 7 BP 661 EP 666 DI 10.1289/ehp.1307055 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AL2AK UT WOS:000338928000014 PM 24659585 ER PT J AU Harlid, S Xu, ZL Panduri, V Sandler, DP Taylor, JA AF Harlid, Sophia Xu, Zongli Panduri, Vijayalakshmi Sandler, Dale P. Taylor, Jack A. TI CpG Sites Associated with Cigarette Smoking: Analysis of Epigenome-Wide Data from the Sister Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID DIFFERENTIAL DNA METHYLATION; ARYL-HYDROCARBON RECEPTOR; TOBACCO-SMOKE; CANCER; DISEASE; LUNG; LYMPHOBLASTS; EXPRESSION; PORPHYRIAS; BLOOD AB Background: Smoking increases the risk of many diseases, and it is also linked to blood DNA methylation changes that may be important in disease etiology. Objectives: We sought to identify novel CpG sites associated with cigarette smoking. Methods: We used two epigenome-wide data sets from the Sister Study to identify and confirm CpG sites associated with smoking. One included 908 women with methylation measurements at 27,578 CpG sites using the Human Methylation27BeadChip; the other included 200 women with methylation measurements for 473,844 CpG sites using the HumanMethylation450 BeadChip. Significant CpGs from the second data set that were not included in the 27K assay were validated by pyrosequencing in a subset of 476 samples from the first data set. Results: Our study successfully confirmed smoking associations for 9 previously established CpGs and identified 2 potentially novel CpGs: cg26764244 in GNG12 (p = 9.0 x 10(-10)) and cg22335340 in PTPN6 (p = 2.9 x 10(-05)). We also found strong evidence of an association between smoking status and cg02657160 in CPOX (p = 7.3 x 10(-7)), which has not been previously reported. All 12 CpGs were undermethylated in current smokers and showed an increasing percentage of methylation in former and never-smokers. Conclusions: We identified 2 potentially novel smoking related CpG sites, and provided independent replication of 10 previously reported CpGs sites related to smoking, one of which is situated in the gene CPOX. The corresponding enzyme is involved in heme biosynthesis, and smoking is known to increase heme production. Our study extends the evidence base for smoking-related changes in DNA methylation. C1 [Harlid, Sophia; Panduri, Vijayalakshmi; Taylor, Jack A.] NIEHS, Mol Carcinogenesis Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Xu, Zongli; Sandler, Dale P.; Taylor, Jack A.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Taylor, JA (reprint author), NIEHS, MD A3-05,Box 12233, Res Triangle Pk, NC 27709 USA. EM taylor@niehs.nih.gov OI Harlid, Sophia/0000-0001-8540-6891; xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the NIEHS; NIH [Z01 ES044005, Z01 ES044032, Z01 ES049033] FX This research was supported by the Intramural Research Program of the NIEHS, NIH (Z01 ES044005, Z01 ES044032, and Z01 ES049033). NR 42 TC 34 Z9 34 U1 3 U2 10 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2014 VL 122 IS 7 BP 673 EP 678 DI 10.1289/ehp.1307480 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AL2AK UT WOS:000338928000016 PM 24704585 ER PT J AU Rooney, AA Boyles, AL Wolfe, MS Bucher, JR Thayer, KA AF Rooney, Andrew A. Boyles, Abee L. Wolfe, Mary S. Bucher, John R. Thayer, Kristina A. TI Systematic Review and Evidence Integration for Literature-Based Environmental Health Science Assessments SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID NATIONAL TOXICOLOGY PROGRAM; PUBLICATION BIAS; HUMAN-REPRODUCTION; GUIDELINES; QUALITY; CAUSATION; SERIES; RISKS AB Background: Systematic-review methodologies provide objectivity and transparency to the process of collecting and synthesizing scientific evidence in reaching conclusions on specific research questions. There is increasing interest in applying these procedures to address environmental health questions. Objectives: The goal was to develop a systematic-review framework to address environmental health questions by extending approaches developed for clinical medicine to handle the breadth of data relevant to environmental health sciences (e.g., human, animal, and mechanistic studies). Methods: The Office of Health Assessment and Translation (OHAT) adapted guidance from authorities on systematic-review and sought advice during development of the OHAT Approach through consultation with technical experts in systematic review and human health assessments, as well as scientific advisory groups and the public. The method was refined by considering expert and public comments and through application to case studies. Results and Discussion: Here we present a seven-step framework for systematic review and evidence integration for reaching hazard identification conclusions: 1) problem formulation and protocol development, 2) search for and select studies for inclusion, 3) extract data from studies, 4) assess the quality or risk of bias of individual studies, 5) rate the confidence in the body of evidence, 6) translate the confidence ratings into levels of evidence, and 7) integrate the information from different evidence streams (human, animal, and "other relevant data" including mechanistic or in vitro studies) to develop hazard identification conclusions. Conclusion: The principles of systematic review can be successfully applied to environmental health questions to provide greater objectivity and transparency to the process of developing conclusions. C1 [Rooney, Andrew A.; Boyles, Abee L.; Wolfe, Mary S.; Bucher, John R.; Thayer, Kristina A.] NIEHS, Off Hlth Assessment & Translat, Div Natl Toxicol Program, NIH,US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Rooney, AA (reprint author), NIEHS, POB 12233,Mail Drop K2-04, Res Triangle Pk, NC 27709 USA. EM andrew.rooney@nih.gov OI Boyles, Abee/0000-0002-8711-2077 NR 48 TC 56 Z9 59 U1 7 U2 23 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2014 VL 122 IS 7 BP 711 EP 718 DI 10.1289/ehp.1307972 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AL2AK UT WOS:000338928000021 PM 24755067 ER PT J AU Engel, LS Buckley, JP Yang, G Liao, LM Satagopan, J Calafat, AM Matthews, CE Cai, QY Ji, BT Cai, H Engel, SM Wolff, MS Rothman, N Zheng, W Xiang, YB Shu, XO Gao, YT Chow, WH AF Engel, Lawrence S. Buckley, Jessie P. Yang, Gong Liao, Linda M. Satagopan, Jaya Calafat, Antonia M. Matthews, Charles E. Cai, Qiuyin Ji, Bu-Tian Cai, Hui Engel, Stephanie M. Wolff, Mary S. Rothman, Nathaniel Zheng, Wei Xiang, Yong-Bing Shu, Xiao-Ou Gao, Yu-Tang Chow, Wong-Ho TI Predictors and Variability of Repeat Measurements of Urinary Phenols and Parabens in a Cohort of Shanghai Women and Men SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID BISPHENOL-A CONCENTRATIONS; TANDEM MASS-SPECTROMETRY; TEMPORAL VARIABILITY; CHINESE ADULTS; PREGNANCY; EXPOSURE; QUANTIFICATION; POPULATION; TRICLOSAN; CHILDREN AB Background: Exposure to certain phenols is ubiquitous because of their use in many consumer and personal care products. However, predictors of exposure have not been well characterized in most populations. Objectives: We sought to identify predictors of exposure and to assess the reproducibility of phenol concentrations across serial spot urine samples among Chinese adults. Methods: We measured 2,4-dichlorophenol, 2,5-dichlorophenol, butyl paraben, methyl paraben, propyl paraben, benzophenone-3, bisphenol A, and triclosan in urine collected during 1997-2006 from 50 participants of the Shanghai Women's Health Study cohort and during 2002-2006 from 50 participants of the Shanghai Men's Health Study cohort. We investigated predictors of concentrations using the Satterthwaite t-test, and assessed reproducibility among serial samples using intraclass correlation coefficients (ICCs) and Spearman correlation coefficients (SCCs). Results: Creatinine-corrected phenol concentrations were generally higher among women than men. Participants who had taken medicine within the previous 24 hr had higher concentrations of propyl paraben. Cigarette smoking was associated with lower concentrations of propyl and methyl parabens among men. Bottled water consumption was associated with higher bisphenol A, 2,4-dichlorophenol, and 2,5-dichlorophenol concentrations among women. Among men, reproducibility across serial samples was moderate for 2,4-dichlorophenol and 2,5-dichlorophenol (ICC = 0.54-0.60, SCC = 0.43-0.56), but lower for other analytes (ICC = 0.20-0.29). Reproducibility among women was low (ICC = 0.13-0.39), but increased when restricted to morning-only urine samples. Conclusions: Among these 100 Shanghai residents, urinary phenol concentrations varied by sex, smoking, and consumption of bottled water. Our results suggest that a single urine sample may be adequate for ranking exposure to the precursors of 2,4-dichlorophenol and 2,5-dichlorophenol among men and, under certain circumstances, among women. C1 [Engel, Lawrence S.; Buckley, Jessie P.; Engel, Stephanie M.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Yang, Gong; Cai, Qiuyin; Cai, Hui; Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. [Liao, Linda M.; Matthews, Charles E.; Ji, Bu-Tian; Rothman, Nathaniel; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Satagopan, Jaya] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Calafat, Antonia M.] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA USA. [Wolff, Mary S.] Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. [Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Canc Inst, Shanghai Canc Registry, Shanghai, Peoples R China. RP Engel, LS (reprint author), Univ N Carolina, Dept Epidemiol, CB 7435, Chapel Hill, NC 27599 USA. EM Larry.Engel@unc.edu RI matthews, Charles/E-8073-2015; OI matthews, Charles/0000-0001-8037-3103; Satagopan, Jaya/0000-0001-7102-5633; Liao, Linda/0000-0002-1923-5294; Engel, Lawrence/0000-0001-9268-4830 FU Vanderbilt-Ingram Cancer Center [P30 CA068485] FX The urine sample preparation was performed at Survey and Biospecimen Shared Resource, which is partially supported by the Vanderbilt-Ingram Cancer Center (P30 CA068485). NR 27 TC 17 Z9 19 U1 1 U2 28 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2014 VL 122 IS 7 BP 733 EP 740 DI 10.1289/ehp.1306830 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AL2AK UT WOS:000338928000024 PM 24659570 ER PT J AU Thayer, KA Wolfe, MS Rooney, AA Boyles, AL Bucher, JR Birnbaum, LS AF Thayer, Kristina A. Wolfe, Mary S. Rooney, Andrew A. Boyles, Abee L. Bucher, John R. Birnbaum, Linda S. TI Intersection of Systematic Review Methodology with the NIH Reproducibility Initiative SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material ID GUIDELINES; STATEMENT C1 [Thayer, Kristina A.; Wolfe, Mary S.; Rooney, Andrew A.; Boyles, Abee L.; Bucher, John R.] NIEHS, Div Natl Toxicol Program, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIEHS, Off Director, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Thayer, KA (reprint author), NIEHS, Div Natl Toxicol Program, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM thayer@niehs.nih.gov OI Boyles, Abee/0000-0002-8711-2077 NR 19 TC 10 Z9 11 U1 0 U2 6 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2014 VL 122 IS 7 BP A176 EP A177 DI 10.1289/ehp.1408671 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AL2AK UT WOS:000338928000001 PM 24984224 ER PT J AU Whitworth, K Bornman, RMS Archer, JI Kudumu, MO Travlos, GS Wilson, RE Longnecker, MP AF Whitworth, Kristina Bornman, Riana M. S. Archer, Janet I. Kudumu, Mwenda O. Travlos, Gregory S. Wilson, Ralph E. Longnecker, Matthew P. TI Predictors of Plasma DDT and DDE Concentrations among Women Exposed to Indoor Residual Spraying for Malaria Control in the South African Study of Women and Babies (SOWB) (vol 122, pg 545, 2014) SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Correction C1 [Whitworth, Kristina] Univ Texas San Antonio, Sch Publ Hlth, San Antonio, TX 78249 USA. [Bornman, Riana M. S.] Univ Pretoria, Dept Urol, Pretoria, South Africa. [Bornman, Riana M. S.] Univ Pretoria, Univ Pretoria Ctr Sustainable Malaria Control, Pretoria, South Africa. [Archer, Janet I.; Kudumu, Mwenda O.] Social & Sci Syst Inc, Durham, NC USA. [Travlos, Gregory S.; Wilson, Ralph E.] NIEHS, Cellular & Mol Pathol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Whitworth, K (reprint author), Univ Texas San Antonio, Sch Publ Hlth, San Antonio Reg Campus, San Antonio, TX 78249 USA. NR 1 TC 0 Z9 0 U1 1 U2 9 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2014 VL 122 IS 7 BP A180 EP A180 DI 10.1289/ehp.122-A180 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AL2AK UT WOS:000338928000004 ER PT J AU Whitworth, KW Bornman, RMS Archer, JI Kudumu, MO Travlos, GS Wilson, RE Longnecker, MP AF Whitworth, Kristina W. Bornman, Riana M. S. Archer, Janet I. Kudumu, Mwenda O. Travlos, Gregory S. Wilson, Ralph E. Longnecker, Matthew P. TI Predictors of Plasma DDT and DDE Concentrations among Women Exposed to Indoor Residual Spraying for Malaria Control in the South African Study of Women and Babies (SOWB) SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Correction C1 [Whitworth, Kristina W.] Univ Texas San Antonio, Sch Publ Hlth, San Antonio, TX 78249 USA. [Bornman, Riana M. S.] Univ Pretoria, Dept Urol, Pretoria, South Africa. [Bornman, Riana M. S.] Univ Pretoria, Univ Pretoria Ctr Sustainable Malaria Control, Pretoria, South Africa. [Archer, Janet I.; Kudumu, Mwenda O.] Social & Sci Syst Inc, Durham, NC USA. [Travlos, Gregory S.; Wilson, Ralph E.] NIEHS, Cellular & Mol Pathol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Whitworth, KW (reprint author), Univ Texas San Antonio, Sch Publ Hlth, San Antonio Reg Campus, San Antonio, TX 78249 USA. NR 1 TC 0 Z9 0 U1 0 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2014 VL 122 IS 7 BP A180 EP A180 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AL2AK UT WOS:000338928000005 ER PT J AU Soeiro-De-Souza, MG Teixeira, AL Mateo, EC Zanetti, MV Rodrigues, FG de Paula, VJ Bezerra, JF Moreno, RA Gattaz, WF Machado-Vieira, R AF Soeiro-de-Souza, Marcio Gerhardt Teixeira, Antonio L. Mateo, Elvis C. Zanetti, Marcus V. Rodrigues, Flavia G. de Paula, Vanessa J. Bezerra, Julia F. Moreno, Ricardo A. Gattaz, Wagner F. Machado-Vieira, Rodrigo TI Leukocyte telomerase activity and antidepressant efficacy in bipolar disorder SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Bipolar disorder; Telomerase; Lithium; Treatment; Depression; Epigenetics ID OXIDATIVE STRESS; LIFE STRESS; DEPRESSION; LENGTH; DISEASE; DYNAMICS; LITHIUM; MOOD AB Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. Recently, shorten telomeres length has been reported in bipolar disorder (BD) and depression. The enzyme telomerase regulates telomerase length, which has been associated with cellular viability; however it is not clear how telomerase may be involved in the pathophysiology and therapeutics of BD. In the present study, leukocyte telomerase activity was assessed in 28 medication-free BD depressed individuals (DSM-IV-TR criteria) at baseline and after 6 weeks of lithium therapy (n=21) also matching with 23 healthy controls. There was no difference between telomerase activity in subjects with BD depression (before or after lithium) and controls. Improvement of depressive symptoms was negatively associated with telomerase. activity after 6 weeks of lithium therapy. This is the first study describing telomerase activity in BD research. Overall, telomerase activity seems not directly involved in the pathophysiology of short-term BD. Lithium's antidepressant effects may involve regulation at telomerase activity. Further studies with larger samples and long-term illness are also warranted. Published by Elsevier B.V. C1 [Soeiro-de-Souza, Marcio Gerhardt; Moreno, Ricardo A.] Univ Sao Paulo, Inst & Dept Psychiat, Mood Disorders Program GRUDA, BR-05508 Sao Paulo, Brazil. [Teixeira, Antonio L.; Mateo, Elvis C.; Rodrigues, Flavia G.] Univ Fed Minas Gerais, IBC, Lab Immunopharmacol, Belo Horizonte, MG, Brazil. [Zanetti, Marcus V.; de Paula, Vanessa J.; Bezerra, Julia F.; Gattaz, Wagner F.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Inst & Dept Psychiat, LIM 27, Neurosci Lab, BR-05508 Sao Paulo, Brazil. [Zanetti, Marcus V.; Gattaz, Wagner F.; Machado-Vieira, Rodrigo] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci, BR-05508 Sao Paulo, Brazil. [Machado-Vieira, Rodrigo] NIMH, ETPB, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Machado-Vieira, Rodrigo] Dept Hlth & Human Serv, Bethesda, MD USA. RP Machado-Vieira, R (reprint author), Univ Sao Paulo, Inst & Dept Psychiat, LIM 27, Neurosci Lab, BR-05508 Sao Paulo, Brazil. EM machadovieirar@gmail.com RI De-Paula, Vanessa/J-4499-2014; Gattaz, Wagner/C-4456-2012; Soeiro-de-Souza, Marcio/J-9430-2012; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI De-Paula, Vanessa/0000-0002-2054-6356; Soeiro-de-Souza, Marcio/0000-0002-9293-3128; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Sao Paulo Research Foundation (Fapesp, Brazil) [2009-14891]; Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS) FX This study was sponsored by Sao Paulo Research Foundation (Fapesp, Brazil, Grant 2009-14891). The Laboratory of Neuroscience (LIM27) is supported by the Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS). NR 34 TC 4 Z9 4 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD JUL PY 2014 VL 24 IS 7 BP 1139 EP 1143 DI 10.1016/j.euroneuro.2014.03.005 PG 5 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AL5AJ UT WOS:000339145600015 PM 24731723 ER PT J AU Brunoni, AR Machado-Vieira, R Zarate, CA Vieira, ELM Vanderhasselt, MA Nitsche, MA Valiengo, L Bensenor, IM Lotufo, PA Gattaz, WF Teixeira, AL AF Brunoni, Andre R. Machado-Vieira, Rodrigo Zarate, Carlos A., Jr. Vieira, Erica L. M. Vanderhasselt, Marie-Anne Nitsche, Michael A. Valiengo, Leandro Bensenor, Isabela M. Lotufo, Paulo A. Gattaz, Wagner F. Teixeira, Antonio L. TI BDNF plasma levels after antidepressant treatment with sertraline and transcranial direct current stimulation: Results from a factorial, randomized, sham-controlled trial SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Brain-derived neurotrophic factor; Transcranial direct current stimulation; Major depressive disorder; Sertraline; Non-invasive brain stimulation; Neuroplasticity ID NEUROTROPHIC FACTOR BDNF; RESISTANT DEPRESSED-PATIENTS; HUMAN MOTOR CORTEX; ELECTROCONVULSIVE-THERAPY ECT; ELECTRICAL-CURRENT THERAPY; MAJOR DEPRESSION; MAGNETIC STIMULATION; BRAIN-STIMULATION; TDCS; NEUROPLASTICITY AB Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention that modifies cortical excitability according to the stimulation parameters. Preclinical and clinical studies in healthy volunteers suggest that tDCS induces neuroplastic alterations of cortical excitability, which might explain its clinical effects in major depressive disorder (MDD). We therefore examined whether tDCS, as compared to the antidepressant sertraline, increases plasma brain-derived neurotrophic factor (BDNF) levels, a neurotrophin associated with neuroplasticity. Patients (n=73) with major depressive disorder were randomized to active/ sham tDCS and sertraline/placebo (four groups) in this 6-week, double-blind, placebocontrolled trial. We measured BDNF plasma levels at baseline and endpoint, observing no significant changes of BDNF levels after treatment. In addition, no significant changes were observed in responders and non-responders as well as no relationships between BDNF levels and clinical and psychopathological variables related to depression. Thus, in one of the few placebo-controlled trials evaluating BDNF changes over an antidepressant treatment course, we did not observe BDNF increase regardless of clinical improvement in depressed patients. Regarding tDCS, BDNF plasma levels might not be a good candidate biomarker to evaluate depression improvement or be a predictor of response in patients treated with tDCS, as our results showed that BDNF increase was not necessary to induce clinical response. Finally, our findings do not support a relationship between BDNF and improvement of depression. (C) 2014 Elsevier B.V. and ECNP. All rights reserved. C1 [Brunoni, Andre R.; Valiengo, Leandro; Bensenor, Isabela M.; Lotufo, Paulo A.] Univ Sao Paulo, Univ Hosp, Ctr Clin & Epidemiol Res, BR-05508000 Sao Paulo, Brazil. [Brunoni, Andre R.; Valiengo, Leandro; Bensenor, Isabela M.; Lotufo, Paulo A.] Univ Sao Paulo, Univ Hosp, Interdisciplinary Ctr Appl Neuromodulat CINA, BR-05508000 Sao Paulo, Brazil. [Brunoni, Andre R.; Valiengo, Leandro] Univ Sao Paulo, Fac Med, Dept & Inst Psychiat, SIN, BR-05508000 Sao Paulo, Brazil. [Brunoni, Andre R.; Machado-Vieira, Rodrigo; Valiengo, Leandro; Gattaz, Wagner F.] Univ Sao Paulo, Dept & Inst Psychiat, Lab Neurosci LIM27, BR-05508000 Sao Paulo, Brazil. [Machado-Vieira, Rodrigo; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD USA. [Vieira, Erica L. M.; Teixeira, Antonio L.] Fac Med Minas Gerais, Interdisciplinary Lab Med Invest, Belo Horizonte, MG, Brazil. [Vanderhasselt, Marie-Anne] Univ Ghent, Dept Expt Clin & Hlth Psychol, B-9000 Ghent, Belgium. [Nitsche, Michael A.] Univ Gottingen, Dept Clin Neurophysiol, Gottingen, Germany. RP Brunoni, AR (reprint author), Univ Sao Paulo, Univ Hosp, Ctr Clin & Epidemiol Res, Av Prof Lineu Prestes 2565,3o Andar, BR-05508000 Sao Paulo, Brazil. EM brunoni@usp.br RI Gattaz, Wagner/C-4456-2012; Brunoni, Andre/H-8394-2012; Vieira, Erica/A-1976-2013; MACHADO-VIEIRA, RODRIGO/D-8293-2012; Lotufo, Paulo/A-9843-2008 OI Brunoni, Andre/0000-0002-6310-3571; Vieira, Erica/0000-0002-4147-5614; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Lotufo, Paulo/0000-0002-4856-8450 FU FAPESP (Sao Paulo Research Foundation) [2009/05728-7]; FAPEMIG; CNPq FX This study was partially funded by FAPESP (Sao Paulo Research Foundation, Grant number: 2009/05728-7), FAPEMIG and CNPq. The sponsors played 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. NR 48 TC 16 Z9 16 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD JUL PY 2014 VL 24 IS 7 BP 1144 EP 1151 DI 10.1016/j.euroneuro.2014.03.006 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AL5AJ UT WOS:000339145600016 PM 24702987 ER PT J AU Bolnick, JM Kilburn, BA Bajpayee, S Reddy, N Jeelani, R Crone, B Simmerman, N Singh, M Diamond, MP Armant, DR AF Bolnick, Jay M. Kilburn, Brian A. Bajpayee, Swati Reddy, Nitya Jeelani, Roohi Crone, Barbara Simmerman, Neil Singh, Manivinder Diamond, Michael P. Armant, D. Randall TI Trophoblast retrieval and isolation from the cervix (TRIC) for noninvasive prenatal screening at 5 to 20 weeks of gestation SO FERTILITY AND STERILITY LA English DT Article DE Endocervical canal; fetal gender; prenatal testing; single-cell analysis; trophoblast ID PREIMPLANTATION GENETIC DIAGNOSIS; POLYMERASE-CHAIN-REACTION; FETAL CELLS; TRANSCERVICAL SAMPLES; HLA-G; IMMUNOHISTOCHEMICAL LOCALIZATION; HUMAN-PREGNANCY; 1ST TRIMESTER; GROWTH-FACTOR; CYTOTROPHOBLASTS AB Objective: To use trophoblast cells accumulating in the endocervical canal at the beginning of pregnancy for noninvasive prenatal testing. Design: Prospective, double-blinded test for fetal gender. Setting: Academic medical center. Patient(s): Fifty-six women with singleton pregnancies at gestational age 5-20 weeks. Intervention(s): Isolation of fetal cells from resident maternal cells in endocervical specimens using anti-human leukocyte antigen G coupled to magnetic nanoparticles; cell phenotyping immunofluorescently with a panel of trophoblast subtype-specific proteins; DNA integrity assessment with terminal dUTP nick-end labeling (TUNEL); and polymerase chain reaction (PCR) and fluorescent in situ hybridization (FISH) to detect sex chromosomes in individual cells. Main Outcome Measure(s): Trophoblast phenotype, TUNEL index, and percentage male cells. Result(s): The women were given a routine Papanicolaou test; fetal genders were verified from medical records. Recovery after immunomagnetic isolation averaged 746 +/- 59 cells across gestational age, with 99% expressing chorionic gonadotropin, whereas the depleted cell fraction expressed none. The isolated cells had an extravillous trophoblast phenotype and intact nuclear DNA (> 95%). Fetal gender was determined in 20 specimens without error by PCR. The FISH analysis of isolated cells from male specimens validated their fetal origin. Conclusion(s): Noninvasive prenatal testing is feasible beginning at a gestational age of 5 weeks. (C) 2014 by American Society for Reproductive Medicine. C1 [Bolnick, Jay M.; Kilburn, Brian A.; Bajpayee, Swati; Reddy, Nitya; Jeelani, Roohi; Crone, Barbara; Simmerman, Neil; Singh, Manivinder; Armant, D. Randall] Wayne State Univ, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Diamond, Michael P.] Georgia Regents Univ, Dept Obstet & Gynecol, Augusta, GA USA. [Armant, D. Randall] Wayne State Univ, CS Mott Ctr Human Growth & Dev, Detroit, MI 48201 USA. [Armant, D. Randall] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Armant, DR (reprint author), Wayne State Univ, Mott Ctr Human Growth Dev, 275 East Hancock St, Detroit, MI 48201 USA. EM d.armant@wayne.edu OI Diamond, Michael/0000-0001-6353-4489; Armant, D. Randall/0000-0001-5904-9325 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH [HD071408]; W.K. Kellogg Foundation FX Supported in part by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH Grant HD071408 and the W.K. Kellogg Foundation. NR 45 TC 5 Z9 5 U1 4 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD JUL PY 2014 VL 102 IS 1 BP 135 EP + AR 142.e1 DI 10.1016/j.fertnstert.2014.04.008 PG 14 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AL2CA UT WOS:000338932300029 PM 24825422 ER PT J AU Levy, G Malik, M Britten, J Gilden, M Segars, J Catherino, WH AF Levy, Gary Malik, Minnie Britten, Joy Gilden, Melissa Segars, James Catherino, William H. TI Liarozole inhibits transforming growth factor-beta 3-mediated extracellular matrix formation in human three-dimensional leiomyoma cultures SO FERTILITY AND STERILITY LA English DT Article DE Extracellular matrix; liarozole; leiomyoma; three-dimensional model; transforming growth factor-beta ID TRANS-RETINOIC ACID; SMOOTH-MUSCLE CELLS; TGF-BETA; UTERINE LEIOMYOMAS; ORAL LIAROZOLE; GENE-EXPRESSION; CANCER CELLS; DOUBLE-BLIND; IN-VITRO; MYOMETRIUM AB Objective: To investigate the impact of liarozole on transforming growth factor-beta 3 (TGF-beta 3) expression, TGF-beta 3 controlled profibrotic cytokines, and extracellular matrix formation in a three-dimensional (3D) leiomyoma model system. Design: Molecular and immunohistochemical analysis in a cell line evaluated in a three-dimensional culture. Setting: Laboratory study. Patient(s): None. Intervention(s): Treatment of leiomyoma and myometrial cells with liarozole and TGF-beta 3 in a three-dimensional culture system. Main Outcome Measure(s): Quantitative real-time reverse-transcriptase polymerase chain reaction and Western blotting to assess fold gene and protein expression of TGF-beta 3 and TGF-beta 3 regulated fibrotic cytokines: collagen 1A1 (COL1A1), fibronectin, and versican before and after treatment with liarozole, and confirmatory immunohistochemical stains of treated three-dimensional cultures. Result(s): Both TGF-beta 3 gene and protein expression were elevated in leiomyoma cells compared with myometrium in two-dimensional and 3D cultures. Treatment with liarozole decreased TGF-beta 3 gene and protein expression. Extracellular matrix components versican, COL1A1, and fibronectin were also decreased by liarozole treatment in 3D cultures. Treatment of 3D cultures with TGF-beta 3 increased gene expression and protein production of COL1A1, fibronectin, and versican. Conclusion(s): Liarozole decreased TGF-beta 3 and TGF-beta 3-mediated extracellular matrix expression in a 3D uterine leiomyoma culture system. (C)2014 by American Society for Reproductive Medicine. C1 [Levy, Gary; Segars, James; Catherino, William H.] NICHHD, Program Reprod & Adult Endocrinol Eunice Kennedy, NIH, Bethesda, MD 20892 USA. [Levy, Gary; Malik, Minnie; Britten, Joy; Gilden, Melissa; Segars, James; Catherino, William H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. RP Catherino, WH (reprint author), Uniformed Serv Univ Hlth Sci, Bldg A,Room 3078,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM william.catherino@usuhs.edu FU Intramural NIH HHS [ZIE HD008737-12] NR 46 TC 5 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD JUL PY 2014 VL 102 IS 1 BP 272 EP + AR 281.e1 DI 10.1016/j.fertnstert.2014.03.042 PG 12 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AL2CA UT WOS:000338932300047 PM 24825427 ER PT J AU Gorodetsky, E Bevilacqua, L Carli, V Sarchiapone, M Roy, A Goldman, D Enoch, MA AF Gorodetsky, E. Bevilacqua, L. Carli, V. Sarchiapone, M. Roy, A. Goldman, D. Enoch, M. -A. TI The interactive effect of MAOA-LPR genotype and childhood physical neglect on aggressive behaviors in Italian male prisoners SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Aggressive behavior; BGHA; childhood trauma; CTQ; interactive effect; MAOA-LPR genotype; MAOA-LPR high-activity variant; MAOA-LPR low-activity variant; physical neglect; prisoners ID MONOAMINE-OXIDASE-A; EARLY-LIFE STRESS; SUICIDAL-BEHAVIOR; GENE PROMOTER; DSM-IV; FUNCTIONAL POLYMORPHISM; PERSONALITY-DISORDERS; TRAIT AGGRESSION; TRAUMA; RISK AB Aggressive disorders are moderately heritable; therefore, identification of genetic influences is important. The X-linked MAOA gene, encoding the MAOA enzyme, has a functional 30 bp repeat polymorphism in the promoter region (MAOA-LPR) that has been shown to influence aggression. Childhood trauma is a known risk factor for numerous psychopathologies in adulthood including aggressive behaviors. We investigated the interactive effect of MAOA-LPR genotype and a history of childhood trauma in predicting aggressive behaviors in a prisoner population. A total of 692 male prisoners were genotyped for MAOA-LPR with genotypes grouped into high and low transcriptional activity. Participant evaluations included measures of aggression (Brown-Goodwin Lifetime History of Aggression, BGHA), hostility (Buss-Durkee Hostility Inventory), impulsivity (Barratt Impulsiveness Scale), violence directed toward self and others, and childhood trauma [Childhood Trauma Questionnaire (CTQ)]. MAOA-LPR interacted with CTQ physical neglect (PN), the most common (47%) form of childhood trauma in this sample, to predict BGHA aggression (P = 0.002). Within the group not exposed to PN, carriers of the MAOA-LPR high-activity variant were more aggressive: (t(R) = 2.47, P < 0.014). We observed a crossover effect in that the increase in aggression scores with PN was greater in low-activity individuals (t(R) = 5.55, P < 0.0001) than in high-activity individuals (t(R) = 4.18, P < 0.0001). These findings suggest that childhood trauma and the functional MAOA-LPR polymorphism may interact to specifically increase risk for over aggressive behavior but not impulsivity or hostility. The MAOA-LPR low-activity variant may be protective against the development of aggressive behavior under low stress conditions, at least in this prisoner population. C1 [Gorodetsky, E.; Bevilacqua, L.; Goldman, D.; Enoch, M. -A.] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Bevilacqua, L.] NYU, Sch Med, Dept Psychiat, New York, NY USA. [Carli, V.; Sarchiapone, M.] Univ Molise, Dept Hlth Sci, Campobasso, Italy. [Carli, V.] Karolinska Inst, Natl Prevent Suicide & Mental Hlth NASP 3, Stockholm, Sweden. [Roy, A.] Vet Affairs Med Ctr, Psychiat Serv, E Orange, NJ USA. RP Gorodetsky, E (reprint author), NIAAA, LNG, NIH, 5625 Fishers Lane,Room 3S-32, Rockville, MD 20852 USA. EM egorod@mail.nih.gov RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Sarchiapone, Marco/0000-0001-9583-3117 FU National Institute on Alcohol Abuse and Alcoholism, NIH; National Institute of Drug Abuse, NIH [R01 DA 10336-02]; Pfizer; Lundbeck FX We wish to thank Dr. Bruna Brunetti for support in the organization of the study, the Societa' Italiana di Medicina e Sanita' Penitenziaria (SIMSPE), the Penitientiary Institutions and the Provveditorato dell'Amministrazione Penitenziaria dell'Abruzzo e Molise (PRAP-Abruzzo-Molise). This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH and in part by grant R01 DA 10336-02 to A.R. from the National Institute of Drug Abuse, NIH. Dr. Sarchiapone has received financial support from Pfizer and Lundbeck. The authors declare no conflict of interest. NR 54 TC 8 Z9 10 U1 3 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JUL PY 2014 VL 13 IS 6 BP 543 EP 549 DI 10.1111/gbb.12140 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AL8JN UT WOS:000339384600004 PM 24805005 ER PT J AU Katzmarzyk, PT Barlow, S Bouchard, C Catalano, PM Hsia, DS Inge, TH Lovelady, C Raynor, H Redman, LM Staiano, AE Spruijt-Metz, D Symonds, ME Vickers, M Wilfley, D Yanovski, JA AF Katzmarzyk, P. T. Barlow, S. Bouchard, C. Catalano, P. M. Hsia, D. S. Inge, T. H. Lovelady, C. Raynor, H. Redman, L. M. Staiano, A. E. Spruijt-Metz, D. Symonds, M. E. Vickers, M. Wilfley, D. Yanovski, J. A. TI An evolving scientific basis for the prevention and treatment of pediatric obesity SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Review DE prevention; treatment; children; adolescents; overweight; therapy ID RANDOMIZED CONTROLLED-TRIAL; BODY-MASS INDEX; POLYCYSTIC-OVARY-SYNDROME; PLACEBO-CONTROLLED TRIAL; PRADER-WILLI-SYNDROME; BROWN ADIPOSE-TISSUE; ACTIVE VIDEO GAMES; CONTROLLED CLINICAL-TRIAL; GROWTH-HORMONE TREATMENT; GESTATIONAL WEIGHT-GAIN AB The 2013 Pennington Biomedical Research Center's Scientific Symposium focused on the treatment and management of pediatric obesity and was designed to (i) review recent scientific advances in the prevention, clinical treatment and management of pediatric obesity, (ii) integrate the latest published and unpublished findings and (iii) explore how these advances can be integrated into clinical and public health approaches. The symposium provided an overview of important new advances in the field, which led to several recommendations for incorporating the scientific evidence into practice. The science presented covered a range of topics related to pediatric obesity, including the role of genetic differences, epigenetic events influenced by in utero development, pre-pregnancy maternal obesity status, maternal nutrition and maternal weight gain on developmental programming of adiposity in offspring. Finally, the relative merits of a range of various behavioral approaches targeted at pediatric obesity were covered, together with the specific roles of pharmacotherapy and bariatric surgery in pediatric populations. In summary, pediatric obesity is a very challenging problem that is unprecedented in evolutionary terms; one which has the capacity to negate many of the health benefits that have contributed to the increased longevity observed in the developed world. C1 [Katzmarzyk, P. T.; Bouchard, C.; Hsia, D. S.; Redman, L. M.; Staiano, A. E.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Barlow, S.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Catalano, P. M.] Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Inge, T. H.] Cincinnati Childrens Hosp Med Ctr, Div Pediat Surg, Cincinnati, OH 45229 USA. [Lovelady, C.] Univ N Carolina, Greensboro, NC 27412 USA. [Raynor, H.] Univ Tennessee, Knoxville, TN USA. [Spruijt-Metz, D.] Univ So Calif, Ctr Econ & Social Res, Los Angeles, CA USA. [Symonds, M. E.] Univ Nottingham, Univ Hosp, Sch Clin Med, Acad Child Hlth, Nottingham NG7 2RD, England. [Vickers, M.] Univ Auckland, Liggins Inst, Auckland 1, New Zealand. [Wilfley, D.] Washington Univ, Dept Psychiat, St Louis, MO USA. [Yanovski, J. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Katzmarzyk, PT (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM Peter.Katzmarzyk@pbrc.edu RI Bouchard, Claude/A-7637-2009; OI Katzmarzyk, Peter/0000-0002-9280-6022; Staiano, Amanda/0000-0001-7846-046X; Symonds, Michael/0000-0001-9649-8963 FU Systems Approach to Obesity Prevention in Underserved Children in Texas, Centers for Disease Control and Prevention [1U18 DP00336l7-01]; NIH/NIDDK Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) [5U01DK 061718]; John W Barton, Sr. Endowed Chair in Genetics and Nutrition; NICHD [HD22965-19]; Clinical Research Unit from NCATS at Case Western Reserve University [CTSCUL1TR000439]; National Institute of Diabetes and Digestive and Kidney Diseases [UM1DK072493]; Marie Edana Corcoran Endowed Chair in Pediatric Obesity and Diabetes; National Center for Research Resources; Office of Science Education of the National Institutes of Health [R25 RR011113]; Weight Watchers, International; National Institutes of Health [U01DK094418, R01099175, R00HD0607662]; National Institute of General Medical Sciences of the National Institutes of Health [1 U54 GM104940]; Gravida: National Centre for Growth and Developmen; Marsden Fund of the Royal Society of New Zealand; Scott Rudolph University Endowed Professor in Psychiatry, Medicine, Pediatrics and Psychology; NIH [K24MH070446-09, R01HD03690401A1, T32HL007456-30, P30DK056341 NORC]; Washington University Institute of Clinical and Translational Sciences from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) [UL1TR000448]; NICHD, NIH FX SB is supported in part by 1U18 DP00336l7-01 Systems Approach to Obesity Prevention in Underserved Children in Texas, Centers for Disease Control and Prevention and by NIH/NIDDK 5U01DK 061718 Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). CB is funded, in part, by the John W Barton, Sr. Endowed Chair in Genetics and Nutrition. PMC is funded by NICHD HD22965-19 and the Clinical Research Unit of the CTSCUL1TR000439 from NCATS at Case Western Reserve University. THI is supported in part by grant UM1DK072493 from the National Institute of Diabetes and Digestive and Kidney Diseases. PTK is partially supported by the Marie Edana Corcoran Endowed Chair in Pediatric Obesity and Diabetes. DS-M is partly supported by National Center for Research Resources and the Office of Science Education of the National Institutes of Health through grant number R25 RR011113. HR has received research funding from Weight Watchers, International. LMR is supported by funding from the National Institutes of Health (U01DK094418, R01099175, R00HD0607662). AES is supported, in part, by 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center. MV is supported in part by Gravida: National Centre for Growth and Development and The Marsden Fund of the Royal Society of New Zealand. DW is supported in part, by the Scott Rudolph University Endowed Professor in Psychiatry, Medicine, Pediatrics and Psychology. Her other support includes NIH grants K24MH070446-09; R01HD03690401A1; T32HL007456-30; P30DK056341 NORC, and her research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. JAY is supported by the Intramural Research Program of NICHD, NIH and is a Commissioned Officer in the US Public Health Service, Department of Health and Human Services. The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of the US Public Health Service, the National Institutes of Health or the US Department of Health and Human Services. NR 318 TC 16 Z9 16 U1 2 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD JUL PY 2014 VL 38 IS 7 BP 887 EP 905 DI 10.1038/ijo.2014.49 PG 19 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AL5TU UT WOS:000339197000001 PM 24662696 ER PT J AU Quick, V Nansel, TR Liu, D Lipsky, LM Due, P Iannotti, RJ AF Quick, V. Nansel, T. R. Liu, D. Lipsky, L. M. Due, P. Iannotti, R. J. TI Body size perception and weight control in youth: 9-year international trends from 24 countries SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE adolescents; body image; dieting; weight perceptions; overweight; development ID CONTROL BEHAVIORS; ADOLESCENT GIRLS; MASS INDEX; FEMALE ADOLESCENTS; YOUNG ADULTHOOD; UNITED-STATES; RISK-FACTORS; OBESITY; OVERWEIGHT; CHILDREN AB OBJECTIVES: To examine 9-year trends and relationships regarding misperceptions of body size and dieting for weight loss among adolescents from 24 countries, and explore the influence of country-level overweight prevalence. METHODS: Sociodemographic characteristics, body size perception and dieting for weight loss were assessed in the Health Behaviour in School-aged Children survey conducted in 24 countries cross-sectionally at three time points (2001/2002, 2005/2006 and 2009/2010). Logistic regression models examined change over time in overestimation of body size in non-overweight adolescents, underestimation of body size in overweight adolescents, dieting for weight loss in non-overweight and overweight adolescents and relationships between body size perception and dieting. Analyses were stratified by weight status and sex. Covariates included country-level overweight prevalence, family affluence and country level of development. Body mass index was only included in models examining dieting for weight loss. RESULTS: Country-level overweight prevalence increased over time (11.6-14.7%). Compared with Time 1, overweight adolescents had greater odds of body size underestimation at Time 3 (odds ratio (OR) = 1.68 for girls; OR = 1.10 for boys), whereas non-overweight adolescents had lower odds of body size overestimation at Time 3 (OR = 0.87 for girls; OR = 0.89 for boys). Controlling for country-level overweight prevalence attenuated these relationships. Compared with Time 1, overweight and non-overweight boys were 10% more likely to diet at Time 3, whereas overweight and non-overweight girls were 19% and 16%, respectively, less likely to diet at Time 3. Controlling for country-level overweight prevalence did not impact trends in dieting for weight loss. Additionally, the association of self-perceived overweight with increased odds of dieting diminished over time. CONCLUSIONS: Body size perceptions among adolescents may have changed over time concurrent with shifts in country-level body weight. However, controlling for country-level overweight prevalence did not impact trends in dieting for weight loss, suggesting a potentially stronger impact of social comparison on weight-related perceptions than on behavior. C1 [Quick, V.; Nansel, T. R.; Liu, D.; Lipsky, L. M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Due, P.] Univ Southern Denmark, Child & Adolescent Hlth Res Programme, Natl Inst Publ Hlth, Copenhagen, Denmark. [Iannotti, R. J.] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. RP Quick, V (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, DHHS, 6100 Execut Blvd,Room 7B13B, Bethesda, MD 20892 USA. EM gingermquick@gmail.com OI Quick, Virginia/0000-0002-4338-963X; Nansel, Tonja/0000-0002-8298-7595; Lipsky, Leah/0000-0003-2645-4388 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-5-3401]; Maternal and Child Health Bureau of the Health Resources and Services Administration FX HBSC is an international study carried out in collaboration with WHO/EURO. The international coordinator of all three waves of data was Candace Currie, University of St Andrews, Scotland, and the data bank manager was Oddrun Samdal, University of Bergen, Norway. A complete list of the participating researchers can be found on the HBSC website (www.HBSC.org). This research was also supported in part by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract no. N01-HD-5-3401) and by the Maternal and Child Health Bureau of the Health Resources and Services Administration. NR 49 TC 10 Z9 11 U1 3 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD JUL PY 2014 VL 38 IS 7 BP 988 EP 994 DI 10.1038/ijo.2014.62 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AL5TU UT WOS:000339197000015 PM 24722544 ER PT J AU Kapogiannis, BG Legins, KE Chandan, U Lee, S AF Kapogiannis, Bill G. Legins, Ken E. Chandan, Upjeet Lee, Sonia TI Evidence-Based Programming for Adolescent HIV Prevention and Care: Operational Research to Inform Best Practices SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE operational research; adolescents; HIV ID INJECTING DRUG-USERS; NIMH PROJECT ACCEPT; PREEXPOSURE PROPHYLAXIS; HEALTH-CARE; ANTIRETROVIRAL PROPHYLAXIS; POSITIVE ADOLESCENTS; INCOME COUNTRIES; UNITED-STATES; YOUNG-PEOPLE; HPTN 043 AB Background: Globally, a staggering number of adolescents, approximately 2.1 million, were estimated to be living with HIV in 2012. Unique developmental, psychosocial, and environmental considerations make them particularly vulnerable to HIV acquisition and argue for a comprehensive response to address this burgeoning problem. Methods: This article explores the current state of the science of HIV prevention, treatment, and care for adolescents and identifies opportunities to address knowledge gaps and improve health outcomes for this age group. Results: Over the past decade, several important milestones have been achieved in HIV prevention and care among adults, and despite evidence that adherence to care and medications among affected adolescents is significantly compromised, critical research among adolescents and young adults substantially lags behind. Operational research, in particular, is crucial to understanding how to use effective services and interventions for HIV prevention and care safely and effectively for adolescents who are in dire need. Conclusions: Operational research among adolescent populations affected by HIV is critically needed to close the knowledge and investment gaps, and scale-up efforts for HIV prevention, treatment, care, and support for this vulnerable age group. C1 [Kapogiannis, Bill G.; Lee, Sonia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Legins, Ken E.; Chandan, Upjeet] UNICEF, New York, NY USA. RP Kapogiannis, BG (reprint author), NICHD, Maternal & Pediat Infect Dis Branch, NIH, 6100 Execut Blvd,Room 4B11J, Bethesda, MD 20892 USA. EM kapogiannisb@mail.nih.gov NR 71 TC 3 Z9 3 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2014 VL 66 SU 2 BP S228 EP S235 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AL3QC UT WOS:000339042400012 PM 24918600 ER PT J AU Kasedde, S Kapogiannis, BG McClure, C Luo, CW AF Kasedde, Susan Kapogiannis, Bill G. McClure, Craig Luo, Chewe TI Executive Summary: Opportunities for Action and Impact to Address HIV and AIDS in Adolescents SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; AIDS; adolescents; prevention; care; treatment AB Introduction: The global HIV epidemic in adolescents is not controlled, and this group has not received sufficient attention in programming and research efforts addressing HIV prevention, treatment, and care. Methods: A global technical consultation on adolescents and HIV addressing services and research gaps was convened by United Nations Children's Fund and the London School of Hygiene and Tropical Medicine in July 2013. Proceedings from this meeting are presented in this issue of the Supplement. Results: Several reviews highlight poor levels of coverage of critical HIV prevention, treatment, and care interventions for adolescents, disparities in HIV prevalence among adolescent girls, and low-risk perceptions associated with risk behaviors among key risk groups. Others underscore the significance of clear national targets and strengthening data, government involvement, enhanced systems capacity and policy, engagement of community and adolescent social networks, and of mobile and internet technologies to the success of interventions for adolescents. Finally, reviews identified several efficacious interventions for adults that could benefit from operational research to inform optimizing implementation in adolescents and how to do so with maximal cost efficiency and impact on the epidemic. Conclusions: Addressing the adolescent gap in the response to the HIV epidemic is essential to a more sustainable and effective response and is critical to overall adolescent health and well-being. The global community has the means and the responsibility to put measures in place to make AIDS-free survival the reality for children in this second decade of life. C1 [Kasedde, Susan; McClure, Craig; Luo, Chewe] United Nations Childrens Fund, HIV & AIDS Sect, New York, NY USA. [Kapogiannis, Bill G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. RP Kasedde, S (reprint author), 3 UN Plaza, New York, NY 10017 USA. EM skasedde@unicef.org NR 19 TC 5 Z9 5 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2014 VL 66 SU 2 BP S139 EP S143 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AL3QC UT WOS:000339042400001 PM 24918589 ER PT J AU Insel, TR Gogtay, N AF Insel, Thomas R. Gogtay, Nitin TI National Institute of Mental Health Clinical Trials New Opportunities, New Expectations SO JAMA PSYCHIATRY LA English DT Editorial Material C1 [Insel, Thomas R.; Gogtay, Nitin] NIMH, Off Director, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, Off Director, NIH, US Dept HHS, 6001 Execut Blvd,Room 8129, Bethesda, MD 20892 USA. EM insel@mail.nih.gov RI Gogtay, Nitin/A-3035-2008 NR 6 TC 34 Z9 34 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUL PY 2014 VL 71 IS 7 BP 745 EP 746 DI 10.1001/jamapsychiatry.2014.426 PG 2 WC Psychiatry SC Psychiatry GA AL5HU UT WOS:000339165200002 PM 24806613 ER PT J AU Gale, SC Gao, L Mikacenic, C Coyle, SM Rafaels, N Dudenkov, TM Madenspacher, JH Draper, DW Ge, W Aloor, JJ Azzam, KM Lai, LH Blackshear, PJ Calvano, SE Barnes, KC Lowry, SF Corbett, S Wurfel, MM Fessler, MB AF Gale, Stephen C. Gao, Li Mikacenic, Carmen Coyle, Susette M. Rafaels, Nicholas Dudenkov, Tanda Murray Madenspacher, Jennifer H. Draper, David W. Ge, William Aloor, Jim J. Azzam, Kathleen M. Lai, Lihua Blackshear, Perry J. Calvano, Steven E. Barnes, Kathleen C. Lowry, Stephen F. Corbett, Siobhan Wurfel, Mark M. Fessler, Michael B. TI APO epsilon 4 is associated with enhanced in vivo innate immune responses in human subjects SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Apolipoprotein; Toll-like receptor; LPS ID APOLIPOPROTEIN-E GENOTYPE; E-DEFICIENT MICE; PLATELET-AGGREGATION; CONSENSUS CONFERENCE; APOE GENOTYPE; DISEASE; SEPSIS; LIPOPOLYSACCHARIDE; POLYMORPHISMS; THROMBOSIS AB Background: The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described wild-type (epsilon 3) and disease-associated (epsilon 2 and epsilon 4) alleles, but its connection to human innate immunity is undefined. Objective: We sought to define the relationship of APO epsilon 4 to the human innate immune response. Methods: We evaluated APO epsilon 4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APO epsilon 4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity. Results: Whole blood from healthy APO epsilon 3/APO epsilon 4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APO epsilon 3/APO epsilon 3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APO epsilon 3/APO epsilon 4 monocytes. By contrast, APO epsilon 3/APO epsilon 3 and APO epsilon 3/APO epsilon 4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe-deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APO epsilon 3/APO epsilon 4 patients had higher hyperthermia and plasma TNF-alpha levels and earlier plasma IL-6 than APO epsilon 3/APO epsilon 3 patients. APO epsilon 4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APO epsilon 3 counterparts. In a cohort of 828 patients with severe sepsis, APO epsilon 4 was associated with increased coagulation system failure among European American patients. Conclusions: APO epsilon 4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis. C1 [Madenspacher, Jennifer H.; Draper, David W.; Ge, William; Aloor, Jim J.; Azzam, Kathleen M.; Lai, Lihua; Fessler, Michael B.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Gale, Stephen C.; Coyle, Susette M.; Calvano, Steven E.; Lowry, Stephen F.; Corbett, Siobhan] UMDNJ Robert Wood Johnson Med Sch, Dept Surg, New Brunswick, NJ USA. [Gao, Li; Rafaels, Nicholas; Dudenkov, Tanda Murray; Barnes, Kathleen C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Mikacenic, Carmen; Wurfel, Mark M.] Univ Washington, Dept Med, Seattle, WA USA. RP Fessler, MB (reprint author), NIEHS, 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov OI Gale, Stephen/0000-0002-6454-4686 FU U.S. PHS [R01 GM-34695]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES102005-08]; Mary Beryl Patch Turnbull Scholar Program; [R01 HL089807-01]; [HL 73994] FX Supported by R01 GM-34695 (U.S. PHS), R01 HL089807-01 (to M. M. W.), HL 73994 (to K. C. B.), and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES102005-08). K. C. B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. NR 51 TC 18 Z9 18 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUL PY 2014 VL 134 IS 1 BP 127 EP + DI 10.1016/j.jaci.2014.01.032 PG 17 WC Allergy; Immunology SC Allergy; Immunology GA AL2BH UT WOS:000338930300017 PM 24655576 ER PT J AU Chan, EC Bai, Y Kirshenbaum, AS Fischer, ER Simakova, O Bandara, G Scott, LM Wisch, LB Cantave, D Carter, MC Lewis, JC Noel, P Maric, I Gilfillan, AM Metcalfe, DD Wilson, TM AF Chan, Eunice Ching Bai, Yun Kirshenbaum, Arnold S. Fischer, Elizabeth R. Simakova, Olga Bandara, Geethani Scott, Linda M. Wisch, Laura B. Cantave, Daly Carter, Melody C. Lewis, John C. Noel, Pierre Maric, Irina Gilfillan, Alasdair M. Metcalfe, Dean D. Wilson, Todd M. TI Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE KIT; K509I; mastocytosis; germline; mast cells; well differentiated ID FC-EPSILON-RI; GASTROINTESTINAL STROMAL TUMORS; C-KIT; SYSTEMIC MASTOCYTOSIS; CUTANEOUS MASTOCYTOSIS; GAMMA-RI; ACTIVATION; LEUKEMIA; IMATINIB; EXPRESSION AB Background: Mastocytosis associated with germline KIT activating mutations is exceedingly rare. We report the unique clinicopathologic features of a patient with systemic mastocytosis caused by a de novo germline KIT K509I mutation. Objectives: We sought to investigate the effect of the germline KIT K509I mutation on human mast cell development and function. Methods: Primary human mast cells derived from CD34(+) peripheral blood progenitors were examined for growth, development, survival, and IgE-mediated activation. In addition, a mast cell transduction system that stably expressed the KIT K509I mutation was established. Results: KIT K509I biopsied mast cells were round, CD25(-), and well differentiated. KIT K509I progenitors cultured in stem cell factor (SCF) demonstrated a 10-fold expansion compared with progenitors from healthy subjects and developed into mature hypergranular mast cells with enhanced antigen-mediated degranulation. KIT K509I progenitors cultured in the absence of SCF survived but lacked expansion and developed into hypogranular mast cells. A KIT K509I mast cell transduction system revealed SCF-independent survival to be reliant on the preferential splicing of KIT at the adjacent exonic junction. Conclusion: Germline KIT mutations associated with mastocytosis drive a well-differentiated mast cell phenotype distinct to that of somatic KIT D816V disease, the oncogenic potential of which might be influenced by SCF and selective KIT splicing. C1 [Chan, Eunice Ching; Bai, Yun; Kirshenbaum, Arnold S.; Bandara, Geethani; Scott, Linda M.; Wisch, Laura B.; Cantave, Daly; Carter, Melody C.; Gilfillan, Alasdair M.; Metcalfe, Dean D.; Wilson, Todd M.] NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Fischer, Elizabeth R.] NIAID, Res Technol Sect, Rocky Mt Labs, NIH, Hamilton, MT USA. [Simakova, Olga; Maric, Irina] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Lewis, John C.] Mayo Clin, Div Allergy Asthma & Clin Immunol, Scottsdale, AZ USA. [Noel, Pierre] Mayo Clin, Div Hematol Oncol, Scottsdale, AZ USA. RP Wilson, TM (reprint author), NIH, 6701 Democracy Blvd,Rm 914, Bethesda, MD 20892 USA. EM twilson@mail.nih.gov FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases/National Institutes of Health FX Supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases/National Institutes of Health. NR 41 TC 13 Z9 13 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUL PY 2014 VL 134 IS 1 BP 178 EP + DI 10.1016/j.jaci.2013.12.1090 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA AL2BH UT WOS:000338930300023 PM 24582309 ER PT J AU Kumar, N Hanks, ME Chandrasekaran, P Davis, BC Hsu, AP Van Wagoner, NJ Merlin, JS Spalding, C La Hoz, RM Holland, SM Zerbe, CS Sampaio, EP AF Kumar, Nilay Hanks, Mary E. Chandrasekaran, Prabha Davis, Brian C. Hsu, Amy P. Van Wagoner, Nicholas J. Merlin, Jessica S. Spalding, Christine La Hoz, Ricardo M. Holland, Steven M. Zerbe, Christa S. Sampaio, Elizabeth P. TI Gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation-related primary immunodeficiency is associated with disseminated mucormycosis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; CHILDREN C1 [Kumar, Nilay; Davis, Brian C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Van Wagoner, Nicholas J.; Merlin, Jessica S.] Univ Alabama Birmingham, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Hanks, Mary E.; Chandrasekaran, Prabha; Hsu, Amy P.; Spalding, Christine; Holland, Steven M.; Zerbe, Christa S.; Sampaio, Elizabeth P.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [La Hoz, Ricardo M.] Wake Forest Univ, Bowman Gray Sch Med, Dept Med, Infect Dis Sect, Winston Salem, NC 27103 USA. RP Kumar, N (reprint author), Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. EM sampaioe@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 11 TC 18 Z9 18 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUL PY 2014 VL 134 IS 1 BP 236 EP 239 DI 10.1016/j.jaci.2014.02.037 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA AL2BH UT WOS:000338930300035 PM 24709374 ER PT J AU Ma, YZ Li, H Yue, ZB Guo, JL Xu, SW Xu, J Jia, YY Yu, N Zhang, BY Liu, SL Liu, M Shao, WW Chen, SR Liu, PQ AF Ma, Yunzi Li, Hong Yue, Zhongbao Guo, Jinlei Xu, Suowen Xu, Jian Jia, Yanyan Yu, Na Zhang, Boyu Liu, Shenglan Liu, Min Shao, Weiwei Chen, Shaorui Liu, Peiqing TI Cryptotanshinone Attenuates Cardiac Fibrosis via Downregulation of COX-2, NOX-2, and NOX-4 SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY LA English DT Article DE Ang II; AMI; cardiac fibrosis; COX-2; cryptotanshinone; ERK1/2; NOX-2; NOX-4 ID ACUTE MYOCARDIAL-INFARCTION; NF-KAPPA-B; ANGIOTENSIN-II; OXIDATIVE STRESS; SIGNALING PATHWAYS; NADPH OXIDASES; MYOCYTE APOPTOSIS; P38 MAPK; FIBROBLASTS; EXPRESSION AB Cryptotanshinone (CTS), a bioactive constituent extracted from a Chinese traditional herb Danshen (Salvia miltiorrhiza), demonstrates multiple protective effects against cardiovascular diseases. The present study was designed to explore the effects of CTS in vitro by cultured adult rat cardiac fibroblasts stimulated with angiotensin II (Ang II) and in vivo by rats with acute myocardial infarction. Our data showed that in cardiac fibroblasts, CTS attenuated Ang II-induced upregulation of fibronectin, connective tissue growth factor, cyclooxygenase-2, and normalized Ang II-induced upregulation of extracellular signal-regulated kinases 1/2 (ERK1/2). Meanwhile, CTS depressed the Ang II-stimulated upregulation of NAD(P) H oxidase 2 and 4 (NOX-2 and NOX-4) and reactive oxygen species production. Similar results were observed in acute myocardial infarction rats with oral administration of CTS, which relieved the pathological changes accompanying myocardial infarction. In conclusion, CTS may exert antifibrotic effects in vitro by inhibiting Ang II-induced extracellular signal-regulated kinases 1/2 phosphorylation and the expression of cyclooxygenase-2, NOX-2, and NOX-4, and also improved the pathological changes and relieved cardiac fibrosis in vivo. C1 [Ma, Yunzi; Li, Hong; Yue, Zhongbao; Guo, Jinlei; Xu, Jian; Jia, Yanyan; Yu, Na; Zhang, Boyu; Liu, Shenglan; Liu, Min; Shao, Weiwei; Chen, Shaorui; Liu, Peiqing] Sun Yat Sen Univ, Sch Pharmaceut Sci, Lab Pharmacol & Toxicol, Guangzhou 510006, Guangdong, Peoples R China. [Xu, Suowen] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Chen, SR (reprint author), Sun Yat Sen Univ, Sch Pharmaceut Sci, Lab Pharmacol & Toxicol, Guangzhou Higher Educ Mega Ctr, 132 East Waihuan Rd, Guangzhou 510006, Guangdong, Peoples R China. EM chshaor@mail.sysu.edu.cn; liupq@mail.sysu.edu.cn FU National Natural Science Foundation of China [81072641, 81273499]; National Science and Technology Major Project of China "Key New Drug Creation and Manufacturing Program" [2011ZX09401-307]; Natural Science Foundation of Guangdong Province [S2011030003190, S2012040006327]; Major Project of Guangdong Province [2008A030201013, 2012A080201007]; Major Project of Guangzhou City [2011-0641]; Department of Education of Guangdong Province [CXZD1006]; Medical Scientific Research Foundation of Guangdong Province [A2012166] FX Supported by the National Natural Science Foundation of China (No. 81072641; No. 81273499), the National Science and Technology Major Project of China "Key New Drug Creation and Manufacturing Program" (No. 2011ZX09401-307), Team item of Natural Science Foundation of Guangdong Province (No. S2011030003190), Major Project of Guangdong Province (No. 2008A030201013, No. 2012A080201007), Major Project of Guangzhou City (No. 2011-0641), Major Project of Department of Education of Guangdong Province (No. CXZD1006), Medical Scientific Research Foundation of Guangdong Province (No. A2012166), and Natural Science Foundation of Guangdong Province (No. S2012040006327). NR 55 TC 9 Z9 10 U1 3 U2 32 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0160-2446 EI 1533-4023 J9 J CARDIOVASC PHARM JI J. Cardiovasc. Pharmacol. PD JUL PY 2014 VL 64 IS 1 BP 28 EP 37 PG 10 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA AL6QP UT WOS:000339258000005 PM 24621647 ER PT J AU Lee, J Miller, BT Damjanovic, A Brooks, BR AF Lee, Juyong Miller, Benjamin T. Damjanovic, Ana Brooks, Bernard R. TI Constant pH Molecular Dynamics in Explicit Solvent with Enveloping Distribution Sampling and Hamiltonian Exchange SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID FREE-ENERGY CALCULATIONS; DISCRETE PROTONATION STATES; GUIDED LANGEVIN DYNAMICS; VALENCE-BOND MODEL; REPLICA-EXCHANGE; WATER PENETRATION; PK(A) VALUES; LIGAND-BINDING; CONTINUUM ELECTROSTATICS; BIOMOLECULAR SYSTEMS AB We present a new computational approach for constant pH simulations in explicit solvent based on the combination of the enveloping distribution sampling (EDS) and Hamiltonian replica exchange (HREX) methods. Unlike constant pH methods based on variable and continuous charge models, our method is based on discrete protonation states. EDS generates a hybrid Hamiltonian of different protonation states. A smoothness parameter s is used to control the heights of energy barriers of the hybrid-state energy landscape. A small s value facilitates state transitions by lowering energy barriers. Replica exchange between EDS potentials with different s values allows us to readily obtain a thermodynamically accurate ensemble of multiple protonation states with frequent state transitions. The analysis is performed with an ensemble obtained from an EDS Hamiltonian without smoothing, s = infinity, which strictly follows the minimum energy surface of the end states. The accuracy and efficiency of this method is tested on aspartic acid, lysine, and glutamic acid, which have two protonation states, a histidine with three states, a four-residue peptide with four states, and snake cardiotoxin with eight states. The pK(a) values estimated with the EDS-HREX method agree well with the experimental pK(a) values. The mean absolute errors of small benchmark systems range from 0.03 to 0.17 pK(a) units, and those of three titratable groups of snake cardiotoxin range from 0.2 to 1.6 pK(a) units. This study demonstrates that EDS-HREX is a potent theoretical framework, which gives the correct description of multiple protonation states and good calculated pK(a) values. C1 [Lee, Juyong; Miller, Benjamin T.; Damjanovic, Ana; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Damjanovic, Ana] Johns Hopkins Univ, Dept Biophys, Baltimore, MD USA. RP Lee, J (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM juyong.lee@nih.gov RI Lee, Juyong/A-7869-2013; OI Lee, Juyong/0000-0003-1174-4358; Miller, Benjamin/0000-0003-1647-0122 FU National Heart, Lung, and Blood Institute, National Institutes of Health; NIH [RO1 GM073838] FX This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. A.D. was partially supported by NIH Grant RO1 GM073838 to Bertrand Garcia-Moreno. The authors thank Gerhard Konig for helpful discussions. NR 109 TC 17 Z9 17 U1 3 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD JUL PY 2014 VL 10 IS 7 BP 2738 EP 2750 DI 10.1021/ct500175m PG 13 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA AL0GR UT WOS:000338805900011 PM 25061443 ER PT J AU Johnson, LM Rothwax, JT Turkbey, B Rais-Bahrami, S Wood, BJ Figg, WD Choyke, PL Merino, MJ Pinto, PA AF Johnson, Linda M. Rothwax, Jason T. Turkbey, Baris Rais-Bahrami, Soroush Wood, Bradford J. Figg, William D. Choyke, Peter L. Merino, Maria J. Pinto, Peter A. TI Multiparametric Magnetic Resonance Imaging of the Prostate Aids to Detect Lesion Progression SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE prostate carcinoma; MRI; active surveillance; MR spectroscopy ID ACTIVE SURVEILLANCE; CANCER AB Multiparametric magnetic resonance imaging (MRI) provides an accurate anatomical assessment of the tumor and its local staging. Herein, we report a case of intermediate-risk prostatic adenocarcinoma, initially followed on active surveillance, which upgraded from Gleason 7 (3 + 4) to Gleason 8 (4 + 4) on transrectal ultrasound/MRI fusion biopsy after progression of MR spectroscopic findings and review of the role of multiparametric MRI in the follow-up of patients with prostate cancer undergoing active surveillance. C1 [Johnson, Linda M.] NCI, Mol Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. [Johnson, Linda M.; Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Rothwax, Jason T.; Rais-Bahrami, Soroush; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci CC, Bethesda, MD 20892 USA. [Figg, William D.] NCI, Clin Pharmacol Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, 10 Ctr Dr,MSC 1182 Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov RI Figg Sr, William/M-2411-2016; OI Rais-Bahrami, Soroush/0000-0001-9466-9925 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Center for Interventional Oncology FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the Center for Interventional Oncology. NR 8 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 EI 1532-3145 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD JUL-AUG PY 2014 VL 38 IS 4 BP 565 EP 567 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AL7RL UT WOS:000339332300013 PM 24733004 ER PT J AU Coleman, B Calzone, KA Jenkins, J Paniagua, C Rivera, R Hong, OS Spruill, I Bonham, V AF Coleman, Bernice Calzone, Kathleen A. Jenkins, Jean Paniagua, Carmen Rivera, Reynaldo Hong, Oi Saeng Spruill, Ida Bonham, Vence TI Multi-Ethnic Minority Nurses' Knowledge and Practice of Genetics and Genomics SO JOURNAL OF NURSING SCHOLARSHIP LA English DT Article DE Minority nurses; nursing; genetics; survey; nursing practice ID CARDIOVASCULAR-DISEASES; CARE AB Purpose: Exploratory studies establishing how well nurses have integrated genomics into practice have demonstrated there remains opportunity for education. However, little is known about educational gaps in multi-ethnic minority nurse populations. The purpose of this study was to determine minority nurses' beliefs, practices, and competency in integrating genetics-genomics information into practice using an online survey tool. Design: A cross-sectional survey with registered nurses (RNs) from the participating National Coalition of Ethnic Minority Organizations (NCEMNA). Two phases were used: Phase one had a sample of 27 nurses who determined the feasibility of an online approach to survey completion and need for tool revision. Phase two was a main survey with 389 participants who completed the revised survey. The survey ascertained the genomic knowledge, beliefs, and practice of a sample of multi-ethnic minority nurses who were members of associations comprising the NCEMNA. Methods: The survey was administered online. Descriptive survey responses were analyzed using frequencies and percentages. Categorical responses in which comparisons were analyzed used chi square tests. Findings: About 40% of the respondents held a master's degree (39%) and 42% worked in direct patient care. The majority of respondents (79%) reported that education in genomics was important. Ninety-five percent agreed or strongly agreed that family health history could identify at-risk families, 85% reported knowing how to complete a second-and third-generation family history, and 63% felt family history was important to nursing. Conversely, 50% of the respondents felt that their understanding of the genetics of common disease was fair or poor, supported by 54% incorrectly reporting they thought heart disease and diabetes are caused by a single gene variant. Only 30% reported taking a genetics course since licensure, and 94% reported interest in learning more about genomics. Eighty-four percent believed that their ethnic minority nurses' organizations should have a visible role in genetics and genomics in their communities. Conclusions: Most respondents felt genomics is important to integrate into practice but demonstrated knowledge deficits. There was strong interest in the need for continuing education and the role of the ethnic minority organizations in facilitating the continuing education efforts. This study provides evidence of the need for targeted genomic education to prepare ethnic minority nurses to better translate genetics and genomics into practice. Clinical Relevance: Genomics is critical to the practice of all nurses, most especially family health history assessment and the genomics of common complex diseases. There is a great opportunity and interest to address the genetic-genomic knowledge deficits in the nursing workforce as a strategy to impact patient outcomes. C1 [Coleman, Bernice] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Coleman, Bernice] Cedars Sinai Med Ctr, Inst Heart, Heart Transplant Program, Los Angeles, CA 90048 USA. [Coleman, Bernice] Cedars Sinai Med Ctr, Inst Heart, Mech Assist Device Program, Los Angeles, CA 90048 USA. [Calzone, Kathleen A.] NCI, NIH, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. [Jenkins, Jean] NHGRI, NIH, Bethesda, MD 20892 USA. [Paniagua, Carmen] Univ Arkansas Med Sci, Coll Med, Dept Emergency Med, Little Rock, AR 72205 USA. [Rivera, Reynaldo] New York Presbyterian Hosp, New York, NY USA. [Hong, Oi Saeng] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. [Spruill, Ida] Med Univ S Carolina, Coll Nursing, Carleston, SC USA. [Bonham, Vence] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Coleman, B (reprint author), Cedars Sinai Med Ctr, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. EM bernice.coleman@cshs.org FU National Institutes of Health, National Cancer Institute; National Institutes of Health, National Human Genome Research Institute FX This research was supported by the Intramural Research Programs of the National Institutes of Health, National Cancer Institute, and National Human Genome Research Institute. NR 25 TC 6 Z9 7 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6546 EI 1547-5069 J9 J NURS SCHOLARSHIP JI J. Nurs. Scholarsh. PD JUL PY 2014 VL 46 IS 4 BP 235 EP 244 DI 10.1111/jnu.12083 PG 10 WC Nursing SC Nursing GA AL7RX UT WOS:000339333600004 PM 24758549 ER PT J AU Tasdemir, S Sahin, I Cayir, A Doneray, H Solomon, BD Muenke, M Yuce, I Tatar, A AF Tasdemir, Sener Sahin, Ibrahim Cayir, Atilla Doneray, Hakan Solomon, Benjamin D. Muenke, Maximilian Yuce, Ihsan Tatar, Abdulgani TI Holoprosencephaly: ZIC2 mutation in a case with panhypopituitarism SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE alobar; holoprosencephaly (HPE); panhypopituitarism; ZIC2 ID GENOTYPE-PHENOTYPE CORRELATIONS; LOSS-OF-FUNCTION; FEATURES; ANOMALIES; SPECTRUM; GENE AB Background: Holoprosencephaly (HPE), the most common malformation of the brain, results from failed or incomplete separation of the embryonic forebrain (prosencephalon). HPE occurs in approximately 1 in 250 embryos and in about 1 in 10,000 births. It is etiologically heterogeneous, and may be caused by cytogenetic anomalies and teratogenic influences; it occurs as part of a syndrome, or due to heterozygous mutations in 1 of over 10 HPE-associated genes. ZIC2 mutations are the second-most common cause of non-syndromic non-chromosomal HPE (after sonic hedgehog) and occur de novo in 74% of the affected probands. Objective: The objective of the study was to describe the first case of ZIC2-related HPE with both anterior and posterior pituitary insufficiencies. Case presentation: We report about a 2-year-8-month-old boy who was born as a second child in a non-consanguineous healthy Turkish family. He has the characteristic ZIC2 phenotype: bitemporal narrowing, upslanting palpebral fissures, large ears, short nose with anteverted nares and broad and deep philtrum. Magnetic resonance imaging revealed alobar HPE. During laboratory investigation, his blood sodium level was 158 mmol/L and the specific gravity of his urine was 1.002. Serum osmolarity was 336 mOsm/L and urine osmolality was 135 mOsm/kg. His FT4 was 0.8 ng/dL and TSH was 0.79 mLU/mL. Response to vasopressin confirmed the diagnosis of central diabetes insipidus and TRH-stimulating test supported the central hypothyroidism. A frameshift mutation (NM_007129.2: c1091_1092 del, p. Gln364Leufs*2) in the ZIC2 gene was detected. Conclusion: Pituitary insufficiency other than isolated diabetes insipidus is a rare finding of HPE, and occurs most frequently in patients with GLI2 mutations (the phenotype of which typically does not include frank neuroanatomic anomalies such as HPE); ours is the only described patient with a ZIC2 mutation and both anterior and posterior pituitary dysfunction. C1 [Tasdemir, Sener; Sahin, Ibrahim; Tatar, Abdulgani] Ataturk Univ, Fac Med, Dept Med Genet, Erzurum, Turkey. [Cayir, Atilla; Doneray, Hakan] Ataturk Univ, Dept Pediat, Div Pediat Endocrinol, Erzurum, Turkey. [Solomon, Benjamin D.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Yuce, Ihsan] Erzurum Reg Training & Res Hosp, Dept Radiol, Erzurum, Turkey. RP Tasdemir, S (reprint author), Ataturk Univ, Fac Med, Dept Med Genet, Erzurum, Turkey. EM senertasdemir@gmail.com NR 15 TC 1 Z9 1 U1 0 U2 4 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-018X EI 2191-0251 J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD JUL PY 2014 VL 27 IS 7-8 BP 777 EP 781 DI 10.1515/jpem-2013-0449 PG 5 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA AL0TK UT WOS:000338839500031 PM 24706429 ER PT J AU Sibley, C Yazici, Y Tascilar, K Khan, N Bata, Y Yazici, H Goldbach-Mansky, R Hatemi, G AF Sibley, Cailin Yazici, Yusuf Tascilar, Koray Khan, Nafiz Bata, Yasmin Yazici, Hasan Goldbach-Mansky, Raphaela Hatemi, Gulen TI Behcet Syndrome Manifestations and Activity in the United States versus Turkey - A Cross-sectional Cohort Comparison SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE BEHCET SYNDROME; TURKEY; UNITED STATES; DISEASE MANIFESTATIONS ID DISEASE-ACTIVITY; ACTIVITY FORM AB Objective To compare clinical manifestations and activity of Behcet syndrome (BS) in the United States versus Turkey using validated outcome measures. Methods. Consecutive patients with BS from the US National Institutes of Health (NIH), New York University, and the University of Istanbul were evaluated. Disease activity was measured using the Behcet's Syndrome Activity Scale (BSAS) and the Behcet's Disease Current. Activity Form (BDCAF) with quality of life measured by the Behcet Disease Quality of Life (BDQOL) form. One-way ANOVA, t-tests, and multivariate regression analyses were performed. Results. Mean age did not differ between sites; however, more women were seen in the United States versus in Turkey (p < 0.001). and disease duration was longer in the United States (p = 0.02). Organ manifestations were similar for oral and genital ulcers, skin disease, arthralgia, eye disease, and thrombosis. however, more gastrointestinal (p < 0.001) and neurologic disease (p = 0.003) was seen in the United States. BSAS and BDCAF scores were worse in the United States compared to Turkey (p = 0.013 and < 0.001, respectively). Worse mean BDQOL, scores were observed at the NIH compared to Istanbul (not significant). Multivariable regression models showed worse scores in ethnically atypical patients for BSAS and BDCAF (p = 0.04 and p = 0.001), American patients for BDCAF (p = 0.01), older age for BDCAF (p = 0.005), and women for BDQOL (p = 0.01). Conclusion. Demographic and clinical manifestations of BS differ between sites with higher disease activity in the United States compared to Turkey. Referral patterns, age, sex, ethnicity, and country of origin may be important in these differences. These observations raise the question of whether pathogenic mechanisms differ in Turkish and American patients. C1 NIAMSD, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. Oregon Hlth & Sci Univ, Dept Rheumatol, Portland, OR 97201 USA. NYU, Dept Rheumatol, New York, NY USA. Univ Istanbul Cerraltpasa, Dept Rheumatol, Istanbul, Turkey. RP Sibley, C (reprint author), NIAMS, Translat Autoinflammatory Dis Sect, NIH, Bldg 10,Room 6N216-G,MSC 1616,10 Ctr Dr, Bethesda, MD 20892 USA. EM sibleychh@mail.nih.gov RI TASCILAR, Koray/F-9070-2015 OI TASCILAR, Koray/0000-0002-8109-826X FU Intramural Research Program of the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health (NIH); New York University; University of Istanbul; BMS; Genentech; Celgene; Regeneron; Novartis; BIovitrum Inc. FX Supported by the Intramural Research Program of the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health (NIH), New York University, and the University of Istanbul. Yusuf Yazici is a consultant for Abbvie, BMS, Celgene, Genentech, Pfizer, UCB, Horizon, and Medac; and holds research grants from BMS, Genentech, and Celgene. Raphaela Goldbach-Mansky has received grant support from Regeneron, Novartis, and BIovitrum Inc. NR 13 TC 7 Z9 7 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD JUL PY 2014 VL 41 IS 7 BP 1379 EP 1384 DI 10.3899/jrheum.131227 PG 6 WC Rheumatology SC Rheumatology GA AL1YU UT WOS:000338923700019 PM 24931953 ER PT J AU Dawson, DA Goldstein, RB Pickering, RP Grant, BF AF Dawson, Deborah A. Goldstein, Rise B. Pickering, Roger P. Grant, Bridget F. TI Nonresponse Bias in Survey Estimates of Alcohol Consumption and Its Association With Harm SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID MENTAL-HEALTH SURVEY; NETHERLANDS; ATTRITION; SAMPLE; RATES; MODE AB Objective: Selective nonresponse represents a major source of potential bias in survey-based estimates of alcohol consumption and its association with harm. This study examined whether consumption differs for respondents and nonrespondents after correcting for their sociodemographic differences. Method: This study compared baseline consumption among initial respondents who did (n = 34,653) and did not (n = 5,306) respond to a 3-year follow-up interview in a prospective study of the U.S. general population. Differences in consumption measures were presented before and after adjustment or sociodemographic differences, and interactions of nonresponse with consumption were assessed in models predicting various types of harm. Results: After we adjusted for sociodemographic differences and factored in the overall level of nonresponse (13.3%), the degree to which the prevalence of drinking was underestimated in the total population was only 1.6%, and the extent to which consumption was overestimated among drinkers lay in the range of 1.7% to 2.4%. There was no consistent evidence that nonresponse moderated the association between consumption and alcohol-related harm. Sociodemographic differentials in nonresponse generally matched those reported for cross-sectional studies in the literature. Conclusions: The extent of nonresponse bias in survey estimates of alcohol consumption should not affect drinking guidelines and planning for prevention and treatment programs. The findings of this study are supportive of study designs that have been used to assess nonresponse bias, including the use of registry data on alcohol-related harms and secondary nonresponse data from prospective studies. C1 [Dawson, Deborah A.] Kelly Govt Serv, Bethesda, MD USA. [Dawson, Deborah A.; Goldstein, Rise B.; Pickering, Roger P.; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD USA. RP Dawson, DA (reprint author), 3025 Exmoor Rd, Ann Arbor, MI 48104 USA. EM Deborah.anne.dawson@gmail.com OI Goldstein, Rise/0000-0002-9603-9473 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, U.S. Department of Health and Human Services; National Institute on Drug Abuse; National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism FX The study on which this article is based, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), is sponsored by the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, U.S. Department of Health and Human Services, with supplemental support from the National Institute on Drug Abuse. This research was supported in part by the Intramural Program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism. The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or the U.S. government. NR 31 TC 6 Z9 6 U1 0 U2 2 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JUL PY 2014 VL 75 IS 4 BP 695 EP 703 PG 9 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA AL4XQ UT WOS:000339138500017 PM 24988268 ER PT J AU Berner, LA Keast, DR Bailey, RL Dwyer, JT AF Berner, Louise A. Keast, Debra R. Bailey, Regan L. Dwyer, Johanna T. TI Fortified Foods Are Major Contributors to Nutrient Intakes in Diets of US Children and Adolescents SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Children; National Health and Nutrition Examination Survey (NHANES); Food; Micronutrients; Fortification ID UNITED-STATES; FORTIFICATION; CALCIUM; SUPPLEMENTS; VITAMIN; ENERGY; HEALTH; LEVEL AB Background Even in an era of obesity and dietary excess, numerous shortfall mictonutrients have been identified in the diets of US children and adolescents. To help tailor strategies for meeting recommendations, it is important to know what foods contribute greatly to micronutrient intakes. Data are lacking on specific contributions made by added nutrients. Objective Our aims were to examine the impact of fortification on nutrient adequacy and excess among US children and adolescents and to rank food sources of added nutrient intake and compare rankings with those based on total nutrient intake from foods. Design and statistical analyses Data were from 7,250 respondents 2 to 18 years old in the National Health and Nutrition Examination Survey 2003-2006. Datasets were developed that distinguished nutrient sources: intrinsic nutrients in foods; added nutrients in foods; foods (intrinsic plus added nutrients); and total diet (foods plus supplements). The National Cancer Institute method was used to determine usual intakes of micronutrients by source. The impact of fortification on the percentages of children having intakes less than the Estimated Average Requirement and more than the Upper Tolerable Intake Level was assessed by comparing intakes from intrinsic nutrients to intakes from intrinsic plus added nutrients. Specific food sources of micronutrients were determined as sample-weighted mean intakes of total and added nutrients contributed from 56 food groupings. The percentage of intake from each grouping was determined separately for total and added nutrients. Results Without added nutrients, a high percentage of all children/adolescents had inadequate intakes of numerous micronutrients, with the greatest inadequacy among older girls. Fortification reduced the percentage less than the Estimated Average Requirement for many, although not all, micronutrients without resulting in excessive intakes. Data demonstrated the powerful influence of fortification on food-source rankings. Conclusions Knowledge about nutrient intakes and sources can help put dietary advice into a practical context. Continued monitoring of top food sources of nutrients and nutrient contributions from fortification will be important. C1 [Berner, Louise A.] Calif Polytech State Univ San Luis Obispo, Food Sci & Nutr Dept, San Luis Obispo, CA 93407 USA. [Keast, Debra R.] Food & Nutr Database Res Inc, Okemos, MI USA. [Bailey, Regan L.; Dwyer, Johanna T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Dwyer, Johanna T.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Dwyer, Johanna T.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. RP Berner, LA (reprint author), Calif Polytech State Univ San Luis Obispo, Food Sci & Nutr Dept, San Luis Obispo, CA 93407 USA. EM lberner@calpoly.edu OI Dwyer, Johanna/0000-0002-0783-1769 FU Fortification Committee of the North American Branch of the International Life Sciences Institute (ILSI NA) FX Data analysis and manuscript preparation Were funded by the Fortification Committee of the North American Branch of the International Life Sciences Institute (ILSI NA), a public, nonprofit foundation that provides a forum to advance understanding of scientific issues related to the nutritional quality and safety of the food supply by sponsoring research programs, educational seminars and workshops, and publications. ILSI NA receives support primarily from its industry membership. The opinions expressed herein are those of the authors and do not necessarily represent the views of the funding organization. NR 35 TC 19 Z9 19 U1 1 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD JUL PY 2014 VL 114 IS 7 BP 1009 EP 1022 DI 10.1016/j.jand.2013.10.012 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AL2RI UT WOS:000338972400005 PM 24462266 ER PT J AU Clark, TS Clark, DD Hoyt, RF AF Clark, Tannia S. Clark, David D. Hoyt, Robert F., Jr. TI Pharmacokinetic Comparison of Sustained-Release and Standard Buprenorphine in Mice SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID PLASMA-CONCENTRATIONS; ANALGESIC PROFILE; PAIN MANAGEMENT; EFFICACY; RATS; DURATION; FENTANYL; ANIMALS; RODENTS; SAFETY AB Effective pain medication is important for animal stewardship and valid research results. We compared the pharmacokinetic assessments of standard, immediate-release buprenorphine (Bup IR) and a sustained-release buprenorphine formulation (Bup SR Lab) in male C57BL/6J mice, a mouse strain commonly used in biomedical research. We postulated that the administration of Bup SR Lab would achieve a more persistent blood drug concentration (>1 ng/mL) compared with single-dose Bup IR. The study assumed a blood buprenorphine concentration of 1 ng/mL as the minimum that may result in adequate analgesia, as previously reported. The 7 experimental groups included Bup IR (0.03, 0.05, 0.1, and 2 mg/kg), Bup SR Lab (0.3 and 1.2 mg/kg), and saline placebo (0.7 mL/100 g). Blood sampling occurred at 0.5, 1, 3, 6, 12, 24, 48, and 72 h for evaluation by using a forensic ELISA. Bup IR at 0.03 and 0.05 mg/kg and Bup SR Lab at 0.3 mg/kg failed to obtain maximal blood concentrations (C-max) above 1 ng/mL. All other doses (0.1 and 2 mg/kg Bup IR and 1.2 mg/kg Bup SR Lab) reached a C-max above 1 ng/mL within 3;after injection. In addition, 1.2 mg/kg Bup SR Lab and 2 mg/kg Bup IR provided blood concentrations above 1 ng/mL for up to 12 h, and 0.1 mg/kg Bup IR achieved this criterion for as long as 3 h. In conclusion, Bup SR Lab at 1.2 mg/kg and Bup IR at 0.1 or 2.0 mg/kg achieve or surpass the published threshold for adequate analgesia in mice. C1 [Clark, Tannia S.; Hoyt, Robert F., Jr.] NHLBI, Bethesda, MD 20892 USA. [Clark, David D.] Eastern Res Grp, Arlington, VA USA. RP Clark, TS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM tannia.clark@nih.gov NR 26 TC 5 Z9 5 U1 2 U2 6 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 JUL PY 2014 VL 53 IS 4 BP 387 EP 391 PG 5 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA AL6GW UT WOS:000339231600008 PM 25199095 ER PT J AU Weintraub, S Dikmen, SS Heaton, RK Tulsky, DS Zelazo, PD Slotkin, J Carlozzi, NE Bauer, PJ Wallner-Allen, K Fox, N Havlik, R Beaumont, JL Mungas, D Manly, JJ Moy, C Conway, K Edwards, E Nowinski, CJ Gershon, R AF Weintraub, Sandra Dikmen, Sureyya S. Heaton, Robert K. Tulsky, David S. Zelazo, Philip David Slotkin, Jerry Carlozzi, Noelle E. Bauer, Patricia J. Wallner-Allen, Kathleen Fox, Nathan Havlik, Richard Beaumont, Jennifer L. Mungas, Dan Manly, Jennifer J. Moy, Claudia Conway, Kevin Edwards, Emmeline Nowinski, Cindy J. Gershon, Richard TI The Cognition Battery of the NIH Toolbox for Assessment of Neurological and Behavioral Function: Validation in an Adult Sample SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE NIH Blueprint; Neuropsychological test; Language test; Memory test; Lifespan ID WORKING-MEMORY; ALZHEIMERS-DISEASE; EXECUTIVE FUNCTION; PROCESSING SPEED; HEAD-INJURY; ENGLISH; DEMENTIA; CHILDREN; CRITERIA; SPANISH AB This study introduces a special series on validity studies of the Cognition Battery (CB) from the U.S. National Institutes of Health Toolbox for the Assessment of Neurological and Behavioral Function (NIHTB) (Gershon, Wagster et al., 2013) in an adult sample. This first study in the series describes the sample, each of the seven instruments in the NIHTB-CB briefly, and the general approach to data analysis. Data are provided on test-retest reliability and practice effects, and raw scores (mean, standard deviation, range) are presented for each instrument and the gold standard instruments used to measure construct validity. Accompanying papers provide details on each instrument, including information about instrument development, psychometric properties, age and education effects on performance, and convergent and discriminant construct validity. One study in the series is devoted to a factor analysis of the NIHTB-CB in adults and another describes the psychometric properties of three composite scores derived from the individual measures representing fluid and crystallized abilities and their combination. The NIHTB-CB is designed to provide a brief, comprehensive, common set of measures to allow comparisons among disparate studies and to improve scientific communication. C1 [Weintraub, Sandra] Northwestern Feinberg Sch Med, Cognit Neurol & Alzheimers Dis Ctr, Chicago, IL 60610 USA. [Weintraub, Sandra] Northwestern Feinberg Sch Med, Dept Psychiat, Chicago, IL 60610 USA. [Weintraub, Sandra] Northwestern Feinberg Sch Med, Dept Neurol, Chicago, IL 60610 USA. [Dikmen, Sureyya S.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Heaton, Robert K.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Tulsky, David S.] NYU, Dept Rehabil Med, Langone Med Ctr, New York, NY USA. [Tulsky, David S.] NYU, Dept Orthoped Surg, Langone Med Ctr, New York, NY USA. [Tulsky, David S.] NYU, Dept Gen Med, Langone Med Ctr, New York, NY USA. [Tulsky, David S.] Kessler Fdn, Spinal Cord Injury & Outcomes Labs, W Orange, NJ USA. [Zelazo, Philip David] Univ Minnesota, Inst Child Dev, Minneapolis, MN 55455 USA. [Slotkin, Jerry; Beaumont, Jennifer L.; Nowinski, Cindy J.; Gershon, Richard] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Carlozzi, Noelle E.] Univ Michigan, Ann Arbor, MI 48109 USA. [Bauer, Patricia J.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Wallner-Allen, Kathleen; Havlik, Richard] WESTAT Corp, Rockville, MD 20850 USA. [Fox, Nathan] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Mungas, Dan] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. [Manly, Jennifer J.] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, Cognit Neurosci Div, New York, NY USA. [Moy, Claudia] NINDS, Bethesda, MD 20892 USA. [Conway, Kevin] NIDA, Rockville, MD USA. [Edwards, Emmeline] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. RP Weintraub, S (reprint author), Northwestern Feinberg Sch Med, Cognit Neurol & Alzheimers Dis Ctr, 320 E Super,Searle 11-467, Chicago, IL 60610 USA. EM sweintraub@northwestern.edu OI Conway, Kevin/0000-0002-7638-339X FU Blueprint for Neuroscience Research; National Institutes of Health [HHS-N-260-2006-00007-C, P20MH085987, R41 TR 000367, HHSN265200423601C, HHSN260200600007C, HHSN267200700027C]; NIH [R01DC008552, P30AG013854, R01 NS058302, R01HD061400, P30MH062512, HHSN271201000036C, R01MH92225, R01MH094160, P50DA026306, H133B090024, H133N060022, H133G070138, B6237R, U01AR057929, R01HD054659, HD067359, HD074724, HD071845]; Ken and Ruth Davee Foundation; NIDRR [H133B090024, H133A080035, H133G090022, H133A980023]; DoD [W81XWH-0802-0159]; Institute for Rehabilitation and Research; Frazier Rehabilitation Institute/Jewish Hospital; Craig Hospital; Casa Colina Centers for Rehabilitation; Jean Piaget Society; Canadian Institute for Health Research [201963]; Institute of Education Science [R305A110528]; Character Lab; NJ Department of Health and Senior Services; National Institute on Aging; California Department of Public Health California Alzheimer's Disease Centers program; Department of Veteran's Affairs; Analysis Group; Novartis; Teva Pharmaceuticals; Alzheimer's Association [IIRG 05-14236]; National Institute of Health [R03NS065194, R01NR013658, R01NS077946, U01NS056975, R37HD017899, MH074454, U01MH080759, R01MH091363, P50MH078105, P01HD064653, R01AG028786, R01AG037212, R01AG016206, N01-AG-6-0007, HHSN260200600007, 1U01DK082342-01, HD05469, 1RC2AG036498-01]; [H133A070037-08A] FX This study is funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research, National Institutes of Health, under Contract No. HHS-N-260-2006-00007-C. Dr. Weintraub is funded by NIH grants # R01DC008552, P30AG013854, and the Ken and Ruth Davee Foundation and conducts clinical neuropsychological evaluations (35% effort) for which her academic-based practice clinic bills. She serves on the editorial board of Dementia & Neuropsychologia and advisory boards of the Turkish Journal of Neurology and Alzheimer's and Dementia. Dr. Dikmen receives research grant funding from NIH R01 NS058302 and R01HD061400, NIDRR H133A080035, NIDRR H133G090022, and NIDRR, H133A980023, and DoD W81XWH-0802-0159. Dr. Heaton is funded by NIH grants # P30MH062512, HHSN271201000036C, R01MH92225, R01MH094160, and P50DA026306. He is on the editorial board of the Journal of the International Neuropsychological Society and The Clinical Neuropsychologist. Dr. Tulsky is funded by NIH contracts H133B090024, H133N060022, H133G070138, B6237R, cooperative agreement U01AR057929, and grant, R01HD054659. He has received consultant fees from the Institute for Rehabilitation and Research, Frazier Rehabilitation Institute/Jewish Hospital, Craig Hospital, and Casa Colina Centers for Rehabilitation. Dr. Zelazo serves on the editorial boards of Child Development, Development and Psychopathology, Frontiers in Human Neuroscience, Cognitive Development, Emotion, Developmental Cognitive Neuroscience, and Monographs of the Society for Research in Child Development. He is a Senior Fellow of the Mind and Life Institute and President of the Jean Piaget Society. He receives research funding from the Canadian Institute for Health Research (Grant # 201963), Institute of Education Science (R305A110528), National Institutes of Health (P20MH085987, R41 TR 000367), and the Character Lab. Dr. Bauer serves as a member of the editorial board for the Journal of Experimental Child Psychology, as Associate Editor for the journals Developmental Review and Memory, and as Editor of the Monographs of the Society for Research in Child Development, for which she receives a stipend. She has received royalties from the publication of Memory in Infancy and Beyond (2007, Erlbaum), and Advances in Child Development and Behavior (Volumes 37 and 38, 2009 and 2010, respectively; Elsevier); and is funded by NIH grants HD067359, HD074724, and HD071845. Dr. Carlozzi is funded by NIH grants R03NS065194, R01NR013658, R01NS077946, U01NS056975. She was previously funded by contracts H133B090024, B6237R, H133G070138, H133A070037-08A and a grant from the NJ Department of Health and Senior Services. Dr. Slotkin reports no disclosures. Dr. Wallner-Allen reports no disclosures. Dr. Fox is funded by NIH grants R37HD017899, MH074454, U01MH080759, R01MH091363, P50MH078105, P01HD064653. He is Associate Editor of the International Journal of Behavioral Development and serves on the scientific board of the National Scientific Council for the Developing Child. Ms. Beaumont served as a consultant for NorthShore University HealthSystem, FACIT. org, and Georgia Gastroenterology Group PC. She received funding for travel as an invited speaker at the North American Neuroendocrine Tumor Symposium. Dr. Mungas is funded by research grants from the National Institute on Aging and a grant from the California Department of Public Health California Alzheimer's Disease Centers program. Dr.; Nowinski receives or has received research support from the National Institutes of Health (contracts HHSN265200423601C, HHSN260200600007C and HHSN267200700027C), the Department of Veteran's Affairs, the Analysis Group, Novartis and Teva Pharmaceuticals. She has also received honoraria for writing and updating an article for Medlink. Dr. Manly is funded by NIH grants R01AG028786, R01AG037212; she had received funding previously from NIH grant R01AG016206 and a grant from the Alzheimer's Association (IIRG 05-14236). She is a consulting editor for the Journal of the International Neuropsychological Society. She serves on the Medical and Scientific Advisory Board of the Alzheimer's Association, and as a member of the Advisory Council on Alzheimer's Research, Care, and Services. Dr. Havlik reports no disclosures. Dr. Conway reports no disclosures. Dr. Moy reports no disclosures. Dr. Edwards reports no disclosures. Dr. Gershon has received personal compensation for activities as a speaker and consultant with Sylvan Learning and the American Board of Podiatric Surgery. He is currently funded by several grants awarded by the NIH: N01-AG-6-0007, HHSN260200600007, 1U01DK082342-01, HD05469, 1RC2AG036498-01; NIDRR: H133B090024. Disclaimer: The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of NIH or any of the sponsoring organizations, agencies, or the U.S. government. NR 50 TC 7 Z9 7 U1 3 U2 14 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 EI 1469-7661 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD JUL PY 2014 VL 20 IS 6 BP 567 EP 578 DI 10.1017/S1355617714000320 PG 12 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA AL7PH UT WOS:000339326300001 PM 24959840 ER PT J AU Heaton, RK Akshoomoff, N Tulsky, D Mungas, D Weintraub, S Dikmen, S Beaumont, J Casaletto, KB Conway, K Slotkin, J Gershon, R AF Heaton, Robert K. Akshoomoff, Natacha Tulsky, David Mungas, Dan Weintraub, Sandra Dikmen, Sureyya Beaumont, Jennifer Casaletto, Kaitlin B. Conway, Kevin Slotkin, Jerry Gershon, Richard TI Reliability and Validity of Composite Scores from the NIH Toolbox Cognition Battery in Adults SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Neuropsychological assessment; Memory; Executive Function; Attention; Cognitive assessment; Cognitive screener ID INTELLIGENCE; ABILITIES; FLUID AB This study describes psychometric properties of the NIH Toolbox Cognition Battery (NIHTB-CB) Composite Scores in an adult sample. The NIHTB-CB was designed for use in epidemiologic studies and clinical trials for ages 3 to 85. A total of 268 self-described healthy adults were recruited at four university-based sites, using stratified sampling guidelines to target demographic variability for age (20-85 years), gender, education, and ethnicity. The NIHTB-CB contains seven computer-based instruments assessing five cognitive sub-domains: Language, Executive Function, Episodic Memory, Processing Speed, and Working Memory. Participants completed the NIHTB-CB, corresponding gold standard validation measures selected to tap the same cognitive abilities, and sociodemographic questionnaires. Three Composite Scores were derived for both the NIHTB-CB and gold standard batteries: "Crystallized Cognition Composite," "Fluid Cognition Composite," and "Total Cognition Composite" scores. NIHTB Composite Scores showed acceptable internal consistency (Cronbach's alphas = 0.84 Crystallized, 0.83 Fluid, 0.77 Total), excellent test-retest reliability (r: 0.86-0.92), strong convergent (r: 0.78-0.90) and discriminant (r: 0.19-0.39) validities versus gold standard composites, and expected age effects (r = 0.18 crystallized, r = -0.68 fluid, r = -0.26 total). Significant relationships with self-reported prior school difficulties and current health status, employment, and presence of a disability provided evidence of external validity. The NIH Toolbox Cognition Battery Composite Scores have excellent reliability and validity, suggesting they can be used effectively in epidemiologic and clinical studies. C1 [Heaton, Robert K.; Akshoomoff, Natacha] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Tulsky, David] NYU, Dept Rehabil Med, Langone Med Ctr, New York, NY USA. [Tulsky, David] NYU, Dept Orthoped Surg, Langone Med Ctr, New York, NY USA. [Tulsky, David] NYU, Dept Gen Med, Langone Med Ctr, New York, NY USA. [Tulsky, David] Kessler Fdn, Spinal Cord Injury, W Orange, NJ USA. [Mungas, Dan] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. [Weintraub, Sandra] Northwestern Feinberg Sch Med, Cognit Neurol & Alzheimers Dis Ctr, Chicago, IL USA. [Weintraub, Sandra] Northwestern Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL USA. [Dikmen, Sureyya] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Beaumont, Jennifer; Slotkin, Jerry; Gershon, Richard] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Casaletto, Kaitlin B.] San Diego State Univ, Univ Calif San Diego, Joint Doctoral Program Clin Psychol, San Diego, CA 92182 USA. [Conway, Kevin] NIDA, Rockville, MD USA. RP Heaton, RK (reprint author), Univ Calif San Diego, Sch Med, Dept Psychiat, 9500 Gillman Dr, La Jolla, CA 92093 USA. EM rheaton@ucsd.edu OI Conway, Kevin/0000-0002-7638-339X FU Blueprint for Neuroscience Research, National Institutes of Health [HHS-N-260-2006-00007-C]; NIH [P30MH062512, P50DA026306, P01DA012065, R01MH060720, R01MH073433, R01MH058076, R01MH078748, R01MH078737, U01MH083506, R01MH083552, R01MH081861]; Institute for Rehabilitation and Research; Frazier Rehabilitation Institute/Jewish Hospital; Craig Hospital; Casa Colina Centers for Rehabilitation; National Institute on Aging; California Department of Public Health California Alzheimer's Disease Centers program; Ken and Ruth Davee Foundation; NIDRR [H133A080035, H133G090022, H133A980023, H133B090024]; DoD [W81XWH-0802-0159]; NINDS [U01 NS 056 975 02]; NHLBI K23 [K23HL085766 NIA, 1RC2AG036498-01]; OppNet [N01-AG-6-0007]; National Institute of Health [H133B090024, N01-AG-6-0007, H133N060022, H133G070138, B6237R, U01AR057929, R01HD054659, R01DC008552, P30AG013854, R01 NS058302, R01HD061400, F31-DA035708, T32-DA31098, 1U5AR057943-01, HHSN260200600007, 1U01DK082342-01, AG-260-06-01, HD05469] FX We thank Abigail Sivan and Edmond Bedjeti (Northwestern University) for their valuable assistance in the validation phase of testing. We also thank the following individuals for their helpful consultation during the development of the NIH Toolbox Cognition Battery: Jean Berko Gleason (Boston University), Rachel Byrne (Kessler Foundation), Gordon Chelune (University of Utah), Nancy Chiaravalotti (Kessler Foundation), Dean Delis (University of California, San Diego), Adele Diamond (University of British Columbia), Roberta Golinkoff (University of Delaware), Kathy Hirsh-Pasek (Temple University), Marilyn Jager Adams (Brown University), Joel Kramer (University of California, San Francisco), Joanie Machamer (University of Washington), Amanda O'Brien (Kessler Foundation), Timothy Salthouse (University of Virginia), Jerry Sweet (University of Chicago), Keith O. Yeates (Ohio State University), and Frank Zelkoe (Northwestern University). This study is funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research, National Institutes of Health, under Contract No. HHS-N-260-2006-00007-C. We have no conflicts of interest to report. Dr. Heaton is funded by NIH grants # P30MH062512, P50DA026306, P01DA012065, R01MH060720, R01MH073433, R01MH058076, R01MH078748, R01MH078737, U01MH083506, R01MH083552, R01MH081861. Dr. Akshoomoff reports no disclosures. Dr. Tulsky is funded by NIH contracts H133B090024, H133N060022, H133G070138, B6237R, cooperative agreement U01AR057929, and grant, R01HD054659. He has received consultant fees from the Institute for Rehabilitation and Research, Frazier Rehabilitation Institute/Jewish Hospital, Craig Hospital, and Casa Colina Centers for Rehabilitation. Dr. Mungas is funded by research grants from the National Institute on Aging and a grant from the California Department of Public Health California Alzheimer's Disease Centers program. Dr. Weintraub is funded by NIH grants # R01DC008552, P30AG013854, and the Ken and Ruth Davee Foundation and conducts clinical neuropsychological evaluations (35% effort) for which her academic-based practice clinic bills. She serves on the editorial board of Dementia & Neuropsychologia and advisory boards of the Turkish Journal of Neurology and Alzheimer's and Dementia. Dr. Dikmen receives research grant funding from NIH R01 NS058302 and R01HD061400, NIDRR H133A080035, NIDRR H133G090022, and NIDRR, H133A980023, and DoD W81XWH-0802-0159. Ms. Beaumont served as a consultant for NorthShore University HealthSystem, FACIT.org, and Georgia Gastroenterology Group PC. She received funding for travel as an invited speaker at the North American Neuroendocrine Tumor Symposium. Ms. Casaletto is supported by NIH grants F31-DA035708 and T32-DA31098. Dr. Conway reports no disclosures. Dr. Slotkin reports no disclosures. Dr. Gershon has received personal compensation for activities as a speaker and consultant with Sylvan Learning, Rockman, and the American Board of Podiatric Surgery. He has several grants awarded by NIH: N01-AG-6-0007, 1U5AR057943-01, HHSN260200600007, 1U01DK082342-01, AG-260-06-01, HD05469, NINDS: U01 NS 056 975 02, NHLBI K23: K23HL085766 NIA; 1RC2AG036498-01; NIDRR: H133B090024, OppNet: N01-AG-6-0007. Disclaimer: The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of NIH or any of the sponsoring organizations, agencies, or the U.S. government. NR 28 TC 10 Z9 10 U1 1 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 EI 1469-7661 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD JUL PY 2014 VL 20 IS 6 BP 588 EP 598 DI 10.1017/S1355617714000241 PG 11 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA AL7PH UT WOS:000339326300003 PM 24960398 ER PT J AU Tulsky, DS Carlozzi, N Chiaravalloti, ND Beaumont, JL Kisala, PA Mungas, D Conway, K Gershon, R AF Tulsky, David S. Carlozzi, Noelle Chiaravalloti, Nancy D. Beaumont, Jennifer L. Kisala, Pamela A. Mungas, Dan Conway, Kevin Gershon, Richard TI NIH Toolbox Cognition Battery (NIHTB-CB): List Sorting Test to Measure Working Memory SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Cognition; Working memory; Memory; Short-term; Neuropsychological tests; Executive function; Adult ID TRAUMATIC BRAIN-INJURY; PROGRESSIVE MULTIPLE-SCLEROSIS; POSITRON EMISSION TOMOGRAPHY; EXECUTIVE FUNCTION; PREFRONTAL CORTEX; BEHAVIORAL FUNCTION; FUNCTIONAL MRI; STILL WORKING; COMPLEX SPAN; SHORT-TERM AB The List Sorting Working Memory Test was designed to assess working memory (WM) as part of the NIH Toolbox Cognition Battery. List Sorting is a sequencing task requiring children and adults to sort and sequence stimuli that are presented visually and auditorily. Validation data are presented for 268 participants ages 20 to 85 years. A subset of participants (N = 89) was retested 7 to 21 days later. As expected, the List Sorting Test had moderately high correlations with other measures of working memory and executive functioning (convergent validity) but a low correlation with a test of receptive vocabulary (discriminant validity). Furthermore, List Sorting demonstrates expected changes over the age span and has excellent test-retest reliability. Collectively, these results provide initial support for the construct validity of the List Sorting Working Memory Measure as a measure of working memory. However, the relationship between the List Sorting Test and general executive function has yet to be determined. C1 [Tulsky, David S.] NYU, Rusk Inst, Dept Rehabil Med, Dept Orthoped Surg,Dept Gen Med,Langone Med Ctr, New York, NY 10016 USA. [Tulsky, David S.; Chiaravalloti, Nancy D.] Kessler Fdn, Spinal Cord Injury Lab, Neuropsychol & Neurosci Lab, West Orange, NJ USA. [Carlozzi, Noelle] Univ Michigan, Dept Phys Med & Rehabil, Ann Arbor, MI 48109 USA. [Beaumont, Jennifer L.; Gershon, Richard] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Tulsky, David S.; Kisala, Pamela A.] NYU, Rusk Inst, Dept Rehabil Med, Langone Med Ctr, New York, NY 10016 USA. [Mungas, Dan] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. [Conway, Kevin] NIDA, Rockville, MD USA. RP Tulsky, DS (reprint author), NYU, Rusk Inst, Dept Rehabil Med, Langone Med Ctr, Ambulatory Care Ctr 240 E 38th St,17th Floor, New York, NY 10016 USA. EM david.tulsky@nyumc.org OI Conway, Kevin/0000-0002-7638-339X FU National Institutes of Health [N01AG60007] FX Funding for this research was provided by contract number N01AG60007 from the National Institutes of Health. The authors have nothing to disclose. NR 106 TC 4 Z9 4 U1 6 U2 13 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 EI 1469-7661 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD JUL PY 2014 VL 20 IS 6 BP 599 EP 610 DI 10.1017/S135561771400040X PG 12 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA AL7PH UT WOS:000339326300004 PM 24959983 ER PT J AU Zelazo, PD Anderson, JE Richler, J Wallner-Allen, K Beaumont, JL Conway, KP Gershon, R Weintraub, S AF Zelazo, Philip David Anderson, Jacob E. Richler, Jennifer Wallner-Allen, Kathleen Beaumont, Jennifer L. Conway, Kevin P. Gershon, Richard Weintraub, Sandra TI NIH Toolbox Cognition Battery (CB): Validation of Executive Function Measures in Adults SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Cognitive control; Cognitive flexibility; Inhibitory control; Lifespan development; Standardized testing; Validation ID LIFE-SPAN; ATTENTIONAL NETWORKS; CHILDREN; TASK; CHILDHOOD; AGE; RESPONSES; MEMORY; MIND AB This study describes psychometric properties of the NIH Toolbox Cognition Battery (NIHTB-CB) executive function measures in an adult sample. The NIHTB-CB was designed for use in epidemiologic studies and clinical trials for ages 3 to 85. A total of 268 self-described healthy adults were recruited at four university-based sites, using stratified sampling guidelines to target demographic variability for age (20-85 years), gender, education and ethnicity. The NIHTB-CB contains two computer-based instruments assessing executive function: the Dimensional Change Card Sort (a measure of cognitive flexibility) and a flanker task (a measure of inhibitory control and selective attention). Participants completed the NIHTB-CB, corresponding gold standard convergent and discriminant measures, and sociodemographic questionnaires. A subset of participants (N = 89) was retested 7 to 21 days later. Results reveal excellent sensitivity to age-related changes during adulthood, excellent test-retest reliability, and adequate to good convergent and discriminant validity. The NIH Toolbox EF measures can be used effectively in epidemiologic and clinical studies. C1 [Zelazo, Philip David; Anderson, Jacob E.] Univ Minnesota, Minneapolis, MN 55455 USA. [Richler, Jennifer] Indiana Univ, Bloomington, IN USA. [Wallner-Allen, Kathleen] Westat Corp, Rockville, MD USA. [Beaumont, Jennifer L.; Gershon, Richard; Weintraub, Sandra] Northwestern Univ, Evanston, IL USA. [Conway, Kevin P.] NIH, Bethesda, MD 20892 USA. RP Zelazo, PD (reprint author), Univ Minnesota, Inst Child Dev, 51 E River Rd, Minneapolis, MN 55455 USA. EM zelazo@umn.edu OI Conway, Kevin/0000-0002-7638-339X FU Blueprint for Neuroscience Research, National Institutes of Health [HHS-N-260-2006-00007-C]; Canadian Institute for Health Research [201963]; NIDDK/NICHD [1699-662-6312]; Character Lab; NIH/NCRR [UL1RR025761]; NIH [N01-AG-6-0007, 1U5AR057943-01, HHSN260200600007, 1U01DK082342-01, AG-260-06-01, HD05469, R01DC008552, P30AG013854]; NINDS [U01 NS 056 975 02]; NHLBI K23 [K23HL085766 NIA, 1RC2AG036498-01]; NIDRR [H133B090024]; OppNet [N01-AG-6-0007]; Ken and Ruth Davee Foundation FX This study was funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research, National Institutes of Health under Contract No. HHS-N-260-2006-00007-C. Disclaimer: The views and opinions expressed in this article are those of the authors and do not necessarily represent the views of the National Institute on Drug Abuse, the National Institutes of Health, or any other governmental agency. COI Disclosures: Dr. Zelazo serves on the editorial boards of Child Development, Development and Psychopathology, Frontiers in Human Neuroscience, Cognitive Development, Emotion, and Developmental Cognitive Neuroscience, and Monographs of the Society for Research in Child Development. He is a Senior Fellow of the Mind and Life Institute and President of the Jean Piaget Society. He receives research funding from the Canadian Institute for Health Research (Grant # 201963), NIDDK/NICHD (1699-662-6312), and the Character Lab. Mr. Anderson reports no disclosures. Dr. Richler is funded by NIH/NCRR grant UL1RR025761. Dr. Wallner-Allen reports no disclosures. Ms. Beaumont served as a consultant for NorthShore University HealthSystem, FACIT.org, and Georgia Gastroenterology Group PC. She received funding for travel as an invited speaker at the North American Neuroendocrine Tumor Symposium. Dr. Conway reports no disclosures. Dr. Gershon has received personal compensation for activities as a speaker and consultant with Sylvan Learning, Rockman, and the American Board of Podiatric Surgery. He has several grants awarded by NIH: N01-AG-6-0007, 1U5AR057943-01, HHSN260200600007, 1U01DK082342-01, AG-260-06-01, HD05469, NINDS: U01 NS 056 975 02, NHLBI K23: K23HL085766 NIA; 1RC2AG036498-01; NIDRR: H133B090024, OppNet: N01-AG-6-0007. Dr. Weintraub is funded by NIH grants # R01DC008552, P30AG013854, and the Ken and Ruth Davee Foundation and conducts clinical neuropsychological evaluations (35% effort) for which her academic-based practice clinic bills. She serves on the editorial board of Dementia & Neuropsychologia and advisory boards of the Turkish Journal of Neurology and Alzheimer's and Dementia. NR 47 TC 4 Z9 4 U1 7 U2 15 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 EI 1469-7661 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD JUL PY 2014 VL 20 IS 6 BP 620 EP 629 DI 10.1017/S1355617714000472 PG 10 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA AL7PH UT WOS:000339326300006 PM 24960301 ER PT J AU Carlozzi, NE Tulsky, DS Chiaravalloti, ND Beaumont, JL Weintraub, S Conway, K Gershon, RC AF Carlozzi, Noelle E. Tulsky, David S. Chiaravalloti, Nancy D. Beaumont, Jennifer L. Weintraub, Sandra Conway, Kevin Gershon, Richard C. TI NIH Toolbox Cognitive Battery (NIHTB-CB): The NIHTB Pattern Comparison Processing Speed Test SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE NIHTB; Processing speed; Pattern Comparison Processing Speed Test; Cognition; Neuropsychological assessment; Mental processes; Outcomes assessment (health care) ID TRAUMATIC BRAIN-INJURY; CHRONIC-FATIGUE-SYNDROME; MULTIPLE-SCLEROSIS; WORKING-MEMORY; SEX-DIFFERENCES; GENERAL INTELLIGENCE; AGE-DIFFERENCES; HEAD-INJURY; ADULT AGE; LIFE-SPAN AB The NIH Toolbox (NIHTB) Pattern Comparison Processing Speed Test was developed to assess processing speed within the NIHTB for the Assessment of Neurological Behavior and Function Cognition Battery (NIHTB-CB). This study highlights validation data collected in adults ages 18-85 on this measure and reports descriptive data, test-retest reliability, construct validity, and preliminary work creating a composite index of processing speed. Results indicated good test-retest reliability. There was also evidence for both convergent and discriminant validity; the Pattern Comparison Processing Speed Test demonstrated moderate significant correlations with other processing speed tests (i.e., WAIS-IV Coding, Symbol Search and Processing Speed Index), small significant correlations with measures of working memory (i.e., WAIS-IV Letter-Number Sequencing and PASAT), and non-significant correlations with a test of vocabulary comprehension (i.e., PPVT-IV). Finally, analyses comparing and combining scores on the NIHTB Pattern Comparison Processing Speed Test with other measures of simple reaction time from the NIHTB-CB indicated that a Processing Speed Composite score performed better than any test examined in isolation. The NIHTB Pattern Comparison Processing Speed Test exhibits several strengths: it is appropriate for use across the lifespan (ages, 3-85 years), it is short and easy to administer, and it has high construct validity. C1 [Carlozzi, Noelle E.] Univ Michigan, Dept Phys Med & Rehabil, Ann Arbor, MI 48109 USA. [Tulsky, David S.] NYU, Rusk Inst, Dept Rehabil Med, Dept Orthoped Surg,Dept Gen Med, New York, NY USA. [Tulsky, David S.] Kessler Fdn, Neuropsychol & Neurosci Lab, Spinal Cord Injury Lab, West Orange, NJ USA. [Chiaravalloti, Nancy D.] Kessler Fdn, Traumat Brain Injury Lab, Neuropsychol & Neurosci Lab, W Orange, NJ USA. [Beaumont, Jennifer L.; Gershon, Richard C.] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Weintraub, Sandra] Northwestern Univ, Dept Psychiat & Cognit Neurol, Chicago, IL 60611 USA. [Weintraub, Sandra] Northwestern Univ, Alzheimers Dis Ctr, Chicago, IL 60611 USA. [Conway, Kevin] NIDA, Washington, DC USA. RP Carlozzi, NE (reprint author), Univ Michigan, Dept Phys Med & Rehabil, North Campus Res Complex,Bldg 14,2800 Plymouth Rd, Ann Arbor, MI 48109 USA. EM carlozzi@med.umich.edu OI Conway, Kevin/0000-0002-7638-339X FU Blueprint for Neuroscience Research, National Institutes of Health [HHS-N-260-2006-00007-C] FX This study is funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research, National Institutes of Health, under Contract No. HHS-N-260-2006-00007-C. The authors do not have any conflicts of interest to report. NR 83 TC 5 Z9 5 U1 15 U2 22 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 EI 1469-7661 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD JUL PY 2014 VL 20 IS 6 BP 630 EP 641 DI 10.1017/S1355617714000319 PG 12 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA AL7PH UT WOS:000339326300007 PM 24960594 ER PT J AU Tempero, M AF Tempero, Margaret TI A Publicly Funded Clinical Trials Network: Do We Need It? SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Tempero, Margaret] Univ Calif San Francisco, Pancreas Ctr, San Francisco, CA 94143 USA. [Tempero, Margaret] NCI Board Sci Counselors Subcomm A, Rockville, MD USA. [Tempero, Margaret] Mayo Clin, Pancreas SPOREs, Rochester, MN USA. [Tempero, Margaret] UAB Minnesota, Birmingham, AL USA. [Tempero, Margaret] Univ Arizona, GI SPORE, Tucson, AZ 85721 USA. [Tempero, Margaret] V Fdn, Alberta Canada Canc Board, Lustgarten Fdn, Pancreat Canc Act Network, Cary, NC USA. [Tempero, Margaret] UNMC Eppley Canc Ctr, Omaha, NE USA. [Tempero, Margaret] Univ Calif San Francisco, Div Med Oncol, San Francisco, CA 94143 USA. [Tempero, Margaret] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Res Programs, San Francisco, CA 94143 USA. RP Tempero, M (reprint author), Univ Calif San Francisco, Pancreas Ctr, San Francisco, CA 94143 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JUL PY 2014 VL 12 IS 7 BP 953 EP 953 PG 1 WC Oncology SC Oncology GA AL1RB UT WOS:000338901800001 PM 24994914 ER PT J AU Jena, AB Prasad, V Romley, JA AF Jena, Anupam B. Prasad, Vinay Romley, John A. TI Long-term Effects of the 2003 ACGME Resident Duty Hour Reform on Hospital Mortality SO MAYO CLINIC PROCEEDINGS LA English DT Letter C1 [Jena, Anupam B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02163 USA. [Jena, Anupam B.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Romley, John A.] Univ So Calif, Leonard D Schaeffer Ctr Hlth Policy & Econ, Los Angeles, CA USA. [Romley, John A.] RAND Corp, Santa Monica, CA USA. RP Jena, AB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02163 USA. OI Prasad, Vinay/0000-0002-6110-8221 FU NIA NIH HHS [R03 AG031990, 1R03AG031990-A1]; NIH HHS [1DP5OD017897-01, DP5 OD017897] NR 8 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD JUL PY 2014 VL 89 IS 7 BP 1023 EP 1025 DI 10.1016/j.mayocp.2014.05.001 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AL0WD UT WOS:000338846900023 PM 24996240 ER PT J AU Wu, JY Li, QDQT Zhou, HP Lu, YY Li, JLM Ma, Y Wang, L Fu, TT Gong, XJ Weintraub, M Wu, SC Ding, H AF Wu, Jianyuan Li, Qingdi Quentin Zhou, Huiping Lu, Yinying Li, Jueli M. Ma, Yao Wang, Li Fu, Tingting Gong, Xingjiang Weintraub, Michael Wu, Shuangchan Ding, Hong TI Selective tumor cell killing by triptolide in p53 wild-type and p53 mutant ovarian carcinomas SO MEDICAL ONCOLOGY LA English DT Article DE Triptolide; Ovarian cancer; Antitumor drug; Apoptosis; Cell cycle; p53 ID CYTOCHROME-C RELEASE; KAPPA-B ACTIVATION; LUNG-CANCER CELLS; INDUCED APOPTOSIS; MYELOGENOUS LEUKEMIA; PATHWAY; DEATH; MITOCHONDRIA; CHEMOTHERAPY; INHIBITION AB Triptolide is a traditional Chinese medicinal herb-derived antineoplastic agent. However, its antitumor activity against gynecologic carcinomas has not yet been well described. It is the purpose of this article to investigate the effect and mechanism of triptolide in human ovarian cancer using both A2780 (p53 wild) and OVCAR-3 (p53 mutated) cells. Our results showed that triptolide exerted a potent inhibitory effect on the growth and proliferation of both cell lines in a dose-and time-dependent manner and that the effect was independent of the expression of p53. In contrast, triptolide had only a marginal cytotoxicity in noncancerous ovary cells, lung fibroblast cells, and macrophage cells, indicating differential inhibitory effects of the drug on cell growth between ovarian cancer cells and normal tissue cells. Exposure of the ovarian cancer cells to triptolide induced apoptosis, as evaluated by annexin V/propidium iodide-labeled flow cytometry. Triptolide-induced apoptosis was accompanied by cytochrome c release and caspase-3 activation and was associated with downregulation of Bcl-2 and upregulation of Bax. Cell cycle analysis demonstrated that treatment with triptolide induced cell cycle S phase arrest in A2780 cells and G2/M phase arrest in OVCAR-3 cells. Further detection by Western blotting revealed that the cell cycle arrest by triptolide in both cell lines occurred in concert with increased expression of p21 CIP1/WAF1. This study shows that triptolide selectively kills ovarian cancer cells with different p53 status predominantly through regulating the coordinate and dynamic cellular processes of proliferation and apoptosis, thereby making it a promising chemotherapeutic agent against a broad spectrum of ovarian carcinomas. C1 [Wu, Jianyuan; Ma, Yao; Wang, Li; Fu, Tingting; Gong, Xingjiang; Wu, Shuangchan; Ding, Hong] Wuhan Univ, Sch Pharmaceut Sci, Minist Educ, Key Lab Combinatorial Biosynth & Drug Discovery, Wuhan 430072, Peoples R China. [Li, Qingdi Quentin; Weintraub, Michael] NCI, NIH, Bethesda, MD 20892 USA. [Zhou, Huiping] Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. [Lu, Yinying] Beijing 302 Hosp, Ctr Therapeut Res Hepatocellular Carcinoma, Beijing 100039, Peoples R China. [Li, Jueli M.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Ding, Hong] Hubei Univ Sci & Technol, Dept Pharmacol, Xianning 437100, Peoples R China. RP Li, QDQT (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM liquenti@mail.nih.gov; dinghong2000@263.net NR 41 TC 4 Z9 7 U1 0 U2 12 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 EI 1559-131X J9 MED ONCOL JI Med. Oncol. PD JUL PY 2014 VL 31 IS 7 AR 14 DI 10.1007/s12032-014-0014-8 PG 11 WC Oncology SC Oncology GA AL3CU UT WOS:000339003700013 PM 24880464 ER PT J AU Palayoor, ST John-Aryankalayil, M Makinde, AY Falduto, MT Magnuson, SR Coleman, CN AF Palayoor, Sanjeewani T. John-Aryankalayil, Molykutty Makinde, Adeola Y. Falduto, Michael T. Magnuson, Scott R. Coleman, C. Norman TI Differential Expression of Stress and Immune Response Pathway Transcripts and miRNAs in Normal Human Endothelial Cells Subjected to Fractionated or Single-Dose Radiation SO MOLECULAR CANCER RESEARCH LA English DT Article ID DNA-DAMAGE RESPONSE; GENE-EXPRESSION; CARDIAC FIBROSIS; GLIOMA-CELLS; CANCER CELLS; THERAPY; APOPTOSIS; IMMUNOTHERAPY; RADIOTHERAPY; MICRORNAS AB Although modern radiotherapy technologies can precisely deliver higher doses of radiation to tumors, thus, reducing overall radiation exposure to normal tissues, moderate dose, and normal tissue toxicity still remains a significant limitation. The present study profiled the global effects on transcript and miR expression in human coronary artery endothelial cells using single-dose irradiation (SD, 10 Gy) or multifractionated irradiation (MF, 2 Gy x 5) regimens. Longitudinal time points were collected after an SD or final dose of MF irradiation for analysis using Agilent Human Gene Expression and miRNA microarray platforms. Compared with SD, the exposure to MF resulted in robust transcript and miR expression changes in terms of the number and magnitude. For data analysis, statistically significant mRNAs (2-fold) and miRs (1.5-fold) were processed by Ingenuity Pathway Analysis to uncover miRs associated with target transcripts from several cellular pathways after irradiation. Interestingly, MF radiation induced a cohort of mRNAs and miRs that coordinate the induction of immune response pathway under tight regulation. In addition, mRNAs and miRs associated with DNA replication, recombination and repair, apoptosis, cardiovascular events, and angiogenesis were revealed. (C) 2014 AACR. C1 [Palayoor, Sanjeewani T.; John-Aryankalayil, Molykutty; Makinde, Adeola Y.; Coleman, C. Norman] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Falduto, Michael T.; Magnuson, Scott R.] GenUs Biosyst Inc, Northbrook, IL USA. RP Palayoor, ST (reprint author), NCI, NIH, 9000 Rockville Pike,Bldg 10,Room B3B406, Bethesda, MD 20892 USA. EM palayoor@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, NCI, NIH FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. NR 48 TC 10 Z9 10 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD JUL PY 2014 VL 12 IS 7 BP 1002 EP 1015 DI 10.1158/1541-7786.MCR-13-0623 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AL7PY UT WOS:000339328200004 PM 24784841 ER PT J AU Mertins, P Yang, F Liu, T Mani, DR Petyuk, VA Gillette, MA Clauser, KR Qiao, JW Gritsenko, MA Moore, RJ Levine, DA Townsend, R Erdmann-Gilmore, P Snider, JE Davies, SR Ruggles, KV Fenyo, D Kitchens, RT Li, SQ Olvera, N Dao, F Rodriguez, H Chan, DW Lieblera, D Whiteb, F Rodland, KD Millsc, GB Smith, RD Paulovichd, AG Ellis, M Carr, SA AF Mertins, Philipp Yang, Feng Liu, Tao Mani, D. R. Petyuk, Vladislav A. Gillette, Michael A. Clauser, Karl R. Qiao, Jana W. Gritsenko, Marina A. Moore, Ronald J. Levine, Douglas A. Townsend, Reid Erdmann-Gilmore, Petra Snider, Jacqueline E. Davies, Sherri R. Ruggles, Kelly V. Fenyo, David Kitchens, R. Thomas Li, Shunqiang Olvera, Narciso Dao, Fanny Rodriguez, Henry Chan, Daniel W. Lieblera, Daniel Whiteb, Forest Rodland, Karin D. Millsc, Gordon B. Smith, Richard D. Paulovichd, Amanda G. Ellis, Matthew Carr, Steven A. TI Ischemia in Tumors Induces Early and Sustained Phosphorylation Changes in Stress Kinase Pathways but Does Not Affect Global Protein Levels SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID COMPREHENSIVE GENOMIC CHARACTERIZATION; BREAST-CANCER; POSTTRANSLATIONAL MODIFICATIONS; ENDOMETRIAL CARCINOMA; INTERACTION NETWORKS; OXIDATIVE STRESS; EXPRESSION; ACTIVATION; INDICATORS; FIXATION AB Protein abundance and phosphorylation convey important information about pathway activity and molecular pathophysiology in diseases including cancer, providing biological insight, informing drug and diagnostic development, and guiding therapeutic intervention. Analyzed tissues are usually collected without tight regulation or documentation of ischemic time. To evaluate the impact of ischemia, we collected human ovarian tumor and breast cancer xenograft tissue without vascular interruption and performed quantitative proteomics and phosphoproteomics after defined ischemic intervals. Although the global expressed proteome and most of the >25,000 quantified phosphosites were unchanged after 60 min, rapid phosphorylation changes were observed in up to 24% of the phosphoproteome, representing activation of critical cancer pathways related to stress response, transcriptional regulation, and cell death. Both pan-tumor and tissue-specific changes were observed. The demonstrated impact of pre-analytical tissue ischemia on tumor biology mandates caution in interpreting stress-pathway activation in such samples and motivates reexamination of collection protocols for phosphoprotein analysis. C1 [Mertins, Philipp; Mani, D. R.; Gillette, Michael A.; Clauser, Karl R.; Qiao, Jana W.; Carr, Steven A.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Yang, Feng; Liu, Tao; Petyuk, Vladislav A.; Gritsenko, Marina A.; Moore, Ronald J.; Rodland, Karin D.; Smith, Richard D.] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Levine, Douglas A.; Olvera, Narciso; Dao, Fanny] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10065 USA. [Townsend, Reid; Erdmann-Gilmore, Petra; Snider, Jacqueline E.; Davies, Sherri R.; Kitchens, R. Thomas; Li, Shunqiang; Ellis, Matthew] Washington Univ, Dept Med, St Louis, MO 63110 USA. [Ruggles, Kelly V.; Fenyo, David] NYU, Dept Biochem, Langone Med Ctr, New York, NY 10016 USA. [Rodriguez, Henry] NCI, NIH, Bethesda, MD 20892 USA. [Chan, Daniel W.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. [Lieblera, Daniel] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. [Whiteb, Forest] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Millsc, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Paulovichd, Amanda G.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. RP Carr, SA (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM pmertins@broadinstitute.org; scarr@broad.mit.edu RI Smith, Richard/J-3664-2012; OI Smith, Richard/0000-0002-2381-2349; Petyuk, Vladislav/0000-0003-4076-151X; Liebler, Daniel/0000-0002-7873-3031; Fenyo, David/0000-0001-5049-3825; Ruggles, Kelly/0000-0002-0152-0863 FU NCI, National Institutes of Health, NCI Clinical Proteomics Tumor Analysis Consortium [U24CA160034, U24CA160019, U24CA160035, U24CA159988, U24CA160036]; Susan G. Komen for the Cure [BCTR0707808, KG090422]; NCI, National Institutes of Health [P30CA091842, 3P50 CA68438]; CTSA [UL1 RR024992]; MD Anderson Cancer Center Support Grant (CCSG) from National Institutes of Health [CA016672]; [PO1CA099031]; [U54CA112970]; [KG081694]; [P30 CA16672] FX This work was supported, in whole or in part, by grants from the NCI, National Institutes of Health (Grant Nos. U24CA160034 to S. A. C. and A. G. P., U24CA160019 to R. D. S. and K. D. R., U24CA160035 to M.J.E. and R. R. T., U24CA159988 to D. L., and U24CA160036 to D. C.), as part of the NCI Clinical Proteomics Tumor Analysis Consortium. The PDX models were developed through grants to Matthew J. Ellis by Susan G. Komen for the Cure (Grant Nos. BCTR0707808 and KG090422). The Siteman Cancer Center Tissue Procurement Core is supported by Grant No. P30CA091842 from NCI, National Institutes of Health. Tissue procurement core was supported Grant No. 3P50 CA68438 from NCI, National Institutes of Health. The HAMLET Core was supported by CTSA grant UL1 RR024992. The ovarian cancer sample collection was supported by the Chia Family Foundation. The RPPA analysis was supported by MD Anderson Cancer Center Support Grant (CCSG) CA016672 from National Institutes of Health and Grant Nos. PO1CA099031, U54CA112970, KG081694, and P30 CA16672 to Gordon Mills. NR 41 TC 67 Z9 68 U1 3 U2 17 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 JUL PY 2014 VL 13 IS 7 BP 1690 EP 1704 DI 10.1074/mcp.M113.036392 PG 15 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AL6OD UT WOS:000339251300005 PM 24719451 ER PT J AU Repunte-Canonigo, V Lefebvre, C George, O Kawamura, T Morales, M Koob, GF Califano, A Masliah, E Sanna, PP AF Repunte-Canonigo, Vez Lefebvre, Celine George, Olivier Kawamura, Tomoya Morales, Marisela Koob, George F. Califano, Andrea Masliah, Eliezer Sanna, Pietro Paolo TI Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats SO MOLECULAR NEURODEGENERATION LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; CENTRAL-NERVOUS-SYSTEM; GROWTH-FACTOR-I; LONG-TERM POTENTIATION; AIDS DEMENTIA COMPLEX; NECROSIS-FACTOR-ALPHA; BLOOD-BRAIN-BARRIER; NEUROCOGNITIVE DISORDERS; PARKINSONS-DISEASE; SYNAPTIC PLASTICITY AB Background: A thorough investigation of the neurobiology of HIV-induced neuronal dysfunction and its evolving phenotype in the setting of viral suppression has been limited by the lack of validated small animal models to probe the effects of concomitant low level expression of multiple HIV-1 products in disease-relevant cells in the CNS. Results: We report the results of gene expression profiling of the hippocampus of HIV-1 Tg rats, a rodent model of HIV infection in which multiple HIV-1 proteins are expressed under the control of the viral LTR promoter in disease-relevant cells including microglia and astrocytes. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analysis. Gene expression changes observed are consistent with astrogliosis and microgliosis and include evidence of inflammation and cell proliferation. Among the genes with increased expression in HIV-1 Tg rats was the interferon stimulated gene 15 (ISG-15), which was previously shown to be increased in the cerebrospinal fluid (CSF) of HIV patients and to correlate with neuropsychological impairment and neuropathology, and prostaglandin D2 (PGD2) synthase (Ptgds), which has been associated with immune activation and the induction of astrogliosis and microgliosis. GSEA-based pathway analysis highlighted a broad dysregulation of genes involved in neuronal trophism and neurodegenerative disorders. Among the latter are genesets associated with Huntington's disease, Parkinson's disease, mitochondrial, peroxisome function, and synaptic trophism and plasticity, such as IGF, ErbB and netrin signaling and the PI3K signal transduction pathway, a mediator of neural plasticity and of a vast array of trophic signals. Additionally, gene expression analyses also show altered lipid metabolism and peroxisomes dysfunction. Supporting the functional significance of these gene expression alterations, HIV-1 Tg rats showed working memory impairments in spontaneous alternation behavior in the T-Maze, a paradigm sensitive to prefrontal cortex and hippocampal function. Conclusions: Altogether, differentially regulated genes and pathway analysis identify specific pathways that can be targeted therapeutically to increase trophic support, e.g. IGF, ErbB and netrin signaling, and reduce neuroinflammation, e.g. PGD2 synthesis, which may be beneficial in the treatment of chronic forms of HIV-associated neurocognitive disorders in the setting of viral suppression. C1 [Repunte-Canonigo, Vez; Kawamura, Tomoya; Sanna, Pietro Paolo] Mol & Cellular Neurosci Dept, La Jolla, CA 92037 USA. [George, Olivier; Koob, George F.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Lefebvre, Celine] Inst Gustave Roussy, INSERM, Unit U981, F-94805 Villejuif, France. [Morales, Marisela] Natl Inst Drug Abuse, Neuronal Networks Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Koob, George F.] NIAAA, Rockville, MD 20852 USA. [Califano, Andrea] Columbia Univ, Dept Syst Biol, New York, NY 10032 USA. [Masliah, Eliezer] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP Sanna, PP (reprint author), Mol & Cellular Neurosci Dept, La Jolla, CA 92037 USA. EM psanna@scripps.edu RI George, Olivier/G-9921-2011; Lefebvre, Celine/E-6290-2013; koob, george/P-8791-2016 OI George, Olivier/0000-0002-3700-5003; FU NIH [AA006420, AA020608, DA004398, MH062962, MH062512, CA121852, AA021667, HL111566, MH090956, MH064376] FX Supported by NIH grants AA006420, AA020608, DA004398 (OG); MH062962, MH062512 (EM); CA121852, AA021667, HL111566 (AC); and MH090956, MH064376 (PPS). NR 130 TC 9 Z9 9 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD JUL 1 PY 2014 VL 9 AR 26 DI 10.1186/1750-1326-9-26 PG 15 WC Neurosciences SC Neurosciences & Neurology GA AL7BD UT WOS:000339287000001 PM 24980976 ER PT J AU Iwamoto, T Brooks, PJ Nishiwaki, T Nishimura, K Kobayashi, N Sugiura, S Mori, T AF Iwamoto, Takaaki Brooks, Philip J. Nishiwaki, Tomohisa Nishimura, Kazuki Kobayashi, Nobuhiko Sugiura, Shigeki Mori, Toshio TI Quantitative and in situ Detection of Oxidatively Generated DNA Damage 8,5 '-Cyclo-2 '-Deoxyadenosine Using an Immunoassay with a Novel Monoclonal Antibody SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; RADICAL-INDUCED FORMATION; IRRADIATED NUCLEIC-ACIDS; FENTON-TYPE REAGENTS; XERODERMA-PIGMENTOSUM; HUMAN-CELLS; COCKAYNE-SYNDROME; MAMMALIAN-CELLS; CELLULAR-DNA; LESIONS AB Xeroderma pigmentosum (XP) is a genetic disorder associated with defects in nucleotide excision repair, which eliminates a wide variety of helix-distorting types of DNA damage including sunlight-induced pyrimidine dimers. In addition to skin disease, approximately 30% of XP patients develop progressive neurological disease, which has been hypothesized to be associated with the accumulation of a particular type of oxidatively generated DNA damage called purine 8,5'-cyclo-2'-deoxynucleosides (purine cyclonucleosides). However, there are no currently available methods to detect purine cyclonucleosides in DNA without the need for DNA hydrolysis. In this study, we generated a novel monoclonal antibody (CdA-1) specific for purine cyclonucleosides in single-stranded DNA that recognizes 8,5'-cyclo-2'-deoxyadenosine (cyclo-dA). An immunoassay using CdA-1 revealed a linear dose response between known amounts of cyclo-dA in oligonucleotides and the antibody binding to them. The quantitative immunoassay revealed that treatment with Fenton-type reagents (CuCl2/H2O2/ascorbate) efficiently produces cyclo-dA in DNA in a dose-dependent manner. Moreover, immunofluorescent analysis using CdA-1 enabled the visualization of cyclo-dA in human osteosarcoma cells, which had been transfected with oligonucleotides containing cyclo-dA. Thus, the CdA-1 antibody is a valuable tool for the detection and quantification of cyclo-dA in DNA, and may be useful for characterizing the mechanism(s) underlying the development of XP neurological disease. C1 [Iwamoto, Takaaki; Nishiwaki, Tomohisa; Nishimura, Kazuki; Mori, Toshio] Nara Med Univ, Sch Med, Radioisotope Res Ctr, Kashihara, Nara 634, Japan. [Brooks, Philip J.] NIAAA, Neurogenet Lab, Bethesda, MD USA. [Kobayashi, Nobuhiko] Nara Med Univ, Sch Med, Dept Dermatol, Kashihara, Nara 634, Japan. [Sugiura, Shigeki] Nara Med Univ, Sch Med, Med Genet Res Ctr, Kashihara, Nara 634, Japan. RP Mori, T (reprint author), Nara Med Univ, Sch Med, Radioisotope Res Ctr, Kashihara, Nara 634, Japan. EM tmori@naramed-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan [24790895, 24651052, 23510081] FX This study has been supported in part by the Ministry of Education, Culture, Sports, Science and Technology of Japan (24790895 to T. I., 24651052 to S. S., 23510081 to T. M.). The authors thank Drs. D. Gasparutto and J. Cadet (CEA/Grenoble) for 5'S-cyclo-dA-oligo14 and 5'R-cyclo-dA-oligo14, and Dr. A. Takahashi (Gunma University) for the human osteosarcoma cell line (U2OS). NR 48 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0031-8655 EI 1751-1097 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL-AUG PY 2014 VL 90 IS 4 BP 829 EP 836 DI 10.1111/php.12239 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AL4IM UT WOS:000339096400012 PM 24471831 ER PT J AU Forsythe, LP Alfano, CM Kent, EE Weaver, KE Bellizzi, K Arora, N Aziz, N Keel, G Rowland, JH AF Forsythe, Laura P. Alfano, Catherine M. Kent, Erin E. Weaver, Kathryn E. Bellizzi, Keith Arora, Neeraj Aziz, Noreen Keel, Gretchen Rowland, Julia H. TI Social support, self-efficacy for decision-making, and follow-up care use in long-term cancer survivors SO PSYCHO-ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; AFRICAN-AMERICAN WOMEN; BREAST-CANCER; SOCIOECONOMIC-STATUS; PSYCHOSOCIAL FACTORS; TREATMENT ADHERENCE; PROSTATE-CANCER; HEALTH; IMPACT; OLDER AB Objective: Cancer survivors play an important role in coordinating their follow-up care and making treatment-related decisions. Little is known about how modifiable factors such as social support are associated with active participation in follow-up care. This study tests associations between social support, cancer-related follow-up care use, and self-efficacy for participation in decision-making related to follow-up care (SEDM). We also identified sociodemographic and clinical factors associated with social support among long-term survivors. Methods: The FOllow-up Care Use among Survivors study is a cross-sectional, population-based survey of breast, prostate, colon, and gynecologic cancer survivors (n = 1522) 4-14 years post-diagnosis. Multivariable regression models were used to test associations between perceived social support (tangible and emotional/informational support modeled separately), follow-up care use (past 2 years), and SEDM, as well as to identify factors associated with perceived support. Results: Neither support type was associated with follow-up care use (all p > 0.05), although marital status was uniquely, positively associated with follow-up care use (p < 0.05). Both tangible support (B for a standard deviation increase (SE) = 9.75(3.15), p < 0.05) and emotional/informational support (B(SE) = 12.61(3.05), p < 0.001) were modestly associated with SEDM. Being married, having adequate financial resources, history of recurrence, and better perceived health status were associated with higher perceived tangible and emotional support (all p < 0.05). Conclusions: While perceived social support may facilitate survivor efficacy for participation in decision-making during cancer follow-up care, other factors, including marital satisfaction, appear to influence follow-up care use. Marital status and social support may be important factors to consider in survivorship care planning. Copyright (C) 2014 John Wiley & Sons, Ltd. C1 [Forsythe, Laura P.] PCORI, Washington, DC 20036 USA. [Forsythe, Laura P.; Alfano, Catherine M.; Rowland, Julia H.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH,DHHS, Bethesda, MD 20892 USA. [Forsythe, Laura P.; Kent, Erin E.] NCI, Canc Prevent Fellowship Program, Ctr Canc Training, NIH,DHHS, Bethesda, MD 20892 USA. [Kent, Erin E.; Arora, Neeraj] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci,NIH,DHHS, Bethesda, MD 20892 USA. [Weaver, Kathryn E.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Social Sci & Hlth Policy, Winston Salem, NC USA. [Bellizzi, Keith] Univ Connecticut, Storrs, CT USA. [Aziz, Noreen] NINR, Off Extramural Programs, NIH, DHHS, Bethesda, MD 20892 USA. [Keel, Gretchen] IMS, Silver Spring, MD USA. RP Forsythe, LP (reprint author), PCORI, 1828 L St NW,Suite 900, Washington, DC 20036 USA. EM lforsythe@pcori.org FU National Cancer Institute at the NIH [N01-PC-35136, HHSN 261201100189P] FX This work was supported by the National Cancer Institute at the NIH. Contracts No. N01-PC-35136 and HHSN 261201100189P. NR 49 TC 7 Z9 7 U1 4 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD JUL PY 2014 VL 23 IS 7 BP 788 EP 796 DI 10.1002/pon.3480 PG 9 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AL4IW UT WOS:000339097400009 PM 24481884 ER PT J AU Brodie, FL Ruggiero, J Ghodasra, DH Hui, JZ Vanderbeek, BL Brucker, AJ AF Brodie, Frank L. Ruggiero, Jason Ghodasra, Devon H. Hui, James Z. Vanderbeek, Brian L. Brucker, Alexander J. TI VOLUME AND COMPOSITION OF REFLUX AFTER INTRAVITREAL INJECTION SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE reflux; intravitreal injection ID MACULAR DEGENERATION; AFLIBERCEPT; THERAPY AB Purpose: To quantify the amount of drug loss from cadaveric human eyes, which are injected via the pars plana with a known volume of dye at variable intraocular pressures. Methods: Eight cadaver eyes were divided into 2 intraocular pressure groups: normal (15 mmHg; 4 eyes) or high (30 mmHg; 4 eyes). Each eye was injected with 50 mu L of hematoxylin dye, and the subsequent reflux was immediately collected on a Schirmer's test strip. The test strip was scanned and digitally analyzed to determine the area of saturation and total color intensity present. Using a previously established equation, total volume of reflux and the amount of dye within that reflux were calculated. Results: The average total volume of refluxed fluid was 1.68 mu L (median, 0.62 mu L), with a range of 0 mu L to 8.05 mu L. The average volume of refluxed dye was 0.37 mu L (median, 0.08 mu L), with a range of 0 mu L to 2.15 mu L. On average, only 0.74% of the original 50 mu L of injected dye was lost (median, 0.15%), with a range from 0% to 4.30%. Conclusion: Although the presence of subconjunctival bleb formation after intravitreal injection may be a concern to the clinician, data from the present study shows that only a very small amount of the injected therapeutic agent is lost in the reflux. C1 [Brodie, Frank L.; Ruggiero, Jason; Ghodasra, Devon H.; Vanderbeek, Brian L.; Brucker, Alexander J.] Univ Penn, Scheie Eye Inst, Dept Ophthalmol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hui, James Z.] Univ Penn, Penn HHMI NIBIB Interface Program Biomed Imaging, Dept Bioengn, Philadelphia, PA 19104 USA. [Vanderbeek, Brian L.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Brucker, AJ (reprint author), Univ Penn, Scheie Eye Inst, Dept Ophthalmol, Perelman Sch Med, 51 North,39th St, Philadelphia, PA 19104 USA. EM ajbrucke@mail.med.upenn.edu FU Richard H. Chartrand Eye Research Foundation; Hope for Vision; National Institutes of Health K12 Award [K12-EY015398]; Research to Prevent Blindness; Paul and Evanina Mackall Foundation; HHMI-NIBIB Biomedical Interface Program Training Grant FX Supported by grants from The Richard H. Chartrand Eye Research Foundation; Hope for Vision; National Institutes of Health K12 Award (B.L.VB.; K12-EY015398). Additional funding was provided by the Research to Prevent Blindness, the Paul and Evanina Mackall Foundation, and the HHMI-NIBIB Biomedical Interface Program Training Grant. NR 14 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD JUL PY 2014 VL 34 IS 7 BP 1473 EP 1476 PG 4 WC Ophthalmology SC Ophthalmology GA AK9UG UT WOS:000338772600028 PM 24451925 ER PT J AU Chaigne-Delalande, B Lenardo, MJ AF Chaigne-Delalande, Benjamin Lenardo, Michael J. TI Divalent cation signaling in immune cells SO TRENDS IN IMMUNOLOGY LA English DT Review ID MITOCHONDRIAL CALCIUM UNIPORTER; BLOOD MONONUCLEAR-CELLS; METAL-ION-BINDING; HUMAN T-CELLS; CA2+ INFLUX; LYMPHOCYTE FUNCTION; ZINC HOMEOSTASIS; MG2+ TRANSPORTER; PERIPHERAL-BLOOD; MAGNESIUM HOMEOSTASIS AB Divalent cations of two alkaline earth metals Ca2+ and Mg2+ and the transition metal Zn2+ play vital roles in the immune system, and several immune disorders are associated with disturbances of their function. Until recently only Ca2+ was considered to serve as a second messenger. However, signaling roles for Mg2+ and Zn2+ have been recently described, leading to a reevaluation of their role as potential second messengers. We review here the roles of these cations as second messengers in light of recent advances in Ca2+, Mg2+, and Zn2+ signaling in the immune system. Developing a better understanding of these signaling cations may lead to new therapeutic strategies for immune disorders. C1 [Chaigne-Delalande, Benjamin; Lenardo, Michael J.] NIAID, Mol Dev Immune Syst Sect, Lymphocyte Mol Genet Unit, Lab Immunol,NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Mol Dev Immune Syst Sect, Lymphocyte Mol Genet Unit, Lab Immunol,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lenardo@NIH.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. We thank past and present members of the laboratory of M.J.L. for their intellectual and experimental contributions to this review. We thank our colleagues at Merck for generous collaborative support. We apologize to the many investigators whose work could not be cited owing to space limitations. NR 129 TC 10 Z9 10 U1 1 U2 22 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 EI 1471-4981 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUL PY 2014 VL 35 IS 7 BP 332 EP 344 DI 10.1016/j.it.2014.05.001 PG 13 WC Immunology SC Immunology GA AL3OO UT WOS:000339038300006 PM 24932518 ER PT J AU Luo, ZP Dauter, M Dauter, Z AF Luo, Zhipu Dauter, Miroslawa Dauter, Zbigniew TI Phosphates in the Z-DNA dodecamer are flexible, but their P-SAD signal is sufficient for structure solution SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID HANDED Z-DNA; X-RAY-DIFFRACTION; SINGLE-CRYSTAL STRUCTURE; 1.0-A ATOMIC RESOLUTION; PURE-SPERMINE FORM; DOUBLE-HELICAL DNA; BASE-PAIRS; MOLECULAR-STRUCTURE; ANGSTROM RESOLUTION; MINOR-GROOVE AB A large number of Z-DNA hexamer duplex structures and a few oligomers of different lengths are available, but here the first crystal structure of the d(CGCGCGCGCGCG)(2) dodecameric duplex is presented. Two synchrotron data sets were collected; one was used to solve the structure by the single-wavelength anomalous dispersion (SAD) approach based on the anomalous signal of P atoms, the other set, extending to an ultrahigh resolution of 0.75 angstrom, served to refine the atomic model to an R factor of 12.2% and an R-free of 13.4%. The structure consists of parallel duplexes arranged into practically infinitely long helices packed in a hexagonal fashion, analogous to all other known structures of Z-DNA oligomers. However, the dodecamer molecule shows a high level of flexibility, especially of the backbone phosphate groups, with six out of 11 phosphates modeled in double orientations corresponding to the two previously observed Z-DNA conformations: Z(I), with the phosphate groups inclined towards the inside of the helix, and Z(II), with the phosphate groups rotated towards the outside of the helix. C1 [Luo, Zhipu; Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne Natl Lab, Argonne, IL 60439 USA. [Dauter, Miroslawa] Argonne Natl Lab, Leidos Biomed Res Inc, Basic Res Program, Argonne, IL 60439 USA. RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne Natl Lab, Argonne, IL 60439 USA. EM dauter@anl.gov RI Luo, Zhipu/P-9168-2014 FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [NO1-CO-12400]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX This project was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and with Federal funds from the National Cancer Institute, National Institutes of Health (Contract No. NO1-CO-12400). Diffraction data were collected at the NE-CAT beamline 24-ID and SER-CAT beamline 22-ID at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. NR 83 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1399-0047 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JUL PY 2014 VL 70 BP 1790 EP 1800 DI 10.1107/S1399004714004684 PN 7 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA AL1WM UT WOS:000338917000001 PM 25004957 ER PT J AU Bhaumik, P Davis, J Tropea, JE Cherry, S Johnson, PF Miller, M AF Bhaumik, Prasenjit Davis, Jamaine Tropea, Joseph E. Cherry, Scott Johnson, Peter F. Miller, Maria TI Structural insights into interactions of C/EBP transcriptional activators with the Taz2 domain of p300 SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID BINDING PROTEIN; PHOSPHORYLATION; BETA; COACTIVATOR; CBP; RECRUITMENT; REFINEMENT; CBP/P300; SOFTWARE; ENHANCER AB Members of the C/EBP family of transcription factors bind to the Taz2 domain of p300/CBP and mediate its phosphorylation through the recruitment of specific kinases. Short sequence motifs termed homology boxes A and B, which comprise their minimal transactivation domains (TADs), are conserved between C/EBP activators and are necessary for specific p300/CBP binding. A possible mode of interaction between C/EBP TADs and the p300 Taz2 domain was implied by the crystal structure of a chimeric protein composed of residues 1723-1818 of p300 Taz2 and residues 37-61 of C/EBP epsilon. The segment corresponding to the C/EBP epsilon TAD forms two orthogonally disposed helices connected by a short linker and interacts with the core structure of Taz2 from a symmetry-related molecule. It is proposed that other members of the C/EBP family interact with the Taz2 domain in the same manner. The position of the C/EBP epsilon peptide on the Taz2 protein interaction surface suggests that the N-termini of C/EBP proteins are unbound in the C/EBP-p300 Taz2 complex. This observation is in agreement with the known location of the docking site of protein kinase HIPK2 in the C/EBP beta N-terminus, which associates with the C/EBP beta-p300 complex. C1 [Bhaumik, Prasenjit; Davis, Jamaine; Miller, Maria] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Tropea, Joseph E.; Cherry, Scott] NCI, Prot Purificat Core, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Johnson, Peter F.] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Miller, M (reprint author), NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM mariami@mail.nih.gov RI Miller, Maria/I-1636-2013; OI Miller, Maria/0000-0003-0252-5348; Johnson, Peter/0000-0002-4145-4725 FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Dr Alexander Wlodawer for support and Dr George Lountos for critical reading of the manuscript. We acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT) located at the Advanced Photon Source, Argonne National Laboratory. This project was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 7 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1399-0047 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JUL PY 2014 VL 70 BP 1914 EP 1921 DI 10.1107/S1399004714009262 PN 7 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA AL1WM UT WOS:000338917000012 PM 25004968 ER PT J AU Kim, J Jang, SG Kwon, SY Park, YS Kang, HS Green, JE Kim, HK Ro, J AF Kim, Joseph Jang, Sang-Geun Kwon, Sun Young Park, Young Soo Kang, Han Sung Green, Jeffrey E. Kim, Hark Kyun Ro, Jungsil TI MicroRNA Signature for HER2-positive Breast and Gastric Cancer SO ANTICANCER RESEARCH LA English DT Article DE miR-139; miR-129; HER2; breast cancer; gastric cancer ID CELLS; HER2 AB Background/Aim: The molecular mechanism for aggressive clinical behaviour related to v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) amplification is not fully-understood. In particular, little is known about microRNAs in the human epidermal growth factor receptor 2 (HER2) signaling network. Patients and Methods: Using microRNA microarray, the microRNA profiles of 16 HER2-positive breast carcinomas were compared with those of five luminal-type breast carcinomas. Additionally, two frozen, ERBB2-amplified gastric carcinomas were compared with their adjacent normal tissue samples. MicroRNAs that were differentially expressed according to the HER2 status in breast and gastric carcinomas were identified as the HER2 microRNA signature. Results: MiR-337 and miR-302f were commonly overexpressed in HER2-postive breast and gastric cancer. MiR-139 and miR-129 were commonly underexpressed in HER2-positive breast and gastric cancer. A concordant pattern of microRNA expression was noted between discovery sets and the majority of candidate microRNAs (two out of three) in three validation sets. Conclusion: Our study identified novel microRNAs that were differentially expressed according to the HER2 status across different tumor types. C1 [Kim, Joseph; Jang, Sang-Geun; Kang, Han Sung; Kim, Hark Kyun; Ro, Jungsil] Natl Canc Ctr, Goyang 410769, Gyeonggi, South Korea. [Kwon, Sun Young] Keimyung Univ, Dongsan Med Ctr, Taegu, South Korea. [Park, Young Soo] Asan Med Ctr, Seoul, South Korea. [Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Ro, J (reprint author), Natl Canc Ctr, Ctr Breast Canc, 323 Ilsanro, Goyang 410769, Gyeonggi, South Korea. EM hkim@ncc.re.kr; jungsro@ncc.re.kr FU NCC [1210051]; Proteogenomic Program; Converging Research Center Program - Korean Ministry of Science, ICT, and Future Planning [2013K000429]; Ministry of Health, Welfare and Family Affairs; National Cancer Center Tumor Bank FX The work was supported by the NCC Grant 1210051; by Proteogenomic Program; and by Converging Research Center Program (2013K000429) funded by the Korean Ministry of Science, ICT, and Future Planning. Biospecimens for this study were provided by Asan Medical Cancer and Keimyung University Medical Center, which are members of the National Biobank of Korea that is supported by the Ministry of Health, Welfare and Family Affairs, and the National Cancer Center Tumor Bank. NR 11 TC 10 Z9 10 U1 2 U2 7 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD JUL PY 2014 VL 34 IS 7 BP 3807 EP 3810 PG 4 WC Oncology SC Oncology GA AK9WW UT WOS:000338780300080 ER PT J AU Kruppa, J Liu, YF Biau, G Kohler, M Konig, IR Malley, JD Ziegler, A AF Kruppa, Jochen Liu, Yufeng Biau, Gerard Kohler, Michael Koenig, Inke R. Malley, James D. Ziegler, Andreas TI Probability estimation with machine learning methods for dichotomous and multicategory outcome: Theory SO BIOMETRICAL JOURNAL LA English DT Article DE Bagged nearest neighbor; Nonparametric regression; Probability estimation; Random forest; Support vector machine ID SUPPORT VECTOR MACHINES; NEAREST-NEIGHBOR CLASSIFIERS; STRONG UNIVERSAL CONSISTENCY; LARGE-MARGIN CLASSIFIERS; RANDOM FORESTS; NONPARAMETRIC REGRESSION; CLASSIFICATION METHODS; LOGISTIC-REGRESSION; RISK MINIMIZATION; DANTZIG SELECTOR AB Probability estimation for binary and multicategory outcome using logistic and multinomial logistic regression has a long-standing tradition in biostatistics. However, biases may occur if the model is misspecified. In contrast, outcome probabilities for individuals can be estimated consistently with machine learning approaches, including k-nearest neighbors (k-NN), bagged nearest neighbors (b-NN), random forests (RF), and support vector machines (SVM). Because machine learning methods are rarely used by applied biostatisticians, the primary goal of this paper is to explain the concept of probability estimation with these methods and to summarize recent theoretical findings. Probability estimation in k-NN, b-NN, and RF can be embedded into the class of nonparametric regression learning machines; therefore, we start with the construction of nonparametric regression estimates and review results on consistency and rates of convergence. In SVMs, outcome probabilities for individuals are estimated consistently by repeatedly solving classification problems. For SVMs we review classification problem and then dichotomous probability estimation. Next we extend the algorithms for estimating probabilities using k-NN, b-NN, and RF to multicategory outcomes and discuss approaches for the multicategory probability estimation problem using SVM. In simulation studies for dichotomous and multicategory dependent variables we demonstrate the general validity of the machine learning methods and compare it with logistic regression. However, each method fails in at least one simulation scenario. We conclude with a discussion of the failures and give recommendations for selecting and tuning the methods. Applications to real data and example code are provided in a companion article C1 [Kruppa, Jochen; Koenig, Inke R.; Ziegler, Andreas] Med Univ Lubeck, Inst Med Biometrie & Stat, Univ Klinikum Schleswig Holstein, D-23562 Lubeck, Germany. [Liu, Yufeng] Univ N Carolina, Carolina Ctr Genome Sci, Dept Stat & Operat Res, Chapel Hill, NC 27599 USA. [Biau, Gerard] Univ Paris 06, F-75252 Paris 05, France. [Biau, Gerard] Ecole Normale Super, Dept Math & Applicat, F-75230 Paris 05, France. [Kohler, Michael] Tech Univ Darmstadt, Fachbereich Math, D-64289 Darmstadt, Germany. [Malley, James D.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Ziegler, Andreas] Zentrum Klin Studien Lubeck, D-23562 Lubeck, Germany. RP Ziegler, A (reprint author), Med Univ Lubeck, Inst Med Biometrie & Stat, Univ Klinikum Schleswig Holstein, Campus Lubeck,Ratzeburger Allee 160,Haus 24, D-23562 Lubeck, Germany. EM ziegler@imbs.uni-luebeck.de RI Konig, Inke/A-4544-2009; OI Ziegler, Andreas/0000-0002-8386-5397 FU German Region of the International Biometric Society; European Union [HEALTH-2011-278913]; German Ministry of Education and Research [01KU0908A, 01KU0908B, 0315536F]; US National Institute of Health [NIH/NCI R01 CA-149569] FX This paper is the summary from a workshop, entitled "Probability Estimation With Data Mining Methods" held at the Meeting of the Central European Network 2011 in Zurich, Switzerland. The authors are grateful to the German Region of the International Biometric Society for their generous funding of the Workshop.; A.Z. acknowledges funding from the European Union (BiomarCare, grant number: HEALTH-2011-278913), and the German Ministry of Education and Research (CARDomics, grant numbers: 01KU0908A and 01KU0908B; Phenomics, grant number: 0315536F). Y.L. acknowledges funding from the US National Institute of Health, grant NIH/NCI R01 CA-149569. NR 105 TC 21 Z9 21 U1 5 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 EI 1521-4036 J9 BIOMETRICAL J JI Biom. J. PD JUL PY 2014 VL 56 IS 4 SI SI BP 534 EP 563 DI 10.1002/bimj.201300068 PG 30 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA AL2GU UT WOS:000338944700002 PM 24478134 ER PT J AU Simon, R AF Simon, Richard TI Class probability estimation for medical studies SO BIOMETRICAL JOURNAL LA English DT Editorial Material DE Logistic regression; Machine learning; Prediction ID RISK; CANCER AB I provide a commentary on two papers "Probability estimation with machine learning methods for dichotomous and multicategory outcome: Theory" by Jochen Kruppa, Yufeng Liu, Gerard Biau, Michael Kohler, Inke R. Konig, James D. Malley, and Andreas Ziegler; and "Probability estimation with machine learning methods for dichotomous and multicategory outcome: Applications" by Jochen Kruppa, Yufeng Liu, Hans-Christian Diener, Theresa Holste, Christian Weimar, Inke R. Konig, and Andreas Ziegler. Those papers provide an up-to-date review of some popular machine learning methods for class probability estimation and compare those methods to logistic regression modeling in real and simulated datasets. C1 NCI, Biometr Res Branch, Rockville, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, 9609 Med Pk Dr, Rockville, MD 20892 USA. EM rsimon@mail.nih.gov NR 13 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 EI 1521-4036 J9 BIOMETRICAL J JI Biom. J. PD JUL PY 2014 VL 56 IS 4 SI SI BP 597 EP 600 DI 10.1002/bimj.201300296 PG 4 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA AL2GU UT WOS:000338944700007 PM 24615788 ER PT J AU Blackford, JA Brimacombe, KR Dougherty, EJ Pradhan, M Shen, M Li, ZY Auld, DS Chow, CC Austin, CP Simons, SS AF Blackford, John A., Jr. Brimacombe, Kyle R. Dougherty, Edward J. Pradhan, Madhumita Shen, Min Li, Zhuyin Auld, Douglas S. Chow, Carson C. Austin, Christopher P. Simons, S. Stoney, Jr. TI Research Resource: Modulators of Glucocorticoid Receptor Activity Identified by a New High-Throughput Screening Assay SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID SMALL-MOLECULE INHIBITOR; MEDIATED GENE INDUCTION; DOSE-RESPONSE CURVE; ESTROGEN-RECEPTOR; COACTIVATOR BINDING; COREPRESSOR BINDING; ANDROGEN RECEPTOR; DISORDERED AF1; TRANSACTIVATION; AGONISTS AB Glucocorticoid steroids affect almost every type of tissue and thus are widely used to treat a variety of human pathological conditions. However, the severity of numerous side effects limits the frequency and duration of glucocorticoid treatments. Of the numerous approaches to control off-target responses to glucocorticoids, small molecules and pharmaceuticals offer several advantages. Here we describe a new, extended high-throughput screen in intact cells to identify small molecule modulators of dexamethasone-induced glucocorticoid receptor (GR) transcriptional activity. The novelty of this assay is that it monitors changes in both GR maximal activity (A(max)) and EC50 (the position of the dexamethasone dose-response curve). Upon screening 1280 chemicals, 10 with the greatest changes in the absolute value of A(max) or EC50 were selected for further examination. Qualitatively identical behaviors for 60% to 90% of the chemicals were observed in a completely different system, suggesting that other systems will be similarly affected by these chemicals. Additional analysis of the 10 chemicals in a recently described competition assay determined their kinetically defined mechanism and site of action. Some chemicals had similar mechanisms of action despite divergent effects on the level of the GR-induced product. These combined assays offer a straightforward method of identifying numerous new pharmaceuticals that can alter GR transactivation in ways that could be clinically useful. C1 [Blackford, John A., Jr.; Dougherty, Edward J.; Pradhan, Madhumita; Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, NIH, Bethesda, MD 20892 USA. [Chow, Carson C.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Chow, Carson C.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Brimacombe, Kyle R.; Shen, Min; Li, Zhuyin; Auld, Douglas S.; Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, LERB, NIH, Bldg 10,Room 8N-307B, Bethesda, MD 20892 USA. EM stoneys@helix.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences; Molecular Libraries Program of the NIH Common Fund; Molecular Libraries Initiative of the NIH Roadmap [U54MH084681] FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases and National Center for Advancing Translational Sciences, and the Molecular Libraries Program of the NIH Common Fund., and the Molecular Libraries Initiative of the NIH Roadmap for Medical Research (Grant U54MH084681). NR 58 TC 3 Z9 3 U1 1 U2 6 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUL PY 2014 VL 28 IS 7 BP 1194 EP 1206 DI 10.1210/me.2014-1069 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AK8SU UT WOS:000338699100017 PM 24850414 ER PT J AU Kruse, AC Kobilka, BK Gautam, D Sexton, PM Christopoulos, A Wess, J AF Kruse, Andrew C. Kobilka, Brian K. Gautam, Dinesh Sexton, Patrick M. Christopoulos, Arthur Wess, Juergen TI Muscarinic acetylcholine receptors: novel opportunities for drug development SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID PROTEIN-COUPLED RECEPTORS; 2ND ALLOSTERIC SITE; BETA-CELL FUNCTION; CRYSTAL-STRUCTURE; IN-VIVO; FUNCTIONAL SELECTIVITY; ALZHEIMERS-DISEASE; MEMBRANE-PROTEINS; BITOPIC LIGANDS; SEROTONIN RECEPTORS AB The muscarinic acetylcholine receptors are a subfamily of G protein-coupled receptors that regulate numerous fundamental functions of the central and peripheral nervous system. The past few years have witnessed unprecedented new insights into muscarinic receptor physiology, pharmacology and structure. These advances include the first structural views of muscarinic receptors in both inactive and active conformations, as well as a better understanding of the molecular underpinnings of muscarinic receptor regulation by allosteric modulators. These recent findings should facilitate the development of new muscarinic receptor subtype-selective ligands that could prove to be useful for the treatment of many severe pathophysiological conditions. C1 [Kruse, Andrew C.; Kobilka, Brian K.] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. [Gautam, Dinesh; Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Sexton, Patrick M.; Christopoulos, Arthur] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia. [Sexton, Patrick M.; Christopoulos, Arthur] Monash Univ, Dept Pharmacol, Parkville, Vic 3052, Australia. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov RI Sexton, Patrick/B-1319-2008; OI Sexton, Patrick/0000-0001-8902-2473; Christopoulos, Arthur/0000-0003-4442-3294 FU US National Science Foundation Graduate Research Fellowship; National Science Foundation [U19GM106990]; National Health and Medical Research Council (NHMRC) of Australia [APP1055134]; NHMRC; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the NIH FX We apologize to all investigators whose important contributions could not be acknowledged owing to space limitations. The work of A.C.K. and B.K.K. was supported by a US National Science Foundation Graduate Research Fellowship (A.C.K.) and by the National Science Foundation grant CHE-1223785 and US National Institutes of Health (NIH) grant U19GM106990 (B.K.K.). A.C. and P.M.S. received funds from Program Grant No. APP1055134 of the National Health and Medical Research Council (NHMRC) of Australia. A.C. and P.M.S. are NHMRC Principal Research Fellows. The research of D.G. and J.W. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the NIH. We thank all our co-workers and collaborators for their invaluable contributions to the work summarized in this Review. NR 122 TC 66 Z9 66 U1 6 U2 52 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD JUL PY 2014 VL 13 IS 7 BP 549 EP 560 DI 10.1038/nrd4295 PG 12 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA AL0VL UT WOS:000338845000016 PM 24903776 ER PT J AU Lamas, GA Boineau, R Goertz, C Mark, DB Rosenberg, Y Stylianou, M Rozema, T Nahin, RL Chappell, LT Lindblad, L Lewis, EF Drisko, J Lee, KL AF Lamas, Gervasio A. Boineau, Robin Goertz, Christine Mark, Daniel B. Rosenberg, Yves Stylianou, Mario Rozema, Theodore Nahin, Richard L. Chappell, L. Terry Lindblad, Lauren Lewis, Eldrin F. Drisko, Jeanne Lee, Kerry L. TI EDTA chelation therapy alone and in combination with oral high-dose multivitamins and minerals for coronary disease: The factorial group results of the Trial to Assess Chelation Therapy SO AMERICAN HEART JOURNAL LA English DT Article ID MYOCARDIAL-INFARCTION; DIABETES COMPLICATIONS; RANDOMIZED-TRIAL; TACT; METAANALYSIS; PREVENTION; MORTALITY; EXPOSURE; REGIMEN; METALS AB Background Disodium ethylenediaminetetraacetic acid (EDTA) reduced adverse cardiac outcomes in a factorial trial also testing oral vitamins. This report describes the intent-to-treat comparison of the 4 factorial groups overall and in patients with diabetes. Methods This was a double-blind, placebo-controlled, 2 x 2 factorial multicenter randomized trial of 1,708 post-myocardial infarction (MI) patients >= 50 years of age and with creatinine <= 2.0 mg/dL randomized to receive 40 EDTA chelation or placebo infusions plus 6 caplets daily of a 28-component multivitamin-multimineral mixture or placebo. The primary end point was a composite of total mortality, MI, stroke, coronary revascularization, or hospitalization for angina. Results Median age was 65 years, 18% were female, 94% were Caucasian, 37% were diabetic, 83% had prior coronary revascularization, and 73% were on statins. Five-year Kaplan-Meier estimates for the primary end point was 31.9% in the chelation + high-dose vitamin group, 33.7% in the chelation + placebo vitamin group, 36.6% in the placebo infusion + active vitamin group, and 40.2% in the placebo infusions + placebo vitamin group. The reduction in primary end point by double active treatment compared with double placebo was significant (hazard ratio 0.74, 95% CI 0.57-0.95, P = .016). In patients with diabetes, the primary end point reduction of double active compared with double placebo was more pronounced (hazard ratio 0.49, 95% CI 0.33-0.75, P < .001). Conclusions In stable post-MI patients on evidence-based medical therapy, the combination of oral high-dose vitamins and chelation therapy compared with double placebo reduced clinically important cardiovascular events to an extent that was both statistically significant and of potential clinical relevance. C1 [Lamas, Gervasio A.] Columbia Univ, Mt Sinai Med Ctr, Div Cardiol, Miami Beach, FL 33140 USA. [Boineau, Robin; Rosenberg, Yves; Stylianou, Mario] NHLBI, Bethesda, MD 20892 USA. [Goertz, Christine] Palmer Ctr Chiropract Res, Davenport, IA USA. [Rozema, Theodore] Biogenesis Med Ctr, Landrum, SC USA. [Nahin, Richard L.] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Chappell, L. Terry] Celebrat Hlth Assoc, Bluffton, OH USA. [Lewis, Eldrin F.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Drisko, Jeanne] Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Mark, Daniel B.; Lindblad, Lauren; Lee, Kerry L.] Duke Clin Res Inst, Durham, NC USA. RP Lamas, GA (reprint author), Columbia Univ, Mt Sinai Med Ctr, Div Cardiol, 4300 Alton Rd, Miami Beach, FL 33140 USA. EM gervasio.lamas@msmc.com OI Mark, Daniel/0000-0001-6340-8087 FU Florida Heart Research Institute FX The authors gratefully acknowledge the organizational skills of Ana Mon, MPH Project Leader at the Clinical Coordinating Center; Alyssa Cotler at the National Center for Complementary and Alternative Medicine; Susan Dambrauskas (formerly at National Heart, Lung, and Blood Institute) and Vivian Thompson at the DCRI for their competent professional assistance; and the Florida Heart Research Institute for supporting the pilot study. Gervasio Lamas, MD, reports that, from 2000 to 2003, he served as a consultant to OmniComm, the electronic data capture company used in the trial. No funds were received, and all ties were severed as of 09/10/2003. The authors have no other conflicts to report. NR 23 TC 9 Z9 9 U1 2 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JUL PY 2014 VL 168 IS 1 BP 37 EP 44 DI 10.1016/j.ahj.2014.02.012 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AK9LO UT WOS:000338748800007 PM 24952858 ER PT J AU Marcos, LA Shapley, NP Eberhard, M Epstein, JI Fox, LM Magill, A Nutman, TB AF Marcos, Luis A. Shapley, Nathan P. Eberhard, Mark Epstein, Jonathan I. Fox, LeAnne M. Magill, Alan Nutman, Thomas B. TI Case Report: Testicular Swelling Due to Lymphatic Filariasis after Brief Travel to Haiti SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID BANCROFTIAN FILARIASIS; ASSAY AB After 6 months of a trip to Haiti, a 25-year-old healthy man presented with a 6-week history of a very slow progressive intermittent bilateral testicular pain and swelling. The biopsies in both testicles revealed the presence of a dead filarial parasite. Polymerase chain reaction products of the DNA from the biopsy were shown to have a 100% identity to Wuchereria bancrofti. Despite being uncommon in travelers, this presentation of W. bancrofti highlights the possibility of acquiring W. bancrofti during short-term trips to highly endemic regions of the world (i.e., Haiti). C1 Hattiesburg Clin, Infect Dis, Hattiesburg, MS 39402 USA. Wesley Med Ctr, Urol Clin, Hattiesburg, MS USA. CDC, Div Parasit Dis & Malaria, Atlanta, GA 30333 USA. Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. Bill & Melinda Gates Fdn, Malaria Global Hlth Program, Seattle, WA USA. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Marcos, LA (reprint author), Hattiesburg Clin, 4 Med Blvd, Hattiesburg, MS 39402 USA. EM marcoslrz@yahoo.com NR 11 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUL PY 2014 VL 91 IS 1 BP 89 EP 91 DI 10.4269/ajtmh.14-0030 PG 3 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA AK9MH UT WOS:000338750700017 PM 24865674 ER PT J AU Hull, LC Farrell, D Grodzinski, P AF Hull, L. C. Farrell, D. Grodzinski, P. TI Highlights of recent developments and trends in cancer nanotechnology research-View from NCI Alliance for Nanotechnology in Cancer SO BIOTECHNOLOGY ADVANCES LA English DT Review DE Cancer; Nanotechnology; Alliance ID MODIFIED GOLD NANOPARTICLES; METASTATIC BREAST-CANCER; PROSTATE-CANCER; IN-VIVO; DRUG-DELIVERY; GENE-REGULATION; NUCLEIC-ACIDS; MATRIX-METALLOPROTEINASE; TARGETED NANOPARTICLES; PERSONALIZED MEDICINE AB Although the incidence of cancer and cancer related deaths in the United States has decreased over the past two decades due to improvements in early detection and treatment, cancer still is responsible for a quarter of the deaths in this country. There is much room for improvement on the standard treatments currently available and the National Cancer Institute (NCI) has recognized the potential for nanotechnology and nanomaterials in this area. The NCI Alliance for Nanotechnology in Cancer was formed in 2004 to support multidisciplinary researchers in the application of nanotechnology to cancer diagnosis and treatment. The researchers in the Alliance have been productive in generating innovative solutions to some of the central issues of cancer treatment including how to detect tumors earlier, how to target cancer cells specifically, and how to improve the therapeutic index of existing chemotherapies and radiotherapy treatments. Highly creative ideas are being pursued where novelty in nanomaterial development enables new modalities of detection or therapy. This review highlights some of the innovative materials approaches being pursued by researchers funded by the NCI Alliance. Their discoveries to improve the functionality of nanoparticles for medical applications includes the generation of new platforms, improvements in the manufacturing of nanoparticles and determining the underlying reasons for the movement of nanoparticles in the blood. Published by Elsevier Inc. C1 [Hull, L. C.; Farrell, D.; Grodzinski, P.] NCI, Off Canc Nanotechnol Res, Ctr Strateg Initiat, NIH, Bethesda, MD 20892 USA. RP Grodzinski, P (reprint author), NCI, 31 Ctr Dr MSC2580,Bldg 31 Room 10A52, Bethesda, MD 20892 USA. EM lynn.hull@nih.gov; dorothy.farrell@nih.gov; piotr.grodzinski@nih.gov NR 127 TC 10 Z9 10 U1 8 U2 59 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0734-9750 EI 1873-1899 J9 BIOTECHNOL ADV JI Biotechnol. Adv. PD JUL-AUG PY 2014 VL 32 IS 4 SI SI BP 666 EP 678 DI 10.1016/j.biotechadv.2013.08.003 PG 13 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AL0LL UT WOS:000338818300002 PM 23948249 ER PT J AU Wang, ZY Liu, G Zheng, HR Chen, XY AF Wang, Zhiyong Liu, Gang Zheng, Hairong Chen, Xiaoyuan TI Rigid nanoparticle-based delivery of anti-cancer siRNA: Challenges and opportunities SO BIOTECHNOLOGY ADVANCES LA English DT Review DE Gene therapy; RNA interference (RNAi); Small-interfering RNA (siRNA); Gene delivery; Nanoparticles ID IRON-OXIDE NANOPARTICLES; FUNCTIONALIZED CARBON NANOTUBES; MESOPOROUS SILICA NANOPARTICLES; INTERSTITIAL FLUID PRESSURE; MINICIRCLE DNA DELIVERY; TARGETED DRUG-DELIVERY; SMALL INTERFERING RNA; GENE DELIVERY; QUANTUM DOTS; GOLD NANOPARTICLES AB Gene therapy is a promising strategy to treat various genetic and acquired diseases. Small interfering RNA (siRNA) is a revolutionary tool for gene therapy and the analysis of gene function. However, the development of a safe, efficient, and targetable non-viral siRNA delivery system remains a major challenge in gene therapy. An ideal delivery system should be able to encapsulate and protect the siRNA cargo from serum proteins, exhibit target tissue and cell specificity, penetrate the cell membrane, and release its cargo in the desired intracellular compartment. Nanomedicine has the potential to deal with these challenges faced by siRNA delivery. The unique characteristics of rigid nanoparticles mostly inorganic nanoparticles and allotropes of carbon nanomaterials, including high surface area, facile surface modification, controllable size, and excellent magnetic/optical/electrical properties, make them promising candidates for targeted siRNA delivery. In this review, recent progresses on rigid nanoparticle-based siRNA delivery systems will be summarized. Published by Elsevier Inc. C1 [Wang, Zhiyong; Liu, Gang] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361102, Fujian, Peoples R China. [Wang, Zhiyong; Zheng, Hairong] Chinese Acad Sci, Shenzhen Inst Adv Technol, Paul C Lauterbur Res Ctr Biomed Imaging, Inst Biomed & Hlth Engn,Shenzhen Key Lab MRI, Shenzhen 518055, Peoples R China. [Liu, Gang] Xiamen Univ, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China. [Liu, Gang] Xiamen Univ, Coll Chem & Chem Engn, MOE Key Lab Spectrochem Anal & Instrumentat, Xiamen 361005, Peoples R China. [Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Liu, G (reprint author), Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361102, Fujian, Peoples R China. EM gangliu.cmitm@xmu.edu.cn; shawn.chen@nih.gov FU Major State Basic Research Development Program of China (973 Program) [2013CB733802, 2014CB744503]; National Science Foundation of China (NSFC) [81101101, 81371596, 51273165, 51203177]; Key Project of Chinese Ministry of Education [212149]; Fundamental Research Funds for the Central Universities [2013121039]; Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX This work was supported by the Major State Basic Research Development Program of China (973 Program) (2013CB733802, 2014CB744503), the National Science Foundation of China (NSFC) (81101101, 81371596, 51273165, 51203177), the Key Project of Chinese Ministry of Education (212149), the Fundamental Research Funds for the Central Universities (2013121039) and the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). NR 166 TC 21 Z9 22 U1 7 U2 124 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0734-9750 EI 1873-1899 J9 BIOTECHNOL ADV JI Biotechnol. Adv. PD JUL-AUG PY 2014 VL 32 IS 4 SI SI BP 831 EP 843 DI 10.1016/j.biotechadv.2013.08.020 PG 13 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AL0LL UT WOS:000338818300013 PM 24013011 ER PT J AU Mahalingam, D Malik, L Beeram, M Rodon, J Sankhala, K Mita, A Benjamin, D Ketchum, N Michalek, J Tolcher, A Wright, J Sarantopoulos, J AF Mahalingam, Devalingam Malik, Laeeq Beeram, Muralidhar Rodon, Jordi Sankhala, Kamalesh Mita, Alain Benjamin, Daniel Ketchum, Norma Michalek, Joel Tolcher, Anthony Wright, John Sarantopoulos, John TI Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Melanoma; Bevacizumab; Sorafenib; VEGF ID ENDOTHELIAL GROWTH-FACTOR; RENAL-CELL CARCINOMA; VASCULOGENIC MIMICRY; CUTANEOUS MELANOMA; THERAPY; CANCER; ANGIOGENESIS; BIOMARKERS; TOXICITY; SURVIVAL AB Melanomas are vascular tumors with a high incidence of BRAF mutations driving tumor proliferation. Complete inhibition of vascular endothelial growth factor (VEGF) signaling has potential for enhanced antitumor efficacy. Patients with advanced melanoma and adequate organ function were eligible. Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was administered 5 mg/kg intravenously every 14 days. The primary objective was to determine clinical biological activity. The secondary objectives were safety, tolerability, and time to progression (TTP). Pharmacodynamic analysis included serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, C1D15 and C2D1. The study was terminated during the first stage of a Simon two-stage design, after 14 of planned 21 subjects were enrolled. Of the 14 patients who received treatment, no objective tumor responses were observed. Stable disease (SD) a parts per thousand yen16 weeks was observed in 57 % patients, including three patients with SD lasting a parts per thousand yen1 year. Median TTP was 32 weeks. The most frequently reported drug-related adverse events (AEs) were hand-foot syndrome (57.1 %), fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 drug-related AEs were hypertension (14.2 %), hand-foot syndrome, proteinuria, and thrombocytopenia (7 % each). Patients with low VEGF (< 300 pg/ml) experienced longer TTP than those with high VEGF [median 50 vs. 15 weeks, p = 0.02). A similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach statistical significance. Combined VEGF/VEGFR blockade using bevacizumab with sorafenib shows clinical activity. The linkage between VEGF levels and time to tumor progression needs further exploration. C1 [Mahalingam, Devalingam; Malik, Laeeq; Beeram, Muralidhar; Rodon, Jordi; Sankhala, Kamalesh; Mita, Alain; Benjamin, Daniel; Tolcher, Anthony; Sarantopoulos, John] Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Ketchum, Norma; Michalek, Joel] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Wright, John] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Mahalingam, D (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. EM Mahalingam@uthscsa.edu FU National Cancer Institute FX This study was funded by National Cancer Institute. NR 27 TC 7 Z9 7 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUL PY 2014 VL 74 IS 1 BP 77 EP 84 DI 10.1007/s00280-014-2479-8 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AK9PT UT WOS:000338759700008 PM 24817603 ER PT J AU Spring, B Moller, AC Colangelo, LA Siddique, J Roehrig, M Daviglus, ML Polak, JF Reis, JP Sidney, S Liu, K AF Spring, Bonnie Moller, Arlen C. Colangelo, Laura A. Siddique, Juned Roehrig, Megan Daviglus, Martha L. Polak, Joseph F. Reis, Jared P. Sidney, Stephen Liu, Kiang TI Healthy Lifestyle Change and Subclinical Atherosclerosis in Young Adults Coronary Artery Risk Development in Young Adults (CARDIA) Study SO CIRCULATION LA English DT Article DE behavioral medicine; behavior modification; cardiovascular diseases; epidemiology; follow-up study; prevention; risk factors ID AMERICAN-HEART-ASSOCIATION; INTIMA-MEDIA THICKNESS; CARDIOVASCULAR-DISEASE; PRIMARY PREVENTION; WALL THICKNESS; PHYSICAL-ACTIVITY; COMBINED IMPACT; WOMEN; MORTALITY; CALCIFICATION AB Background-The benefits of healthy habits are well established, but it is unclear whether making health behavior changes as an adult can still alter coronary artery disease risk. Methods and Results-The Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study (n=3538) assessed 5 healthy lifestyle factors (HLFs) among young adults aged 18 to 30 years (year 0 baseline) and 20 years later (year 20): not overweight/obese, low alcohol intake, healthy diet, physically active, nonsmoker. We tested whether change from year 0 to 20 in a continuous composite HLF score (HLF change; range, -5 to +5) is associated with subclinical atherosclerosis (coronary artery calcification and carotid intima-media thickness) at year 20, after adjustment for demographics, medications, and baseline HLFs. By year 20, 25.3% of the sample improved (HLF change >=+1); 40.4% deteriorated (had fewer HLFs); 34.4% stayed the same; and 19.2% had coronary artery calcification (>0). Each increase in HLFs was associated with reduced odds of detectable coronary artery calcification (odds ratio=0.85; 95% confidence interval, 0.74-0.98) and lower intima-media thickness (carotid bulb beta=-0.024, P=0.001), and each decrease in HLFs was predictive to a similar degree of greater odds of coronary artery calcification (odds ratio=1.17; 95% confidence interval, 1.02-1.33) and greater intima-media thickness (beta=+0.020, P<0.01). Conclusions-Healthy lifestyle changes during young adulthood are associated with decreased risk and unhealthy lifestyle changes are associated with increased risk for subclinical atherosclerosis in middle age. C1 [Spring, Bonnie; Moller, Arlen C.; Colangelo, Laura A.; Siddique, Juned; Roehrig, Megan; Daviglus, Martha L.; Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Polak, Joseph F.] Tufts Univ, Sch Med, Dept Radiol, Boston, MA 02111 USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Sidney, Stephen] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. RP Spring, B (reprint author), Northwestern Univ, Dept Prevent Med, 680 N Lakeshore Dr,Suite 1400, Chicago, IL 60611 USA. EM bspring@northwestern.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health [N01-HC-48047, N01-HC-48050, N01-HC-95095]; [HL075451]; [CA154862] FX This research was funded by contracts N01-HC-48047 through N01-HC-48050 and N01-HC-95095 from the National Heart, Lung, and Blood Institute, National Institutes of Health; by HL075451 to Dr Spring; and by CA154862 to Dr Siddique. NR 50 TC 38 Z9 40 U1 0 U2 13 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 JUL 1 PY 2014 VL 130 IS 1 BP 10 EP + DI 10.1161/CIRCULATIONAHA.113.005445 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AK8YS UT WOS:000338715300007 PM 24982115 ER PT J AU McDermott, MM Guralnik, JM Criqui, MH Liu, K Kibbe, MR Ferrucci, L AF McDermott, Mary M. Guralnik, Jack M. Criqui, Michael H. Liu, Kiang Kibbe, Melina R. Ferrucci, Luigi TI Six-Minute Walk Is a Better Outcome Measure Than Treadmill Walking Tests in Therapeutic Trials of Patients With Peripheral Artery Disease SO CIRCULATION LA English DT Editorial Material ID ANKLE-BRACHIAL INDEX; FUNCTIONAL PERFORMANCE PREDICTS; OBSTRUCTIVE PULMONARY-DISEASE; RANDOMIZED CONTROLLED-TRIAL; AMERICAN-HEART-ASSOCIATION; INTERMITTENT CLAUDICATION; LOWER-EXTREMITY; PHYSICAL-ACTIVITY; MOBILITY LOSS; LEG SYMPTOMS C1 [McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [McDermott, Mary M.; Liu, Kiang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Kibbe, Melina R.] Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU NHLBI NIH HHS [R01 HL107510, R01-HL107510]; NIA NIH HHS [Z01 AG000015-50] NR 43 TC 15 Z9 15 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 1 PY 2014 VL 130 IS 1 BP 61 EP 68 DI 10.1161/CIRCULATIONAHA.114.007002 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AK8YS UT WOS:000338715300012 PM 24982117 ER PT J AU Burns, KM Byrne, BJ Gelb, BD Kuhn, B Leinwand, LA Mital, S Pearson, GD Rodefeld, M Rossano, JW Stauffer, BL Taylor, MD Towbin, JA Redington, AN AF Burns, Kristin M. Byrne, Barry J. Gelb, Bruce D. Kuehn, Bernhard Leinwand, Leslie A. Mital, Seema Pearson, Gail D. Rodefeld, Mark Rossano, Joseph W. Stauffer, Brian L. Taylor, Michael D. Towbin, Jeffrey A. Redington, Andrew N. TI New Mechanistic and Therapeutic Targets for Pediatric Heart Failure Report From a National Heart, Lung, and Blood Institute Working Group SO CIRCULATION LA English DT Article DE heart defects, congenital; heart failure; pediatrics ID VENTRICULAR SYSTOLIC FUNCTION; DIFFUSE MYOCARDIAL FIBROSIS; TO-MESENCHYMAL TRANSITION; DILATED CARDIOMYOPATHY; CARDIAC FIBROSIS; UNITED-STATES; HYPERTROPHIC CARDIOMYOPATHY; CIRCULATORY SUPPORT; MICRORNA EXPRESSION; CLINICAL-TRIALS C1 [Burns, Kristin M.; Pearson, Gail D.] NHLBI, Bethesda, MD 20892 USA. [Byrne, Barry J.] Univ Florida, Gainesville, FL USA. [Gelb, Bruce D.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Kuehn, Bernhard] Boston Childrens Hosp, Boston, MA USA. [Kuehn, Bernhard] Harvard Univ, Sch Med, Boston, MA USA. [Leinwand, Leslie A.] Biofrontiers Inst, Boulder, CO USA. [Mital, Seema; Redington, Andrew N.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Rodefeld, Mark] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Rossano, Joseph W.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Stauffer, Brian L.] Univ Colorado, Sch Med, Aurora, CO USA. [Taylor, Michael D.; Towbin, Jeffrey A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. RP Burns, KM (reprint author), NHLBI, NIH, 6701 Rockledge Dr,Rm 8220, Bethesda, MD 20892 USA. EM kristin.burns@nih.gov OI LEINWAND, LESLIE/0000-0003-1470-4810; Stauffer, Brian/0000-0003-3418-7750 FU Intramural NIH HHS [Z99 HL999999]; NHLBI NIH HHS [R01 HL106302, R01 HL107715] NR 77 TC 12 Z9 12 U1 1 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 JUL 1 PY 2014 VL 130 IS 1 BP 79 EP 86 DI 10.1161/CIRCULATIONAHA.113.007980 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AK8YS UT WOS:000338715300014 PM 24982119 ER PT J AU Anuradha, R George, PJ Chandrasekaran, V Kumaran, PP Nutman, TB Babu, S AF Anuradha, R. George, P. Jovvian Chandrasekaran, V. Kumaran, P. Paul Nutman, Thomas B. Babu, Subash TI Interleukin 1 (IL-1)- and IL-23-Mediated Expansion of Filarial Antigen-Specific Th17 and Th22 Cells in Filarial Lymphedema SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID HELPER 17 CELLS; T-CELLS; BANCROFTIAN FILARIASIS; FIBROSIS; IL-17; SCHISTOSOMIASIS; DISEASES; MICE AB Lymphatic filarial disease is known to be associated with elevated Th1 responses and normal or diminished Th2 responses to parasite-specific antigens. The roles of Th17 cells and the recently described Th22 cells have not been examined in detail in either filarial infection itself or in filarial disease (e. g., lymphedema and elephantiasis). To explore the roles of Th17 and Th22 cells and their subsets, we examined the frequencies of these cells in individuals with filarial lymphedema (chronic pathology [CP]), in clinically asymptomatic infected (INF) individuals, and in uninfected (UN) individuals ex vivo and in response to parasite and nonparasite antigens. Those with disease (CP) had significantly expanded frequencies of Th17 and Th22 cells, compared with either INF or UN individuals, at baseline (ex vivo) and in response to parasite antigens. This antigen-driven expansion of Th17 and Th22 cells was dependent on interleukin 1 (IL-1), IL-23, and, to lesser extent, transforming growth factor beta (TGF-beta), as blockade of any of these cytokines resulted in significantly diminished frequencies of Th17 and Th22 cells. Our findings, therefore, suggest that filarial parasite-driven expansion of Th17 and Th22 cells is associated with the pathogenesis of filarial infections and disease. C1 [Anuradha, R.; George, P. Jovvian; Babu, Subash] Int Ctr Excellence Res, Natl Inst Hlth, Chennai, Tamil Nadu, India. [Chandrasekaran, V.; Kumaran, P. Paul] Natl Inst Res TB, Chennai, Tamil Nadu, India. [Nutman, Thomas B.; Babu, Subash] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Babu, S (reprint author), Int Ctr Excellence Res, Natl Inst Hlth, Chennai, Tamil Nadu, India. EM sbabu@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 34 TC 3 Z9 3 U1 2 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD JUL PY 2014 VL 21 IS 7 BP 960 EP 965 DI 10.1128/CVI.00257-14 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AK9SY UT WOS:000338768300006 PM 24807054 ER PT J AU Foster, B Bagci, U Mansoor, A Xu, ZY Mollura, DJ AF Foster, Brent Bagci, Ulas Mansoor, Awais Xu, Ziyue Mollura, Daniel J. TI A review on segmentation of positron emission tomography images SO COMPUTERS IN BIOLOGY AND MEDICINE LA English DT Review DE Image segmentation; PET; SUV; Thresholding; PET-CT; MRI-PET; Review ID CELL LUNG-CANCER; STANDARDIZED UPTAKE VALUE; GROSS TUMOR VOLUME; DYNAMIC PET IMAGES; GAUSSIAN MIXTURE MODEL; GRADIENT-BASED METHOD; TO-BACKGROUND RATIO; F-18-FDG PET; FDG-PET; CT IMAGES AB Positron Emission Tomography (PET), a non-invasive functional imaging method at the molecular level, images the distribution of biologically targeted radiotracers with high sensitivity. PET imaging provides detailed quantitative information about many diseases and is often used to evaluate inflammation, infection, and cancer by detecting emitted photons from a radiotracer localized to abnormal cells. In order to differentiate abnormal tissue from surrounding areas in PET images, image segmentation methods play a vital role; therefore, accurate image segmentation is often necessary for proper disease detection, diagnosis, treatment planning, and follow-ups. In this review paper, we present state-of-the-art PET image segmentation methods, as well as the recent advances in image segmentation techniques. In order to make this manuscript self-contained, we also briefly explain the fundamentals of PET imaging, the challenges of diagnostic PET image analysis, and the effects of these challenges on the segmentation results. Published by Elsevier Ltd. C1 [Foster, Brent; Bagci, Ulas; Mansoor, Awais; Xu, Ziyue; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Bagci, U (reprint author), NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. EM ulas.bagci@nih.gov RI Xy, Ziyue/K-9438-2014; OI Xy, Ziyue/0000-0002-5728-6869; Bagci, Ulas/0000-0001-7379-6829 FU Center for Infectious Disease Imaging (CIDI); Intramural Program of the National Institutes of Allergy and Infectious Diseases (NIAID); National Institutes of Bio-imaging and Bioengineering (NIBIB) at the National Institutes of Health (NIH) FX This research is supported by the Center for Infectious Disease Imaging (CIDI), the Intramural Program of the National Institutes of Allergy and Infectious Diseases (NIAID), and the National Institutes of Bio-imaging and Bioengineering (NIBIB) at the National Institutes of Health (NIH). We thank Dr. Sanjay Jain for kindly providing the rabbit TB images. NR 182 TC 37 Z9 39 U1 2 U2 37 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0010-4825 EI 1879-0534 J9 COMPUT BIOL MED JI Comput. Biol. Med. PD JUL 1 PY 2014 VL 50 BP 76 EP 96 DI 10.1016/j.compbiomed.2014.04.014 PG 21 WC Biology; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Computer Science; Engineering; Mathematical & Computational Biology GA AK7KJ UT WOS:000338606900010 PM 24845019 ER PT J AU Lee, NR Wallace, GL Raznahan, A Clasen, LS Giedd, JN AF Lee, Nancy Raitano Wallace, Gregory L. Raznahan, Armin Clasen, Liv S. Giedd, Jay N. TI Trail making test performance in youth varies as a function of anatomical coupling between the prefrontal cortex and distributed cortical regions SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE executive function; anatomical covariance; cortical thickness; magnetic resonance imaging; Trail Making Test; brain; child; adolescent ID TYPICALLY DEVELOPING-CHILDREN; AUTOMATED 3-D EXTRACTION; LATENT VARIABLE ANALYSIS; D-KEFS TRAIL; FRONTAL-LOBE; EXECUTIVE FUNCTION; ALZHEIMERS-DISEASE; COMPREHENSIVE TRAIL; CEREBRAL-CORTEX; WORKING-MEMORY AB While researchers have gained a richer understanding of the neural correlates of executive function in adulthood, much less is known about how these abilities are represented in the developing brain and what structural brain networks underlie them. Thus, the current study examined how individual differences in executive function, as measured by the Trail Making Test (TMT), relate to structural covariance in the pediatric brain. The sample included 146 unrelated, typically developing youth (80 females), ages 9-14 years, who completed a structural MRI scan of the brain and the Halstead-Reitan TMT (intermediate form). TMT scores used to index executive function included those that evaluated set-shifting ability: Trails B time (number-letter sequencing) and the difference in time between Trails B and A (number sequencing only). Anatomical coupling was measured by examining correlations between mean cortical thickness (MCT) across the entire cortical ribbon and individual vertex thickness measured at similar to 81,000 vertices. To examine how TMT scores related to anatomical coupling strength, linear regression was utilized and the interaction between age-normed TMT scores and both age and sex-normed MCT was used to predict vertex thickness. Results revealed that stronger Trails B scores were associated with greater anatomical coupling between a large swath of prefrontal cortex and the rest of cortex. For the difference between Trails B and A, a network of regions in the frontal, temporal, and parietal lobes was found to be more tightly coupled with the rest of cortex in stronger performers. This study is the first to highlight the importance of structural covariance in in the prediction of individual differences in executive function skills in youth. Thus, it adds to the growing literature on the neural correlates of childhood executive functions and identifies neuroanatomic coupling as a biological substrate that may contribute to executive function and dysfunction in childhood. C1 [Lee, Nancy Raitano; Raznahan, Armin; Clasen, Liv S.; Giedd, Jay N.] NIMH, Child Psychiat Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Wallace, Gregory L.] George Washington Univ, Dept Speech & Hearing Sci, Washington, DC USA. RP Lee, NR (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Room 4C110,10 Ctr Dr,MSC1367, Bethesda, MD 20892 USA. EM lnancy@mail.nih.gov RI Giedd, Jay/J-9644-2015; Lee, Nancy/M-7492-2016; OI Giedd, Jay/0000-0003-2002-8978; Lee, Nancy/0000-0002-6663-0713; Wallace, Gregory/0000-0003-0329-5054 NR 64 TC 5 Z9 5 U1 2 U2 16 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD JUL 1 PY 2014 VL 5 AR 496 DI 10.3389/fpsyg.2014.00496 PG 14 WC Psychology, Multidisciplinary SC Psychology GA AK9IU UT WOS:000338741600001 PM 25071613 ER PT J AU D'Angelo, H Fleischhacker, S Rose, SW Ribisl, KM AF D'Angelo, Heather Fleischhacker, Sheila Rose, Shyanika W. Ribisl, Kurt M. TI Field validation of secondary data sources for enumerating retail tobacco outlets in a state without tobacco outlet licensing SO HEALTH & PLACE LA English DT Article DE Evidence for validity; Tobacco outlets; Commercial secondary data ID HEALTH DISPARITIES; CIGARETTE-SMOKING; FOOD STORES; TRACT LEVEL; DENSITY; DEMOGRAPHICS; ENVIRONMENT; ACCESS; PROXIMITY; VALIDITY AB Identifying tobacco retail outlets for U.S. FDA compliance checks or calculating tobacco outlet density is difficult in the 13 States without tobacco retail licensing or where licensing lists are unavailable for research. This study uses primary data collection to identify tobacco outlets in three counties in a non-licensing state and validate two commercial secondary data sources. We calculated sensitivity and positive predictive values (PPV) to examine the evidence of validity for two secondary data sources, and conducted a geospatial analysis to determine correct allocation to census tract. ReferenceUSA had almost perfect sensitivity (0.82) while Dun & Bradstreet (D&B) had substantial sensitivity (0.69) for identifying tobacco outlets; combined, sensitivity improved to 0.89. D&B identified fewer "false positives" with a PPV of 0.82 compared to 0.71 for ReferenceUSA. More than 90% of the outlets identified by ReferenceUSA were geocoded to the correct census tract. Combining two commercial data sources resulted in enumeration of nearly 90% of tobacco outlets in a three county area Commercial databases appear to provide a reasonably accurate way to identify tobacco outlets for enforcement operations and density estimation. (C) 2014 Elsevier Ltd. All rights reserved. C1 [D'Angelo, Heather; Rose, Shyanika W.; Ribisl, Kurt M.] Univ N Carolina, Dept Hlth Behav, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Fleischhacker, Sheila] NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. [Ribisl, Kurt M.] UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. RP D'Angelo, H (reprint author), Univ N Carolina, Dept Hlth Behav, Gillings Sch Global Publ Hlth, CB 7440, Chapel Hill, NC 27599 USA. EM hdangelo@email.unc.edu OI D'Angelo, Heather/0000-0002-7271-0832 FU University Cancer Research Fund at UNC Chapel Hill; National Cancer Institute [1U01CA154281]; UNC Lineberger Comprehensive Cancer Center at UNC Chapel Hill [R25 CA57726] FX Funding for this study was provided by the University Cancer Research Fund to UNC Lineberger Comprehensive Cancer Center at UNC Chapel Hill. Funding was also provided by a grant from the National Cancer Institute to Dr. Ribisl (1U01CA154281). Shyanika Rose received funding from the UNC Lineberger Comprehensive Cancer Center at UNC Chapel Hill (R25 CA57726). The funders had no involvement in the study design, collection, analysis, writing, or interpretation. Lisa Isgett geocoded addresses and created maps used during primary data collection using ArcGIS. NR 37 TC 10 Z9 10 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8292 EI 1873-2054 J9 HEALTH PLACE JI Health Place PD JUL PY 2014 VL 28 BP 38 EP 44 DI 10.1016/j.healthplace.2014.03.006 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AK9HD UT WOS:000338737300005 PM 24742811 ER PT J AU Cresswell, P Roche, PA AF Cresswell, Peter Roche, Paul A. TI Invariant chain-MHC class II complexes: always odd and never invariant SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Editorial Material ID TRANSPORT; TRIMERS C1 [Cresswell, Peter] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA. [Cresswell, Peter] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. [Roche, Paul A.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Cresswell, P (reprint author), Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA. EM peter.cresswell@yale.edu NR 9 TC 5 Z9 5 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 EI 1440-1711 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD JUL PY 2014 VL 92 IS 6 BP 471 EP 472 DI 10.1038/icb.2014.36 PG 2 WC Cell Biology; Immunology SC Cell Biology; Immunology GA AK8WP UT WOS:000338709600001 PM 24777311 ER PT J AU Ribeiro-Gomes, FL Roma, EH Carneiro, MBH Doria, NA Sacks, DL Peters, NC AF Ribeiro-Gomes, Flavia L. Roma, Eric Henrique Carneiro, Matheus B. H. Doria, Nicole A. Sacks, David L. Peters, Nathan C. TI Site-Dependent Recruitment of Inflammatory Cells Determines the Effective Dose of Leishmania major SO INFECTION AND IMMUNITY LA English DT Article ID IMMUNE-RESPONSES; BALB/C MICE; INFECTION INFLUENCES; PROTECTIVE IMMUNITY; SAND FLIES; T-CELLS; ROUTE; INOCULATION; IMMUNIZATION; SKIN AB The route of pathogen inoculation by needle has been shown to influence the outcome of infection. Employing needle inoculation of the obligately intracellular parasite Leishmania major, which is transmitted in nature following intradermal (i.d.) deposition of parasites by the bite of an infected sand fly, we identified differences in the preexisting and acute cellular responses in mice following i.d. inoculation of the ear, subcutaneous (s.c.) inoculation of the footpad, or inoculation of the peritoneal cavity (intraperitoneal [i.p.] inoculation). Initiation of infection at different sites was associated with different phagocytic populations. Neutrophils were the dominant infected cells following i.d., but not s.c. or i.p., inoculation. Inoculation of the ear dermis resulted in higher frequencies of total and infected neutrophils than inoculation of the footpad, and these higher frequencies were associated with a 10-fold increase in early parasite loads. Following inoculation of the ear in the absence of neutrophils, parasite phagocytosis by other cell types did not increase, and fewer parasites were able to establish infection. The frequency of infected neutrophils within the total infected CD11b(+) population was higher than the frequency of total neutrophils within the total CD11b(+) population, demonstrating that neutrophils are overrepresented as a proportion of infected cells. Employing i.d. inoculation to model sand fly transmission of parasites has significant consequences for infection outcome relative to that of s.c. or i.p. inoculation, including the phenotype of infected cells and the number of parasites that establish infection. Vector-borne infections initiated in the dermis likely involve adaptations to this unique microenvironment. Bypassing or altering this initial step has significant consequences for infection. C1 [Ribeiro-Gomes, Flavia L.; Roma, Eric Henrique; Carneiro, Matheus B. H.; Doria, Nicole A.; Sacks, David L.; Peters, Nathan C.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Roma, Eric Henrique; Carneiro, Matheus B. H.] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, Lab Gnotobiol & Imunol, Belo Horizonte, MG, Brazil. RP Peters, NC (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM NPeters@niaid.nih.gov RI Roma, Eric /E-2752-2014; Ribeiro-Gomes, Flavia/F-7609-2015 OI Roma, Eric /0000-0001-5265-5277; FU NIH, National Institute of Allergy and Infectious Diseases; NIH-CAPES (CAPES) [0062/11-1, 8619/12-3] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. Financial support was provided by the NIH-CAPES sandwich program to Eric Henrique Roma (CAPES no. 0062/11-1) and Matheus B. H. Carneiro (CAPES no. 8619/12-3). NR 48 TC 15 Z9 15 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUL PY 2014 VL 82 IS 7 BP 2713 EP 2727 DI 10.1128/IAI.01600-13 PG 15 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AK9DS UT WOS:000338728400005 PM 24733090 ER PT J AU Abdallah, DSA Bitar, AP Oliveira, F Meneses, C Park, JJ Mendez, S Kamhawi, S Valenzuela, JG Marquis, H AF Abdallah, Delbert S. Abi Bitar, Alan Pavinski Oliveira, Fabiano Meneses, Claudio Park, Justin J. Mendez, Susana Kamhawi, Shaden Valenzuela, Jesus G. Marquis, Helene TI A Listeria monocytogenes-Based Vaccine That Secretes Sand Fly Salivary Protein LJM11 Confers Long-Term Protection against Vector-Transmitted Leishmania major SO INFECTION AND IMMUNITY LA English DT Article ID CUTANEOUS LEISHMANIASIS; LUTZOMYIA-LONGIPALPIS; DENDRITIC CELLS; NATURAL MODEL; T-CELLS; INFECTION; IMMUNITY; RESISTANCE; IMMUNOLOGY; IMMUNOTHERAPIES AB Cutaneous leishmaniasis is a sand fly-transmitted disease characterized by skin ulcers that carry significant scarring and social stigmatization. Over the past years, there has been cumulative evidence that immunity to specific sand fly salivary proteins confers a significant level of protection against leishmaniasis. In this study, we used an attenuated strain of Listeria monocytogenes as a vaccine expression system for LJM11, a sand fly salivary protein identified as a good vaccine candidate. We observed that mice were best protected against an intradermal needle challenge with Leishmania major and sand fly saliva when vaccinated intravenously. However, this protection was short-lived. Importantly, groups of vaccinated mice were protected long term when challenged with infected sand flies. Protection correlated with smaller lesion size, fewer scars, and better parasite control between 2 and 6 weeks postchallenge compared to the control group of mice vaccinated with the parent L. monocytogenes strain not expressing LJM11. Moreover, protection correlated with high numbers of CD4(+), gamma interferon-positive (IFN-gamma(+)), tumor necrosis factor alpha-positive/negative (TNF-alpha(+/-)), interleukin-10-negative (IL-10(-)) cells and low numbers of CD4(+) IFN gamma(+/-) TNF-alpha(-) IL-10(+) T cells at 2 weeks postchallenge. Overall, our data indicate that delivery of LJM11 by Listeria is a promising vaccination strategy against cutaneous leishmaniasis inducing long-term protection against ulcer formation following a natural challenge with infected sand flies. C1 [Abdallah, Delbert S. Abi; Bitar, Alan Pavinski; Park, Justin J.; Mendez, Susana; Marquis, Helene] Cornell Univ, Dept Microbiol & Immunol, Ithaca, NY 14850 USA. [Oliveira, Fabiano; Meneses, Claudio; Kamhawi, Shaden; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Mendez, Susana] Cornell Univ, Baker Inst Anim Hlth, Ithaca, NY USA. RP Marquis, H (reprint author), Cornell Univ, Dept Microbiol & Immunol, Ithaca, NY 14850 USA. EM hm72@cornell.edu RI Oliveira, Fabiano/B-4251-2009 OI Oliveira, Fabiano/0000-0002-7924-8038 FU Department of Defense Peer Reviewed Medical Research Program of the Office of the Congressionally Directed Medical Research Programs [W81XWH-10-2-0022]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The study was funded by the Department of Defense Peer Reviewed Medical Research Program of the Office of the Congressionally Directed Medical Research Programs (W81XWH-10-2-0022) and in part by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 49 TC 2 Z9 3 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUL PY 2014 VL 82 IS 7 BP 2736 EP 2745 DI 10.1128/IAI.01633-14 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AK9DS UT WOS:000338728400007 ER PT J AU Kari, L Southern, TR Downey, CJ Watkins, HS Randall, LB Taylor, LD Sturdevant, GL Whitmire, WM Caldwell, HD AF Kari, Laszlo Southern, Timothy R. Downey, Carey J. Watkins, Heather S. Randall, Linnell B. Taylor, Lacey D. Sturdevant, Gail L. Whitmire, William M. Caldwell, Harlan D. TI Chlamydia trachomatis Polymorphic Membrane Protein D Is a Virulence Factor Involved in Early Host-Cell Interactions SO INFECTION AND IMMUNITY LA English DT Article ID OBLIGATE INTRACELLULAR PATHOGEN; GENITAL-TRACT; III SECRETION; AUTOTRANSPORTER; INFECTIONS; MODEL; EXPRESSION; INCLUSION; LINES AB Chlamydia trachomatis is an obligate intracellular mucosotropic pathogen of significant medical importance. It is the etiological agent of blinding trachoma and bacterial sexually transmitted diseases, infections that afflict hundreds of millions of people globally. The C. trachomatis polymorphic membrane protein D (PmpD) is a highly conserved autotransporter and the target of broadly cross-reactive neutralizing antibodies; however, its role in host-pathogen interactions is unknown. Here we employed a targeted reverse genetics approach to generate a pmpD null mutant that was used to define the role of PmpD in the pathogenesis of chlamydial infection. We show that pmpD is not an essential chlamydial gene and the pmpD null mutant has no detectable deficiency in cultured murine cells or in a murine mucosal infection model. Notably, however, the pmpD null mutant was significantly attenuated for macaque eyes and cultured human cells. A reduction in pmpD null infection of human endocervical cells was associated with a deficiency in chlamydial attachment to cells. Collectively, our results show that PmpD is a chlamydial virulence factor that functions in early host-cell interactions. This study is the first of its kind using reverse genetics to evaluate the contribution of a C. trachomatis gene to disease pathogenesis. C1 [Kari, Laszlo; Southern, Timothy R.; Downey, Carey J.; Watkins, Heather S.; Randall, Linnell B.; Taylor, Lacey D.; Sturdevant, Gail L.; Whitmire, William M.; Caldwell, Harlan D.] NIAID, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. RP Caldwell, HD (reprint author), NIAID, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. EM hcaldwell@niaid.nih.gov 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 34 TC 9 Z9 10 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUL PY 2014 VL 82 IS 7 BP 2756 EP 2762 DI 10.1128/IAI.01686-14 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AK9DS UT WOS:000338728400009 PM 24733093 ER PT J AU Robertson, GT Case, ED Dobbs, N Ingle, C Balaban, M Celli, J Norgard, MV AF Robertson, Gregory T. Case, Elizabeth Di Russo Dobbs, Nicole Ingle, Christine Balaban, Murat Celli, Jean Norgard, Michael V. TI FTT0831c/FTL_0325 Contributes to Francisella tularensis Cell Division, Maintenance of Cell Shape, and Structural Integrity SO INFECTION AND IMMUNITY LA English DT Article ID IMMUNE-RESPONSE; ESCHERICHIA-COLI; RECEPTOR 2; IN-VITRO; VIRULENCE; IDENTIFICATION; LIPOPROTEIN; INFECTION; PAL; INFLAMMASOME AB The Francisella FTT0831c/FTL_0325 gene encodes amino acid motifs to suggest it is a lipoprotein and that it may interact with the bacterial cell wall as a member of the OmpA-like protein family. Previous studies have suggested that FTT0831c is surface exposed and required for virulence of Francisella tularensis by subverting the host innate immune response (M. Mahawar et al., J. Biol. Chem. 287:25216-25229, 2012). We also found that FTT0831c is required for murine pathogenesis and intramacrophage growth of Schu S4, but we propose a different model to account for the proinflammatory nature of the resultant mutants. First, inactivation of FTL_0325 from live vaccine strain (LVS) or FTT0831c from Schu S4 resulted in temperature-dependent defects in cell viability and morphology. Loss of FTT0831c was also associated with an unusual defect in lipopolysaccharide O-antigen synthesis, but loss of FTL_0325 was not. Full restoration of these properties was observed in complemented strains expressing FTT0831c in trans, but not in strains lacking the OmpA motif, suggesting that cell wall contact is required. Finally, growth of the LVS FTL_0325 mutant in Mueller-Hinton broth at 37 degrees C resulted in the appearance of membrane blebs at the poles and midpoint, prior to the formation of enlarged round cells that showed evidence of compromised cellular membranes. Taken together, these data are more consistent with the known structural role of OmpA-like proteins in linking the OM to the cell wall and, as such, maintenance of structural integrity preventing altered surface exposure or release of Toll-like receptor 2 agonists during rapid growth of Francisella in vitro and in vivo. C1 [Robertson, Gregory T.; Dobbs, Nicole; Ingle, Christine; Balaban, Murat; Norgard, Michael V.] Univ Texas SW Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA. [Case, Elizabeth Di Russo; Celli, Jean] NIAID, Intracellular Parasites Lab, NIH, Rocky Mt Labs, Hamilton, MT USA. RP Norgard, MV (reprint author), Univ Texas SW Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA. EM Michael.Norgard@UTSouthwestern.edu RI Robertson, Gregory/E-1601-2017; OI Robertson, Gregory/0000-0001-7157-4034; Case, Elizabeth/0000-0002-9129-3894 FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) [U54 AI057156] FX This study was supported by grant U54 AI057156 from National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 49 TC 5 Z9 5 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD JUL PY 2014 VL 82 IS 7 BP 2935 EP 2948 DI 10.1128/IAI.00102-14 PG 14 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AK9DS UT WOS:000338728400025 PM 24778115 ER PT J AU King, MR Matzat, LH Dale, RK Lim, SJ Lei, EP AF King, Matthew R. Matzat, Leah H. Dale, Ryan K. Lim, Su Jun Lei, Elissa P. TI The RNA-binding protein Rumpelstiltskin antagonizes gypsy chromatin insulator function in a tissue-specific manner SO JOURNAL OF CELL SCIENCE LA English DT Article DE Chromatin; Insulator; Nuclear organization ID MESSENGER-RNA; DROSOPHILA INSULATOR; NUCLEAR-ORGANIZATION; ACTIVE PROMOTERS; LOCALIZATION; GENOME; GENE; CTCF; COMPONENT; DOMAINS AB Chromatin insulators are DNA-protein complexes that are situated throughout the genome that are proposed to contribute to higher-order organization and demarcation into distinct transcriptional domains. Mounting evidence in different species implicates RNA and RNA-binding proteins as regulators of chromatin insulator activities. Here, we identify the Drosophila hnRNP M homolog Rumpelstiltskin (Rump) as an antagonist of gypsy chromatin insulator enhancer-blocking and barrier activities. Despite ubiquitous expression of Rump, decreasing Rump levels leads to improvement of barrier activity only in tissues outside of the central nervous system (CNS). Furthermore, rump mutants restore insulator body localization in an insulator mutant background only in non-CNS tissues. Rump associates physically with core gypsy insulator proteins, and chromatin immunoprecipitation and sequencing analysis of Rump demonstrates extensive colocalization with a subset of insulator sites across the genome. The genome-wide binding profile and tissue specificity of Rump contrast with that of Shep, a recently identified RNA-binding protein that antagonizes gypsy insulator activity primarily in the CNS. Our findings indicate parallel roles for RNA-binding proteins in mediating tissue-specific regulation of chromatin insulator activity. C1 [King, Matthew R.; Matzat, Leah H.; Dale, Ryan K.; Lim, Su Jun; Lei, Elissa P.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Lei, EP (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM leielissa@niddk.nih.gov OI Dale, Ryan/0000-0003-2664-3744 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [DK015602-07] FX This work was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [grant number DK015602-07 to E. P. L.]. Deposited in PMC for release after 12 months. NR 50 TC 5 Z9 5 U1 1 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD JUL 1 PY 2014 VL 127 IS 13 BP 2956 EP 2966 DI 10.1242/jcs.151126 PG 11 WC Cell Biology SC Cell Biology GA AK9YW UT WOS:000338785500016 PM 24706949 ER PT J AU Mukouyama, Y AF Mukouyama, Yoh-suke TI Vessel-dependent recruitment of sympathetic axons: looking for innervation in all the right places SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID ARTERIAL DIFFERENTIATION; NEURONS; NERVE; SURVIVAL; PATTERN; SKIN; GUT AB Autonomic sympathetic axons extend along and innervate resistance arteries to control vascular tone and participate in blood pressure regulation. In this issue of the JCI, Brunet and colleagues reveal that sympathetic innervation of arteries is facilitated by secretion of the axon guidance molecule netrin-1 by arterial VSMCs. Furthermore, disruption of the signaling cascade induced by netrin-1 through its receptor DCC resulted in defective arterial innervation and sympathetic control of vasoconstriction. This comprehensive study represents a major step forward in our understanding of the coordinated wiring of the vascular and nervous systems in various tissues. C1 NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Mukouyama, Y (reprint author), NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bldg 10-6C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukoyamay@mail.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [HL006116, Z01 HL005702] NR 19 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2014 VL 124 IS 7 BP 2855 EP 2857 DI 10.1172/JCI76622 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AK8OV UT WOS:000338688400013 PM 24937419 ER PT J AU Park, KS Raffeld, M Moon, YW Xi, LQ Bianco, C Pham, T Lee, LC Mitsudomi, T Yatabe, Y Okamoto, I Subramaniam, D Mok, T Rosell, R Luo, J Salomon, DS Wang, YS Giaccone, G AF Park, Kang-Seo Raffeld, Mark Moon, Yong Wha Xi, Liqiang Bianco, Caterina Trung Pham Lee, Liam C. Mitsudomi, Tetsuya Yatabe, Yasushi Okamoto, Isamu Subramaniam, Deepa Mok, Tony Rosell, Rafael Luo, Ji Salomon, David S. Wang, Yisong Giaccone, Giuseppe TI CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CELL LUNG-CANCER; TYROSINE KINASE INHIBITORS; FACTOR-RECEPTOR GENE; DIFFERENTIAL IMMUNOHISTOCHEMICAL DETECTION; MESENCHYMAL TRANSITION; E-CADHERIN; ACQUIRED-RESISTANCE; BREAST-CANCER; GEFITINIB RESISTANCE; TARGETED THERAPY AB The majority of non-small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI-sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC. C1 [Park, Kang-Seo; Moon, Yong Wha; Trung Pham; Lee, Liam C.; Luo, Ji; Wang, Yisong; Giaccone, Giuseppe] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Park, Kang-Seo; Subramaniam, Deepa; Wang, Yisong; Giaccone, Giuseppe] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Raffeld, Mark; Xi, Liqiang] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bianco, Caterina; Salomon, David S.] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. [Mitsudomi, Tetsuya] Kinki Univ, Fac Med, Dept Surg, Div Thorac Surg, Osaka, Japan. [Yatabe, Yasushi] Kinki Univ, Fac Med, Dept Med Oncol, Osaka, Japan. [Okamoto, Isamu] Aichi Canc Ctr Hosp, Nagoya, Aichi 464, Japan. [Mok, Tony] Chinese Univ Hong Kong, Dept Clin Oncol, State Key Lab Oncol South China, Shatin, Hong Kong, Peoples R China. [Rosell, Rafael] Hosp Badalona Germans Trias & Pujol, Catalan Inst Oncol, Barcelona, Spain. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM yw350@georgetown.edu; gg496@georgetown.edu RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Mitsudomi, Tetsuya/0000-0001-9860-8505 FU NCI Intramural Research Program; Lombardi Comprehensive Cancer Center, Georgetown University FX The study was supported by the NCI Intramural Research Program, and the Lombardi Comprehensive Cancer Center, Georgetown University. NR 64 TC 22 Z9 23 U1 2 U2 13 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2014 VL 124 IS 7 BP 3003 EP 3015 DI 10.1172/JCI73048 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AK8OV UT WOS:000338688400025 PM 24911146 ER PT J AU Liu, GX Yu, J Ding, JH Xie, CS Sun, LX Rudenko, I Zheng, W Sastry, N Luo, J Rudow, G Troncoso, JC Cai, HB AF Liu, Guoxiang Yu, Jia Ding, Jinhui Xie, Chengsong Sun, Lixin Rudenko, Iakov Zheng, Wang Sastry, Namratha Luo, Jing Rudow, Gay Troncoso, Juan C. Cai, Huaibin TI Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MUTANT ALPHA-SYNUCLEIN; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; MICE; VULNERABILITY; METABOLITE; BRAIN; 3,4-DIHYDROXYPHENYLACETALDEHYDE; NEUROTOXICITY; PATHOGENESIS AB Subpopulations of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) display a differential vulnerability to loss in Parkinson's disease (PD); however, it is not clear why these subsets are preferentially selected in PD-associated neurodegeneration. In rodent SNpc, DA neurons can be divided into two subpopulations based on the expression of aldehyde dehydrogenase 1 (ALDH1A1). Here, we have shown that, in alpha-synuclein transgenic mice, a murine model of PD-related disease, DA neurodegeneration occurs mainly in a dorsomedial ALDH1A1-negative subpopulation that is also prone to cytotoxic aggregation of alpha-synuclein. Notably, the topographic ALDH1A1 pattern observed in alpha-synuclein transgenic mice was conserved in human SNpc. Postmortem evaluation of brains of patients with PD revealed a severe reduction of ALDH1A1 expression and neurodegeneration in the ventral ALDH1A1-positive DA subpopulations. ALDH1A1 expression was also suppressed in alpha-synuclein transgenic mice. Deletion of Aldh1a1 exacerbated alpha-synuclein-mediated DA neurodegeneration and alpha-synuclein aggregation, whereas Aldh1a1-null and control DA neurons were comparably susceptible to 1-methyl-4-phenylpyridinium-, glutamate-, or camptothecin-induced cell death. ALDH1A1 overexpression appeared to preferentially protect against alpha-synuclein-mediated DA neurodegeneration but did not rescue alpha-synuclein-induced loss of cortical neurons. Together, our findings suggest that ALDH1A1 protects subpopulations of SNpc DA neurons by preventing the accumulation of dopamine aldehyde intermediates and formation of cytotoxic alpha-synuclein oligomers. C1 [Liu, Guoxiang; Yu, Jia; Xie, Chengsong; Sun, Lixin; Rudenko, Iakov; Zheng, Wang; Sastry, Namratha; Cai, Huaibin] NIA, Transgen Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Ding, Jinhui] NIA, Transgen Sect, Computat Biol Core, Neurogenet Lab, Bethesda, MD 20892 USA. [Luo, Jing] Beijing Normal Univ, Coll Life Sci, Dept Biochem & Mol Biol, Beijing 100875, Peoples R China. [Rudow, Gay; Troncoso, Juan C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. RP Cai, HB (reprint author), NIA, Transgen Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM caih@mail.nih.gov RI Yu, Jia/J-2792-2014; OI Sastry, Namratha/0000-0003-4056-6044 FU National Institute on Aging [AG000959-07, AG000945-03]; NIH funding of the Johns Hopkins University Alzheimer's Disease Research Center [P50AG05146]; Morris K. Udall Centers of Excellence in Parkinson's Disease Research FX This work was supported by the intramural research programs of National Institute on Aging (AG000959-07 and AG000945-03) and by extramural NIH funding of the Johns Hopkins University Alzheimer's Disease Research Center (P50AG05146) and Morris K. Udall Centers of Excellence in Parkinson's Disease Research. We thank David Goldstein of National Institute of Neurological Disorders and Stroke Intramural Research Program for advice on ALDH1A1 in dopamine metabolism, Thomas Beach of Brain and Body Donation Program for help in obtaining postmortem human brain sections, Xing-Long Gu for mouse breeding and genotyping, Joanna Jankowsky of Baylor College of Medicine for providing pAAV-NMCS vector, and Kazuhiro Oka of Baylor College of Medicine for packaging recombinant AAV viruses. We also thank the NIH Fellows Editorial Board for editorial assistance. NR 46 TC 20 Z9 20 U1 0 U2 10 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2014 VL 124 IS 7 BP 3032 EP 3046 DI 10.1172/JCI72176 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AK8OV UT WOS:000338688400027 PM 24865427 ER PT J AU Hansen, FH Skjorringe, T Yasmeen, S Arends, NV Sahai, MA Erreger, K Andreassen, TF Holy, M Hamilton, PJ Neergheen, V Karlsborg, M Newman, AH Pope, S Heales, SJR Friberg, L Law, I Pinborg, LH Sitte, HH Loland, C Shi, L Weinstein, H Galli, A Hjermind, LE Moller, LB Gether, U AF Hansen, Freja H. Skjorringe, Tina Yasmeen, Saiqa Arends, Natascha V. Sahai, Michelle A. Erreger, Kevin Andreassen, Thorvald F. Holy, Marion Hamilton, Peter J. Neergheen, Viruna Karlsborg, Merete Newman, Amy H. Pope, Simon Heales, Simon J. R. Friberg, Lars Law, Ian Pinborg, Lars H. Sitte, Harald H. Loland, Claus Shi, Lei Weinstein, Harel Galli, Aurelio Hjermind, Lena E. Moller, Lisbeth B. Gether, Ulrik TI Missense dopamine transporter mutations associate with adult parkinsonism and ADHD SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NEUROTRANSMITTER SODIUM SYMPORTERS; DEFICIT HYPERACTIVITY DISORDER; CONFORMATIONAL DYNAMICS; MONOAMINE TRANSPORTERS; SEQUENCE VARIATION; BINDING-SITE; OUTWARD-OPEN; C-TERMINUS; DISEASE; GENE AB Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies. C1 [Hansen, Freja H.; Arends, Natascha V.; Andreassen, Thorvald F.; Loland, Claus; Gether, Ulrik] Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, Mol Neuropharmacol & Genet Lab, DK-2200 Copenhagen N, Denmark. [Skjorringe, Tina; Yasmeen, Saiqa; Moller, Lisbeth B.] Copenhagen Univ Hosp, Kennedy Ctr, Ctr Appl Human Genet, Glostrup, Denmark. [Sahai, Michelle A.; Shi, Lei; Weinstein, Harel] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA. [Erreger, Kevin; Hamilton, Peter J.; Galli, Aurelio] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Holy, Marion; Sitte, Harald H.] Med Univ Vienna, Ctr Physiol & Pharmacol, Inst Pharmacol, Vienna, Austria. [Neergheen, Viruna; Pope, Simon; Heales, Simon J. R.] Natl Hosp Neurol & Neurosurg, Neurometab Unit, London WC1N 3BG, England. [Karlsborg, Merete; Friberg, Lars] Copenhagen Univ Hosp, Bispebjerg Hosp, Dept Neurol, Copenhagen, Denmark. [Newman, Amy H.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Heales, Simon J. R.] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Law, Ian] Copenhagen Univ Hosp, Rigshosp, Dept Clin Physiol Nucl Med & PET, Copenhagen, Denmark. [Pinborg, Lars H.] Copenhagen Univ Hosp, Epilepsy Clin, Neurobiol Res Unit, Copenhagen, Denmark. [Hjermind, Lena E.] Copenhagen Univ Hosp, Rigshosp, Dept Neurol, Danish Dementia Res Ctr,Clin Neurogenet, Copenhagen, Denmark. [Hjermind, Lena E.] Univ Copenhagen, Fac Hlth & Med Sci, Neurogenet Sect, Dept Cellular & Mol Med, DK-2200 Copenhagen N, Denmark. RP Gether, U (reprint author), Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, Mol Neuropharmacol & Genet Lab, DK-2200 Copenhagen N, Denmark. EM gether@sund.ku.dk OI Gether, Ulrik/0000-0002-0020-3807; Sitte, Harald/0000-0002-1339-7444; Loland, Claus/0000-0002-1773-1446 FU NIH [P01 DA012408, DA035263]; Danish Medical Research Council; University of Copenhagen BioScaRT Program of Excellence; Lundbeck Foundation Center for Biomembranes in Nanomedicine; Lundbeck Foundation; Novo Nordisk Foundation; Fabrikant Vilhelm Pedersen og Hustrus Mindelegat; Austrian Science Fund (FWF) [F3506]; Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship; National Science Foundation Terascale Computing System at the Texas Advanced Computing Center [TG-MCB130180, TG-MCB120073] FX We thank all the patients and their relatives for participating in this study. We thank Lone Rosenquist for excellent technical assistance and Mu-Fa Zou for synthesizing JHC 1-64. The work was supported by grants from the NIH (P01 DA012408, to A. Galli, H. Weinstein, and U. Gether and DA035263 to A. Galli); the Danish Medical Research Council (to U. Gether); the University of Copenhagen BioScaRT Program of Excellence (to U. Gether); the Lundbeck Foundation Center for Biomembranes in Nanomedicine (to U. Gether); the Lundbeck Foundation (to L.B. Moller and U. Gether); the Novo Nordisk Foundation (to U. Gether); Fabrikant Vilhelm Pedersen og Hustrus Mindelegat (to U. Gether); the Austrian Science Fund (FWF) (F3506, to H.H. Sitte), and the Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship (to M.A. Sahai). Computational support was provided by the National Science Foundation Terascale Computing System at the Texas Advanced Computing Center (TG-MCB130180 and TG-MCB120073) and by the computer facilities at the Institute of Computational Biomedicine of Weill Cornell Medical College. NR 82 TC 22 Z9 23 U1 4 U2 15 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2014 VL 124 IS 7 BP 3107 EP 3120 DI 10.1172/JCI73778 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AK8OV UT WOS:000338688400033 PM 24911152 ER PT J AU Kardava, L Moir, S Shah, N Wang, W Wilson, R Buckner, CM Santich, BH Kim, LJY Spurlin, EE Nelson, AK Wheatley, AK Harvey, CJ McDermott, AB Wucherpfennig, KW Chun, TW Tsang, JS Li, YX Fauci, AS AF Kardava, Lela Moir, Susan Shah, Naisha Wang, Wei Wilson, Richard Buckner, Clarisa M. Santich, Brian H. Kim, Leo J. Y. Spurlin, Emily E. Nelson, Amy K. Wheatley, Adam K. Harvey, Christopher J. McDermott, Adrian B. Wucherpfennig, Kai W. Chun, Tae-Wook Tsang, John S. Li, Yuxing Fauci, Anthony S. TI Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; VACCINE DEVELOPMENT; HUMORAL IMMUNITY; BINDING-SITE; CD4 BINDING; EXPRESSION; BROAD; IMMUNIZATION AB Recently, several neutralizing anti-HIV antibodies have been isolated from memory B cells of HIV-infected individuals. Despite extensive evidence of B cell dysfunction in HIV disease, little is known about the cells from which these rare HIV-specific antibodies originate. Accordingly, we used HIV envelope gp140 and CD4 or coreceptor (CoR) binding site (bs) mutant probes to evaluate HIV-specific responses in peripheral blood B cells of HIV-infected individuals at various stages of infection. In contrast to non-HIV responses, HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated and exhausted memory subsets, which are largely absent in the blood of uninfected individuals. Responses against the CoRbs, which is a poorly neutralizing epitope, arose early, whereas those against the well-characterized neutralizing epitope CD4bs were delayed and infrequent. Enrichment of the HIV-specific response within resting memory B cells, the predominant subset in uninfected individuals, did occur in certain infected individuals who maintained low levels of plasma viremia and immune activation with or without antiretroviral therapy. The distribution of HIV-specific responses among memory B cell subsets was corroborated by transcriptional analyses. Taken together, our findings provide valuable insight into virus-specific B cell responses in HIV infection and demonstrate that memory B cell abnormalities may contribute to the ineffectiveness of the antibody response in infected individuals. C1 [Kardava, Lela; Moir, Susan; Wang, Wei; Buckner, Clarisa M.; Santich, Brian H.; Kim, Leo J. Y.; Spurlin, Emily E.; Nelson, Amy K.; Chun, Tae-Wook; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Shah, Naisha; Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Wilson, Richard; Li, Yuxing] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Wheatley, Adam K.; McDermott, Adrian B.; Li, Yuxing] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Harvey, Christopher J.; Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Program Immunol, Boston, MA USA. [Tsang, John S.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. [Li, Yuxing] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. RP Moir, S (reprint author), NIH, 9000 Rockville Pike,Bldg 10,Room 6A02, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov OI Wheatley, Adam/0000-0002-5593-9387 FU Intramural Research Program of the NIAID; NIH [P01 AI045757]; NIH/NIAID [R01AI102766]; NIAID Development [P30AI36214]; Center for AIDS Research (CFAR); University of California, San Diego FX We thank the patients for their willingness to participate in this study. We thank Shyam Kottilil for patient recruitment and care and Catherine Rehm and Sara Jones for specimen processing. This work was supported by the Intramural Research Program of the NIAID, NIH. Y. Li was supported by NIH/NIAID grant R01AI102766 and NIAID Development Grant P30AI36214, Center for AIDS Research (CFAR), University of California, San Diego. K. W. Wucherpfennig was supported by NIH grant P01 AI045757. NR 59 TC 25 Z9 25 U1 0 U2 11 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2014 VL 124 IS 7 BP 3252 EP 3262 DI 10.1172/JCI74351 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AK8OV UT WOS:000338688400045 PM 24892810 ER PT J AU Grasperge, BJ Morgan, TW Paddock, CD Peterson, KE Macaluso, KR AF Grasperge, Britton J. Morgan, Timothy W. Paddock, Christopher D. Peterson, Karin E. Macaluso, Kevin R. TI Feeding by Amblyomma maculatum (Acari: Ixodidae) Enhances Rickettsia parkeri (Rickettsiales: Rickettsiaceae) Infection in the Skin SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE Rickettsia; Amblyomma; tick-borne; C3H/HeJ ID SPOTTED-FEVER GROUP; MOUNTAIN WOOD TICK; UNITED-STATES; DERMACENTOR-ANDERSONI; BORRELIA-BURGDORFERI; DENDRITIC CELLS; RECEPTOR 4; INBRED MICE; TRANSMISSION; PROTEIN AB Rickettsia parkeri Luckman (Rickettsiales: Rickettsiaceae), a member of the spotted fever group of Rickettsia, is the tick-borne causative agent of a newly recognized, eschar-associated rickettsiosis. Because of its relatively recent designation as a pathogen, few studies have examined the pathogenesis of transmission of R. parkeri to the vertebrate host. To further elucidate the role of tick feeding in rickettsial infection of vertebrates, nymphal Amblyomma maculatum Koch (Acari: Ixodidae) were fed on C3H/HeJ mice intradermally inoculated with R. parkeri (Portsmouth strain). The ticks were allowed to feed to repletion, at which time samples were taken for histopathology, immunohistochemistry (IHC), quantitative polymerase chain reaction (qPCR) for rickettsial quantification, and reverse transcriptase polymerase chain reaction(RT-PCR) for expression of Itgax, Mcp1, and Il1 beta. The group of mice that received intradermal inoculation of R. parkeri with tick feeding displayed significant increases in rickettsial load and IHC staining, but not in cytokine expression, when compared with the group of mice that received intradermal inoculation of R. parkeri without tick feeding. Tick feeding alone was associated with histopathologic changes in the skin, but these changes, and particularly vascular pathology, were more pronounced in the skin of mice inoculated previously with R. parkeri and followed by tick feeding. The marked differences in IHC staining and qPCR for the R. parkeri with tick feeding group strongly suggest an important role for tick feeding in the early establishment of rickettsial infection in the skin. C1 [Grasperge, Britton J.; Macaluso, Kevin R.] Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Vector Borne Dis Labs, Baton Rouge, LA 70803 USA. [Morgan, Timothy W.] Mississippi State Univ, Coll Vet Med, Dept Pathobiol & Populat Med, Mississippi State, MS 39762 USA. [Paddock, Christopher D.] Ctr Dis Control & Prevent, Infect Dis Pathol Branch, Atlanta, GA 30341 USA. [Peterson, Karin E.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Grasperge, BJ (reprint author), Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Vector Borne Dis Labs, Baton Rouge, LA 70803 USA. EM bgrasp1@tigers.lsu.edu RI Peterson, Karin/D-1492-2016; OI Peterson, Karin/0000-0003-4177-7249; Grasperge, Britton/0000-0001-5592-9413 FU National Institutes of Health [AI077784, OD011124] FX We thank Michael T. Kearney for his assistance with statistical analysis, also, the members of the Macaluso laboratory for their technical assistance. This work was supported by the National Institutes of Health (AI077784 and OD011124). This work was also part of B. Grasperge's doctoral dissertation. NR 40 TC 4 Z9 4 U1 1 U2 3 PU ENTOMOLOGICAL SOC AMER PI ANNAPOLIS PA 3 PARK PLACE, STE 307, ANNAPOLIS, MD 21401-3722 USA SN 0022-2585 EI 1938-2928 J9 J MED ENTOMOL JI J. Med. Entomol. PD JUL PY 2014 VL 51 IS 4 BP 855 EP 863 DI 10.1603/ME13248 PG 9 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA AL0TW UT WOS:000338840700017 PM 25118419 ER PT J AU Niu, G Lang, LX Kiesewetter, DO Ma, Y Sun, ZC Guo, N Guo, JX Wu, CX Chen, XY AF Niu, Gang Lang, Lixin Kiesewetter, Dale O. Ma, Ying Sun, Zhongchan Guo, Ning Guo, Jinxia Wu, Chenxi Chen, Xiaoyuan TI In Vivo Labeling of Serum Albumin for PET SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE serum albumin; in vivo labeling; Evans blue; PET; vascular permeability ID EVANS BLUE-DYE; TUMOR ANGIOGENESIS; MURINE MODELS; BLOOD-VOLUME; MARKER; MICE; POOL; ACCUMULATION; CLEARANCE; MECHANISM AB The purpose of this study was to develop a novel in vivo albumin-labeling method to allow PET of cardiac function after myocardial infarction and vascular leakage and increased permeability in inflammatory diseases and malignant tumors. Methods: To label albumin in vivo, we synthesized a NOTA (1,4,7-triazacyclononane-N,N',N ''-triacetic acid)-conjugated truncated form of Evans blue (NEB). F-18 labeling was achieved by the formation of an F-18-aluminum fluoride (F-18-AIF) complex, and Cu-64 labeling was obtained by a standard chelation method. Sixty-minute dynamic PET imaging was performed on normal mice to evaluate the distribution of F-18-AIF-NEB, which was compared with in vitro-labeled mouse serum albumin (F-18-fluorobenzyl-MSA). Electrocardiography-gated PET imaging was performed in a mouse model of myocardial infarction. Both dynamic and static PET scans were obtained in a mouse inflammation model induced by local injection of turpentine to evaluate vascular leakage. Tumor permeability was studied by dynamic and late-point static PET using Cu-64-NEB in a UM-22B xenograft model. Results: NEB was successfully synthesized, and F-18 labeling including work-up took about 20-30 min, with a radiochemical purity greater than 95% without the need for high-performance liquid chromatography purification. Most of the radioactivity was retained in the circulation system at 60 min after injection (26.35 +/- 1.52 percentage injected dose per gram [%ID/g]). With electrocardiography-gated PET, ventricles of the heart and major arteries were clearly visualized. The myocardial infarction mice showed much lower left ventricular ejection fraction than the control mice. Inflammatory muscles showed significantly higher tracer accumulation than the contralateral healthy ones. UM-22B tumor uptake of 64Cu-NEB gradually increased with time (5.73 +/- 1.11 %ID/g at 1 h and 8.03 +/- 0.77 %ID/g at 2 h after injection). Conclusion: The distribution and local accumulation of serum albumin can be noninvasively visualized and quantified by F-18-AIF-NEB and Cu-64-NEB PET. The simple labeling and broad applications make these imaging probes attractive for clinical translation. C1 [Niu, Gang; Lang, Lixin; Kiesewetter, Dale O.; Ma, Ying; Sun, Zhongchan; Guo, Ning; Guo, Jinxia; Wu, Chenxi; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bldg 35A,Rm GD737, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). No other potential conflict of interest relevant to this article was reported. NR 34 TC 17 Z9 17 U1 1 U2 17 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD JUL PY 2014 VL 55 IS 7 BP 1150 EP 1156 DI 10.2967/jnumed.114.139642 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AL0KA UT WOS:000338814600043 PM 24842890 ER PT J AU Lee, JS Collins, MT Somerman, MJ AF Lee, Janice S. Collins, Michael T. Somerman, Martha J. TI Partnerships in rare disorders SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Editorial Material ID MCCUNE-ALBRIGHT-SYNDROME; FIBROUS DYSPLASIA C1 [Lee, Janice S.; Somerman, Martha J.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, NIH, Bethesda, MD 20892 USA. RP Lee, JS (reprint author), Natl Inst Dent & Craniofacial Res, NIH, 10 Ctr Dr,Room 5-2531, Bethesda, MD 20892 USA. EM janice.lee@nih.gov NR 11 TC 0 Z9 0 U1 1 U2 1 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD JUL PY 2014 VL 145 IS 7 BP 694 EP 695 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AK9WN UT WOS:000338779400001 PM 24982266 ER PT J AU Ferrari, R Hernandez, DG Nalls, MA Rohrer, JD Ramasamy, A Kwok, JBJ Dobson-Stone, C Brooks, WS Schofield, PR Halliday, GM Hodges, JR Piguet, O Bartley, L Thompson, E Haan, E Hernandez, I Ruiz, A Boada, M Borroni, B Padovani, A Cruchaga, C Cairns, NJ Benussi, L Binetti, G Ghidoni, R Forloni, G Galimberti, D Fenoglio, C Serpente, M Scarpini, E Clarimon, J Lleo, A Blesa, R Waldo, ML Nilsson, K Nilsson, C Mackenzie, IRA Hsiung, GYR Mann, DMA Grafman, J Morris, CM Attems, J Griffiths, TD McKeith, IG Thomas, AJ Pietrini, P Huey, ED Wassermann, EM Baborie, A Jaros, E Tierney, MC Pastor, P Razquin, C Ortega-Cubero, S Alonso, E Perneczky, R Diehl-Schmid, J Alexopoulos, P Kurz, A Rainero, I Rubino, E Pinessi, L Rogaeva, E St George-Hyslop, P Rossi, G Tagliavini, F Giaccone, G Rowe, JB Schlachetzki, JCM Uphill, J Collinge, J Mead, S Danek, A Van Deerlin, VM Grossman, M Trojanowski, JQ van der Zee, J Deschamps, W Van Langenhove, T Cruts, M Van Broeckhoven, C Cappa, SF Le Ber, I Hannequin, D Golfier, V Vercelletto, M Brice, A Nacmias, B Sorbi, S Bagnoli, S Piaceri, I Nielsen, JE Hjermind, LE Riemenschneider, M Mayhaus, M Ibach, B Gasparoni, G Pichler, S Gu, W Rossor, MN Fox, NC Warren, JD Spillantini, MG Morris, HR Rizzu, P Heutink, P Snowden, JS Rollinson, S Richardson, A Gerhard, A Bruni, AC Maletta, R Frangipane, F Cupidi, C Bernardi, L Anfossi, M Gallo, M Conidi, ME Smirne, N Rademakers, R Baker, M Dickson, DW Graff-Radford, NR Petersen, RC Knopman, D Josephs, KA Boeve, BF Parisi, JE Seeley, WW Miller, BL Karydas, AM Rosen, H van Swieten, JC Dopper, EGP Seelaar, H Al Pijnenburg, Y Scheltens, P Logroscino, G Capozzo, R Novelli, V Puca, AA Franceschi, M Postiglione, A Milan, G Sorrentino, P Kristiansen, M Chiang, HH Graff, C Pasquier, F Rollin, A Deramecourt, V Lebert, F Kapogiannis, D Ferrucci, L Pickering-Brown, S Singleton, AB Hardy, J Momeni, P AF Ferrari, Raffaele Hernandez, Dena G. Nalls, Michael A. Rohrer, Jonathan D. Ramasamy, Adaikalavan Kwok, John B. J. Dobson-Stone, Carol Brooks, William S. Schofield, Peter R. Halliday, Glenda M. Hodges, John R. Piguet, Olivier Bartley, Lauren Thompson, Elizabeth Haan, Eric Hernandez, Isabel Ruiz, Agustin Boada, Merce Borroni, Barbara Padovani, Alessandro Cruchaga, Carlos Cairns, Nigel J. Benussi, Luisa Binetti, Giuliano Ghidoni, Roberta Forloni, Gianluigi Galimberti, Daniela Fenoglio, Chiara Serpente, Maria Scarpini, Elio Clarimon, Jordi Lleo, Alberto Blesa, Rafael Waldo, Maria Landqvist Nilsson, Karin Nilsson, Christer Mackenzie, Ian R. A. Hsiung, Ging-Yuek R. Mann, David M. A. Grafman, Jordan Morris, Christopher M. Attems, Johannes Griffiths, Timothy D. McKeith, Ian G. Thomas, Alan J. Pietrini, P. Huey, Edward D. Wassermann, Eric M. Baborie, Atik Jaros, Evelyn Tierney, Michael C. Pastor, Pau Razquin, Cristina Ortega-Cubero, Sara Alonso, Elena Perneczky, Robert Diehl-Schmid, Janine Alexopoulos, Panagiotis Kurz, Alexander Rainero, Innocenzo Rubino, Elisa Pinessi, Lorenzo Rogaeva, Ekaterina St George-Hyslop, Peter Rossi, Giacomina Tagliavini, Fabrizio Giaccone, Giorgio Rowe, James B. Schlachetzki, Johannes C. M. Uphill, James Collinge, John Mead, Simon Danek, Adrian Van Deerlin, Vivianna M. Grossman, Murray Trojanowski, John Q. van der Zee, Julie Deschamps, William Van Langenhove, Tim Cruts, Marc Van Broeckhoven, Christine Cappa, Stefano F. Le Ber, Isabelle Hannequin, Didier Golfier, Veronique Vercelletto, Martine Brice, Alexis Nacmias, Benedetta Sorbi, Sandra Bagnoli, Silvia Piaceri, Irene Nielsen, Jorgen E. Hjermind, Lena E. Riemenschneider, Matthias Mayhaus, Manuel Ibach, Bernd Gasparoni, Gilles Pichler, Sabrina Gu, Wei Rossor, Martin N. Fox, Nick C. Warren, Jason D. Spillantini, Maria Grazia Morris, Huw R. Rizzu, Patrizia Heutink, Peter Snowden, Julie S. Rollinson, Sara Richardson, Anna Gerhard, Alexander Bruni, Amalia C. Maletta, Raffaele Frangipane, Francesca Cupidi, Chiara Bernardi, Livia Anfossi, Maria Gallo, Maura Conidi, Maria Elena Smirne, Nicoletta Rademakers, Rosa Baker, Matt Dickson, Dennis W. Graff-Radford, Neill R. Petersen, Ronald C. Knopman, David Josephs, Keith A. Boeve, Bradley F. Parisi, Joseph E. Seeley, William W. Miller, Bruce L. Karydas, Anna M. Rosen, Howard van Swieten, John C. Dopper, Elise G. P. Seelaar, Harro Al Pijnenburg, Yolande Scheltens, Philip Logroscino, Giancarlo Capozzo, Rosa Novelli, Valeria Puca, Annibale A. Franceschi, Massimo Postiglione, Alfredo Milan, Graziella Sorrentino, Paolo Kristiansen, Mark Chiang, Huei-Hsin Graff, Caroline Pasquier, Florence Rollin, Adeline Deramecourt, Vincent Lebert, Florence Kapogiannis, Dimitrios Ferrucci, Luigi Pickering-Brown, Stuart Singleton, Andrew B. Hardy, John Momeni, Parastoo TI Frontotemporal dementia and its subtypes: a genome-wide association study SO LANCET NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; LOBAR DEGENERATION; GENETIC-VARIATION; HEXANUCLEOTIDE REPEAT; SUSCEPTIBILITY LOCI; DIAGNOSTIC-CRITERIA; PARKINSONS-DISEASE; MULTIPLE-SCLEROSIS; ALZHEIMER-DISEASE; COMMON VARIANTS AB Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 x 10(-8)) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 x 10-8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1.05 x 10(-8); odds ratio=1.204 [95% CI 1.11-1.30]), rs9268856 (p=5.51 x 10(-9); 0.809 [0.76-0.86]) and rs1980493 (p value=1.57 x 10(-8), 0.775 [0.69-0-86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2.44 x 10(-7); 0.814 [0.71-0.92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. C1 [Ferrari, Raffaele; Momeni, Parastoo] Texas Tech Univ, Hlth Sci Ctr, Dept Internal Med, Neurogenet Lab, Lubbock, TX 79430 USA. [Ferrari, Raffaele; Hernandez, Dena G.; Rohrer, Jonathan D.; Ramasamy, Adaikalavan; Hardy, John] UCL, Inst Neurol, Reta Lila Weston Res Labs, Dept Mol Neurosci, London WC1N 3BG, England. [Hernandez, Dena G.; Nalls, Michael A.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, Bethesda, MD 20892 USA. [Snowden, Julie S.; Rollinson, Sara; Pickering-Brown, Stuart] Univ Manchester, Fac Med & Human Sci, Inst Brain Behav & Mental Hlth, Manchester, Lancs, England. [Dobson-Stone, Carol; Brooks, William S.; Schofield, Peter R.; Halliday, Glenda M.; Hodges, John R.; Piguet, Olivier; Bartley, Lauren] Neurosci Res Australia, Sydney, NSW, Australia. [Kwok, John B. J.; Dobson-Stone, Carol; Brooks, William S.; Schofield, Peter R.; Halliday, Glenda M.; Hodges, John R.; Piguet, Olivier] Univ New S Wales, Sydney, NSW, Australia. [Thompson, Elizabeth; Haan, Eric] Womens & Childrens Hosp, SA Pathol, South Australian Clin Genet Serv, Adelaide, SA, Australia. [Haan, Eric; Thomas, Alan J.] Univ Adelaide, Dept Paediat, Adelaide, SA, Australia. [Hernandez, Isabel; Ruiz, Agustin; Boada, Merce] Inst Catala Neurociencies Aplicades, Memory Clin Fundacio ACE, Barcelona, Spain. [Boada, Merce] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Inst Recerca, E-08193 Barcelona, Spain. [Borroni, Barbara; Padovani, Alessandro] Univ Brescia, Neurol Clin, Brescia, Italy. [Cruchaga, Carlos] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Cruchaga, Carlos; Cairns, Nigel J.] Washington Univ, Sch Med, Hope Ctr, St Louis, MO USA. [Cairns, Nigel J.] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Benussi, Luisa; Binetti, Giuliano] IRCCS Ist Ctr San Giovanni Dio Fatebenefratelli, NeuroBioGen Lab, Memory Clin, Brescia, Italy. [Ghidoni, Roberta] IRCCS Ist Ctr San Giovanni Dio Fatebenefratelli, Prote Unit, Brescia, Italy. [Forloni, Gianluigi] IRCCS Ist Ric Farmacol Mario Negri, Milan, Italy. [Galimberti, Daniela; Fenoglio, Chiara; Serpente, Maria; Scarpini, Elio] Univ Milan, Milan, Italy. [Galimberti, Daniela; Fenoglio, Chiara; Serpente, Maria; Scarpini, Elio] IRCCS Osped Maggiore Policlin, Fdn Ca Granda, Milan, Italy. [Clarimon, Jordi; Lleo, Alberto; Blesa, Rafael] Univ Autonoma Barcelona, Memory Unit, Dept Neurol, E-08193 Barcelona, Spain. [Clarimon, Jordi; Lleo, Alberto; Blesa, Rafael] Univ Autonoma Barcelona, St Pau Biomed Res Inst, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain. [Clarimon, Jordi; Lleo, Alberto; Blesa, Rafael; Pastor, Pau; Ortega-Cubero, Sara] Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Madrid, Spain. [Waldo, Maria Landqvist; Nilsson, Karin] Lund Univ, Unit Geriatr Psychiat, Dept Clin Sci, Lund, Sweden. [Nilsson, Christer] Lund Univ, Clin Memory Res Unit, Dept Clin Sci, Lund, Sweden. [Mackenzie, Ian R. A.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Hsiung, Ging-Yuek R.] Univ British Columbia, Div Neurol, Vancouver, BC V5Z 1M9, Canada. [Mann, David M. A.] Univ Manchester, Salford Royal Hosp, Inst Brain Behav & Mental Hlth, Salford, Lancs, England. [Grafman, Jordan; Morris, Christopher M.; Attems, Johannes; Griffiths, Timothy D.] Northwestern Univ, Feinberg Sch Med, Rehabil Inst Chicago, Dept Phys Med, Evanston, IL 60208 USA. [Grafman, Jordan; Morris, Christopher M.; Attems, Johannes; Griffiths, Timothy D.] Northwestern Univ, Feinberg Sch Med, Rehabil Inst Chicago, Dept Rehabil Psychiat & Cognit Neurol, Evanston, IL 60208 USA. [Grafman, Jordan; Morris, Christopher M.; Attems, Johannes; Griffiths, Timothy D.] Northwestern Univ, Feinberg Sch Med, Alzheimers Dis Ctr, Evanston, IL 60208 USA. [Grafman, Jordan] Northwestern Univ, Weinberg Coll Arts & Sci, Dept Psychol, Evanston, IL 60208 USA. [Morris, Christopher M.; Attems, Johannes; Griffiths, Timothy D.] Newcastle Univ, Newcastle Brain Tissue Resource, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Morris, Christopher M.; Attems, Johannes; Thomas, Alan J.; Jaros, Evelyn] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Morris, Christopher M.; Griffiths, Timothy D.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [McKeith, Ian G.] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Pietrini, P.] Pisa Univ Hosp, Psychol Branch, Pisa, Italy. [Pietrini, P.] Univ Pisa, Lab Clin Biochem & Mol Biol, Pisa, Italy. [Huey, Edward D.] Columbia Univ, Taub Inst, Dept Psychiat, New York, NY 10032 USA. [Huey, Edward D.] Columbia Univ, Taub Inst, Dept Neurol, New York, NY 10032 USA. [Wassermann, Eric M.; Tierney, Michael C.] NINDS, Behav Neurol Unit, NIH, Bethesda, MD 20892 USA. [Baborie, Atik] Walton Ctr FT, Dept Neuropathol, Liverpool, Merseyside, England. [Jaros, Evelyn] Royal Victoria Infirm, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Pastor, Pau; Razquin, Cristina; Ortega-Cubero, Sara; Alonso, Elena] Univ Navarra, Ctr Appl Med Res, Div Neurosci, Neurogenet Lab, E-31080 Pamplona, Spain. [Pastor, Pau] Univ Navarra, Sch Med, Dept Neurol, Univ Navarra Clin, E-31080 Pamplona, Spain. [Perneczky, Robert] Univ London Imperial Coll Sci Technol & Med, Neuroepidemiol & Ageing Res Unit, Sch Publ Hlth, Fac Med, London, England. [Perneczky, Robert] West London Mental Hlth Trust, West London Cognit Disorders Treatment & Res Unit, London TW8 8DS, England. [Perneczky, Robert; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Kurz, Alexander] Tech Univ Munich, Dept Psychiat & Psychotherapy, D-80290 Munich, Germany. [Rainero, Innocenzo] Univ Turin, Dept Neurosci, I-10124 Turin, Italy. [Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo] AO Citta Salute & Sci Torino, Turin, Italy. [Rogaeva, Ekaterina; St George-Hyslop, Peter] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. [St George-Hyslop, Peter] Univ Toronto, Dept Med, Toronto, ON, Canada. [St George-Hyslop, Peter] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [St George-Hyslop, Peter] Univ Cambridge, Dept Clin Neurosci, Cambridge, England. [Rossi, Giacomina; Tagliavini, Fabrizio; Giaccone, Giorgio] Fdn IRCCS Ist Neurol Carlo Besta, Div Neurol & Neuropathol 5, Milan, Italy. [Rowe, James B.] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0SZ, England. [Rowe, James B.] MRC, Cognit & Brain Sci Unit, Cambridge, England. [Schlachetzki, Johannes C. M.] Univ Freiburg, Dept Psychiat & Psychotherapy, Freiburg, Germany. [Schlachetzki, Johannes C. M.] Univ Hosp Erlangen, Dept Mol Neurol, Erlangen, Germany. [Uphill, James; Collinge, John; Mead, Simon] UCL, Inst Neurol, Dept Neurodegenerat Dis, MRC,Prion Unit, London WC1N 3BG, England. [Danek, Adrian] Univ Munich, Neurol Klin & Poliklin, Munich, Germany. [Danek, Adrian] German Ctr Neurodegenerat Dis, Munich, Germany. [Van Deerlin, Vivianna M.; Grossman, Murray; Trojanowski, John Q.] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Van Deerlin, Vivianna M.; Grossman, Murray; Trojanowski, John Q.] Penn Frontotemporal Degenerat Ctr, Philadelphia, PA USA. [van der Zee, Julie; Deschamps, William; Van Langenhove, Tim; Cruts, Marc; Van Broeckhoven, Christine] VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, Antwerp, Belgium. [van der Zee, Julie; Deschamps, William; Van Langenhove, Tim; Cruts, Marc; Van Broeckhoven, Christine] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2020 Antwerp, Belgium. [Cappa, Stefano F.] Univ Vita Salute San Raffaele, Dept Clin Neurosci, Neurorehabil Unit, Milan, Italy. [Cappa, Stefano F.] Ist Sci San Raffaele, I-20132 Milan, Italy. [Le Ber, Isabelle; Brice, Alexis] Univ Paris 06, INSERM, UMR S975, CRICM, F-75013 Paris, France. [Le Ber, Isabelle; Brice, Alexis] Univ Paris 06, UMR S975, F-75013 Paris, France. [Le Ber, Isabelle; Brice, Alexis] CNRS, UMR 7223, F-75013 Paris, France. [Le Ber, Isabelle; Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Dept Neurol, Ctr References Demences Bares, F-75013 Paris, France. [Hannequin, Didier] Rouen Univ Hosp, Serv Neurol, INSERM, U1079,CNR MAJ, Rouen, France. [Golfier, Veronique] CH St Brieuc, Serv Neurol, St Brieuc, France. [Vercelletto, Martine] CHU Nantes, Serv Neurol, Nantes, France. [Nacmias, Benedetta; Sorbi, Sandra; Bagnoli, Silvia; Piaceri, Irene] Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth NEURO, Florence, Italy. [Nielsen, Jorgen E.; Hjermind, Lena E.] Copenhagen Univ Hosp, Dept Neurol, Rigshosp, Danish Dementia Res Ctr,Neurogenet Clin, Copenhagen, Denmark. [Nielsen, Jorgen E.; Hjermind, Lena E.] Univ Copenhagen, Panum Inst, Neurogenet Sect, Dept Cellular & Mol Med, DK-1168 Copenhagen, Denmark. [Riemenschneider, Matthias] Saarland Univ Hosp, Dept Psychiat & Psychotherapy, Homburg, Germany. [Riemenschneider, Matthias; Mayhaus, Manuel; Gasparoni, Gilles; Pichler, Sabrina; Gu, Wei] Univ Saarland, Neurogenet Lab, Homburg, Germany. [Ibach, Bernd] Univ Regensburg, Dept Psychiat Psychotherapy Psychosomat, D-93053 Regensburg, Germany. [Gu, Wei] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Luxembourg, Luxembourg. [Rohrer, Jonathan D.; Rossor, Martin N.; Fox, Nick C.; Warren, Jason D.] UCL, Inst Neurol, Dept Neurodegenerat Dis, Dementia Res Ctr, London WC1N 3BG, England. [Spillantini, Maria Grazia] Univ Cambridge, Dept Clin Neurosci, John van Geest Brain Repair Ctr, Cambridge, England. [Morris, Huw R.] Cardiff Univ, Sch Med, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Rizzu, Patrizia; Heutink, Peter] German Ctr Neurodegenerat Dis Tubingen, Tubingen, Germany. [Richardson, Anna] Univ Manchester, Fac Med & Human Sci, Salford Royal Fdn Trust, Manchester M13 9PL, Lancs, England. [Gerhard, Alexander] Univ Manchester, Inst Brain Behav & Mental Hlth, Manchester, Lancs, England. [Bruni, Amalia C.; Maletta, Raffaele; Frangipane, Francesca; Cupidi, Chiara; Bernardi, Livia; Anfossi, Maria; Gallo, Maura; Conidi, Maria Elena; Smirne, Nicoletta] ASPCZ, Reg Neurogenet Ctr, Lamezia Terme, Italy. [Rademakers, Rosa; Baker, Matt; Dickson, Dennis W.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Graff-Radford, Neill R.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Petersen, Ronald C.; Knopman, David; Josephs, Keith A.; Boeve, Bradley F.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Parisi, Joseph E.] Mayo Clin, Dept Pathol, Rochester, MN USA. [Seeley, William W.; Miller, Bruce L.; Karydas, Anna M.; Rosen, Howard] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [van Swieten, John C.; Dopper, Elise G. P.; Seelaar, Harro] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [van Swieten, John C.] Vrije Univ Amsterdam, Med Ctr, Dept Med Genet, Amsterdam, Netherlands. [Al Pijnenburg, Yolande; Scheltens, Philip] Vrije Univ Amsterdam, Med Ctr, Alzheimer Ctr, Amsterdam, Netherlands. [Al Pijnenburg, Yolande; Scheltens, Philip] Vrije Univ Amsterdam, Med Ctr, Dept Neurol, Amsterdam, Netherlands. [Logroscino, Giancarlo; Capozzo, Rosa] Univ Bari, Dept Basic Med Sci Neurosci & Sense Organs Aldo M, I-70121 Bari, Italy. [Ramasamy, Adaikalavan] Kings Coll London, Guys Hosp, Dept Med & Mol Genet, London WC2R 2LS, England. [Novelli, Valeria] IRCCS Fdn S Maugeri, Dept Mol Cardiol, Pavia, Italy. [Puca, Annibale A.] IRCCS Multimed, Cardiovasc Res Unit, Milan, Italy. [Puca, Annibale A.] Univ Salerno, Dept Med & Surg, I-84081 Baronissi, SA, Italy. [Franceschi, Massimo] IRCCS Multimed, Dept Neurol, Milan, Italy. [Postiglione, Alfredo] Univ Naples Federico II, Dept Clin Med & Surg, Naples, Italy. [Milan, Graziella; Sorrentino, Paolo] Geriatr Ctr Frullone ASL Napoli 1 Ctr, Naples, Italy. [Kristiansen, Mark] UCL, Inst Child Hlth, London WC1N 3BG, England. [Chiang, Huei-Hsin; Graff, Caroline] Karolinska Inst, Dept NVS, KI Alzheimer Dis Res Ctr, Stockholm, Sweden. [Chiang, Huei-Hsin; Graff, Caroline] Karolinska Univ Hosp, Genet Unit, Dept Geriatr Med, Stockholm, Sweden. [Pasquier, Florence; Rollin, Adeline; Deramecourt, Vincent; Lebert, Florence] Univ Lille Nord France, Lille, France. [Kapogiannis, Dimitrios] NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), UCL, Inst Neurol, Reta Lila Weston Res Labs, Dept Mol Neurosci, London WC1N 3BG, England. EM j.hardy@ucl.ac.uk RI , raffaele/K-4421-2016; Rowe, James/C-3661-2013; Piaceri, Irene /J-4310-2016; Rubino, Elisa/K-3282-2016; BENUSSI, LUISA/K-4409-2016; Ghidoni, Roberta/K-4507-2016; Binetti, Giuliano/K-4519-2016; LOGROSCINO, GIANCARLO/K-5148-2016; Danek, Adrian/G-7339-2011; Fox, Nick/B-1319-2009; Attems, Johannes/B-8368-2015; LICEND, CEMND/F-1296-2015; Hardy, John/C-2451-2009; Pastor, Pau/C-9834-2009; Singleton, Andrew/C-3010-2009; Pickering-Brown, Stuart/D-4008-2009; Halliday, Glenda/E-8555-2011; Rossi, Giacomina/I-2783-2012; Morris, Huw/B-8527-2008; Ramasamy, Adaikalavan/G-2632-2010; graff, caroline/A-2545-2009 OI Griffiths, Timothy/0000-0001-8066-4381; , raffaele/0000-0002-0758-1835; Snowden, Julie/0000-0002-3976-4310; scarpini, elio/0000-0002-6395-2119; Clarimon, Jordi/0000-0002-6824-6942; Rowe, James/0000-0001-7216-8679; Schlachetzki, Johannes/0000-0002-7801-9743; Piaceri, Irene /0000-0001-6787-2223; Rubino, Elisa/0000-0002-7553-7553; BENUSSI, LUISA/0000-0003-2836-8141; Ghidoni, Roberta/0000-0002-7691-1957; Binetti, Giuliano/0000-0003-2759-5844; LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Danek, Adrian/0000-0001-8857-5383; galimberti, daniela/0000-0002-9284-5953; Dickson, Dennis W/0000-0001-7189-7917; NACMIAS, Benedetta/0000-0001-9338-9040; Cruchaga, Carlos/0000-0002-0276-2899; sorbi, sandro/0000-0002-0380-6670; Fox, Nick/0000-0002-6660-657X; Pastor, Pau/0000-0002-7493-8777; Pickering-Brown, Stuart/0000-0003-1561-6054; Halliday, Glenda/0000-0003-0422-8398; Rossi, Giacomina/0000-0001-6680-2725; Morris, Huw/0000-0002-5473-3774; Ramasamy, Adaikalavan/0000-0002-7598-2892; FU National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA); Wellcome/MRC Centre on Parkinson's disease; Alzheimer's Research UK (ARUK) [ARUK-PG2012-18]; office of the Dean of the School of Medicine, Department of Internal Medicine, at Texas Tech University Health Sciences Center; Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the US Department of Health and Human Services [ZIA AG000932-04]; Department of Defense [W81XWH-09-2-0128]; MRC through the MRC Sudden Death Brain Bank; King Faisal Specialist Hospital and Research Centre, Saudi Arabia; National Health and Medical Resarch Council (NHMRC), Australia [510217, 1005769]; NHMRC [510217, 1005769, 630428]; NHMRC Enabling Grant [401184]; NHMRC Research Fellowship [630434, 1029538, 1037746]; Australian Research Council Federation Fellowship; NHMRC Project Grant [1029538]; NHMRC Program Grant [1037746]; NHMRC Career Development Fellowship [1022684, 1003139]; Ricerca Corrente, Italian Ministry of Health; Fondazione CARIPLO, Ricerca Corrente, Italian Ministry of Health [2009-2633]; Fondazione CARIPLO [2009-2633]; Italian Ministry of Health; Fondazione Cariplo; Italian Ministry of Health (Ricerca Corrente); Government funding of clinical research within NHS Sweden (ALF); Thure Carlsson Foundation; Swedish Alzheimer Fund; CIHR [74580]; PARF [C06-01]; NINDS intramural research funds for FTD research; Medical Research Council UK; Brains for Dementia Research; Alzheimer's Society; Alzheimer's Research UK; National Institutes for Health Research; Department of Health; Yvonne Mairy Bequest; UK MRC [G0400074, G1100540]; Alzheimer's Research Trust; Alzheimer's Society through the Brains for Dementia Research Initiative; NIHR Biomedical Research Centre Grant in Ageing and Health; NIHR Biomedical Research Unit in Lewy Body Disorders; UK Department of Health; Medical Research Council; National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust; Newcastle University; MRC; Dunhill Medical Trust; NIHR Biomedical Research Centre and Unit on Ageing Grants; NIHR; Newcastle Biomedical Research Centre; FIMA (Foundation for Applied Medical Research); German Federal Ministry of Education and Research (BMBF-German FTLD consortium) [FKZ 01GI1007A]; Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR) of Italy; Canadian Institutes of Health Research; Wellcome Trust; Ontario Research Fund; MIUR grant [RBAP11FRE9]; Cambridge NIHR Biomedical Research Centre; Wellcome Trust [088324]; MRC Prion Unit core Binding; MetLife Foundation Award for Medical Research; Belgian Science Policy Office Interuniversity Attraction Poles programme; Foundation for Alzheimer Research (SAO-FRA); Medical Foundation Queen Elisabeth; Flemish Government Methusalem Excellence award; Research Foundation Flanders (FWO); University of Antwerp Research Fund; FWO; programme Investissements d'avenir [ANR-10-IAIHU-06]; Cassa di Rispario di Firenze e Cassa di Risparmio di Pistoia e Pescia; Novo Nordisk Foundation, Denmark; German National Genome Network (NGFN); German Ministry for Education and Research Grant [01GS0465]; MRC programme grant; NIHR Queen Square Dementia Biomedical Research Unit; Leonard Wolfson Experimental Neurology Centre; MRC grant [G0301152]; Cambridge Biomedical Research Centre; Motor Neuron Disease Association [6057]; Consortium for Frontotemporal Dementia; State of Florida Alzheimer Disease Initiative; CurePSP Inc.; NIH, Consortium for Frontotemporal Dementia Research [AG023501, AG019724]; Consortium for FTD Research [P50AG023501, P01AG019724]; Stichting Dioraphte Foundation [11 02 03 00]; Nuts Ohra Foundation [0801-69]; Hersenstichting Nederland [BG 2010-02]; Alzheimer Nederland; Swedish Brain Power (SBP); Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro); Stockholm County Council; Karolinska Institutet; Swedish Alzheimer Foundation; Swedish Research Council; Karolinska Institutet PhD-student funding; King Gustaf V, and Queen Victoria's Free Mason Foundation; [G0901254]; [G0802462]; [P30-NS069329-01]; [AG032953]; [AG017586]; [AG010124]; [NS044266]; [Prin 2010-prot.2010PWNJXK]; [P50 AG016574]; [R01 NS080882]; [R01 NS065782]; [P50 NS72187]; [P50NS072187]; [P50AG016574]; [R01 AG037491]; [AG032306] FX We received intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA), the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK (ARUK, Grant ARUK-PG2012-18), and by the office of the Dean of the School of Medicine, Department of Internal Medicine, at Texas Tech University Health Sciences Center. We thank Mike Hubank and Kerra Pearce at the Genomic core facility at the Institute of Child Health (ICH), UCL, for assisting RF in doing Illumina genotyping experiments (FTD-GWAS genotyping). The work done by the North American Brain Expression Consortium (NABEC) was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the US Department of Health and Human Services (project number ZIA AG000932-04), and by a Research Grant from the Department of Defense (W81XWH-09-2-0128). Work done by the UK Brain Expression Consortium (UKBEC) was supported by the MRC through the MRC Sudden Death Brain Bank (CS), by a Project Grant (G0901254 to JH and MW), and by a Fellowship award (G0802462 to MR). DT was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Computing facilities used at King's College London were supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. We thank AROS Applied Biotechnology AS company laboratories and Affymetrix for their valuable input. JBJK was supported by the National Health and Medical Resarch Council (NHMRC), Australia (project grants 510217 and 1005769). CDS was supported by NHMRC (project grants 630428 and 1005769). PRS was supported by NHMRC (project grants 510217 and 1005769) and acknowledges that DNA samples were prepared by Genetic Repositories Australia, supported by NHMRC Enabling Grant 401184. GMH was supported by NHMRC Research Fellowship 630434, Project Grant 1029538, and Program Grant 1037746. JRH was supported by the Australian Research Council Federation Fellowship, NHMRC Project Grant 1029538 and NHMRC Program Grant 1037746. OP was supported by NHMRC Career Development Fellowship 1022684, Project Grant 1003139. IH, AR, and MB acknowledge the patients and controls who participated in this project and the Trinitat Port-Carbo (deceased) and her extended family who are supporting Fundacio ACE research programmes. CC was supported by Grant P30-NS069329-01 and acknowledges that the recruitment and clinical characterisation of, research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. LB and GB were supported by the Ricerca Corrente, Italian Ministry of Health. RG was supported by Fondazione CARIPLO 2009-2633, Ricerca Corrente, Italian Ministry of Health. GF was supported by Fondazione CARIPLO 2009-2633. ES was supported by the Italian Ministry of Health. CF was supported by Fondazione Cariplo. MS was supported from the Italian Ministry of Health (Ricerca Corrente). MLW was supported by Government funding of clinical research within NHS Sweden (ALF). KN was supported by Thure Carlsson Foundation. CN was supported by Swedish Alzheimer Fund. IRAM and GYRH were supported by CIHR (grant 74580) PARF (grant C06-01). JG was supported by the NINDS intramural research funds for FTD research.; CMM was supported by Medical Research Council UK, Brains for Dementia Research, Alzheimer's Society, Alzheimer's Research UK, National Institutes for Health Research, Department of Health, and Yvonne Mairy Bequest, and acknowledges that tissue samples made available for this study were provided by the Newcastle Brain Tissue Resource, which was funded in part by grants G0400074 and G1100540 from the UK MRC, the Alzheimer's Research Trust and Alzheimer's Society through the Brains for Dementia Research Initiative and an NIHR Biomedical Research Centre Grant in Ageing and Health, and NIHR Biomedical Research Unit in Lewy Body Disorders. CMM was supported by the UK Department of Health and Medical Research Council and the Research was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust and Newcastle University and acknowledges that the views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. JA was supported by MRC, Dunhill Medical Trust, and Alzheimer's Research UK. TDG was supported by Wellcome Trust Senior Clinical Fellow. IGM was supported by NIHR Biomedical Research Centre and Unit on Ageing Grants and acknowledges the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust and Newcastle University. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. AJT was supported by Medical Research Council, Alzheimer's Society, Alzheimer's Research UK, and the National Institutes for Health Research. EJ was supported by NIHR and Newcastle Biomedical Research Centre. PP, CR, SOC, and EA were supported partially by FIMA (Foundation for Applied Medical Research). PP acknowledges Manuel Seijo-Martinez (Department of Neurology, Hospital do Salnes, Pontevedra, Spain) and Ramon Rene, Jordi Gascon, and Jaume Campdelacreu (Department of Neurology, Hospital de Bellvitge, Barcelona, Spain) for providing FTD DNA samples. RP, JDS, PA, AK, and AD were supported by the German Federal Ministry of Education and Research (BMBF; grant number FKZ 01GI1007A-German FTLD consortium). IR was supported by Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR) of Italy. PStG-H was supported by the Canadian Institutes of Health Research, Wellcome Trust, Ontario Research Fund. FT was supported by the Italian Ministry of Health (ricerca corrente) and MIUR grant RBAP11FRE9. GR and GG were supported by the Italian Ministry of Health (ricerca corrente). JBR was supported by Cambridge NIHR Biomedical Research Centre and Wellcome Trust (088324). JU, JC, and SM were supported by the MRC Prion Unit core Binding and acknowledge MRC UK, UCLH Biomedical Research Centre, and Queen Square Dementia BRU. SM thanks John Beck, Tracy Campbell, Gary Adamson, Ron Druyeh, Jessica Lowe, and Mark Pointer. AD thanks Benedikt Bader, Manuela Neumann, Sigrun Roeber, Thomas Arzberger, and Hans Kretzschmar (deceased). VMVD and JQT were supported by grants AG032953, AG017586 and AG010124. MG was supported by Grants AG032953, AG017586, AG010124, and NS044266. VMVD thanks EunRan Suh for assistance with sample handling and Elisabeth McCarty-Wood for help in selection of patients. JQT thanks Terry Schuck, John Robinson, and Kevin Raible for assistance with neuropathological assessment of patients.; CVB and the Antwerp site were in part funded by the MetLife Foundation Award for Medical Research (to CVB), the Belgian Science Policy Office Interuniversity Attraction Poles programme; the Foundation for Alzheimer Research (SAO-FRA); the Medical Foundation Queen Elisabeth; the Flemish Government Methusalem Excellence award (to CVB); the Research Foundation Flanders (FWO); and the University of Antwerp Research Fund. JvdZ holds a postdoctoral fellowship of the FWO. CVB and the Antwerp site authors thanks neurologists S Engelborghs, P P De Deyn, A Sieben, and Rik Vandenberghe and neuropathologist J J Martin for the clinical and pathological diagnoses. Isabelle Leber and Alexis Brice were supported by the programme Investissements d'avenir ANR-10-IAIHU-06 and acknowledges the contribution of The French Research Network on FTLD/FTLD-ALS for the contribution in samples collection. BN, SS, SB, and IP were supported by Prin 2010-prot.2010PWNJXK; Cassa di Rispario di Firenze e Cassa di Risparmio di Pistoia e Pescia. JEN was supported by the Novo Nordisk Foundation, Denmark. MR was supported by the German National Genome Network (NGFN) and the German Ministry for Education and Research Grant Number 01GS0465. JDR, MNR, NCF, and JDW were supported by an MRC programme grant, the NIHR Queen Square Dementia Biomedical Research Unit and the Leonard Wolfson Experimental Neurology Centre. MGS was supported by MRC grant n G0301152, Cambridge Biomedical Research Centre, and thanks K Westmore for extracting DNA. HM was supported by the Motor Neuron Disease Association (Grant 6057). RR was supported by P50 AG016574, R01 NS080882, R01 NS065782, P50 NS72187, and the Consortium for Frontotemporal Dementia. DWD was supported by P50NS072187, P50AG016574, State of Florida Alzheimer Disease Initiative, and CurePSP Inc. NRGR, JEP, RCP, DK, and BFB were supported by P50 AG016574. KAJ was supported by R01 AG037491. WWS was supported by NIH AG023501, AG019724, Consortium for Frontotemporal Dementia Research. BLM was supported by P50AG023501, P01AG019724, Consortium for FTD Research. HR was supported by AG032306. JCvS was supported by Stichting Dioraphte Foundation (11 02 03 00), Nuts Ohra Foundation (0801-69), Hersenstichting Nederland (BG 2010-02), and Alzheimer Nederland. CG and HHC acknowledge families, patients, clinicians including Inger Nennesmo and Vesna Jelic, Laura Fratiglioni for control samples and Jenny Bjorkstrom, Hakan Thonberg, Charlotte Forsell, Anna-Karin Lindstrom, and Lena Lilius for sample handling CG was supported by Swedish Brain Power (SBP), the Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro), the regional agreement on medical training and clinical research (ALP) between Stockholm County Council and Karolinska Institutet, Swedish Alzheimer Foundation, Swedish Research Council, Karolinska Institutet PhD-student funding, King Gustaf V, and Queen Victoria's Free Mason Foundation. FP, AR, VD, and FL acknowledge Labex DISTALZ. RF acknowledges the help and support of June Howard at the Texas Tech University Health Sciences Center Office of Sponsored Programs for tremendous help in managing Material Transfer Agreement at TTUHSC. NR 56 TC 45 Z9 45 U1 3 U2 55 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD JUL PY 2014 VL 13 IS 7 BP 686 EP 699 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA AK5RI UT WOS:000338483600015 PM 24943344 ER PT J AU Shukla, S Kouanda, A Silverton, L Talele, TT Ambudkar, SV AF Shukla, Suneet Kouanda, Abdul Silverton, Latoya Talele, Tanaji T. Ambudkar, Suresh V. TI Pharmacophore Modeling of Nilotinib as an Inhibitor of ATP-Binding Cassette Drug Transporters and BCR-ABL Kinase Using a Three-Dimensional Quantitative Structure-Activity Relationship Approach SO MOLECULAR PHARMACEUTICS LA English DT Article DE ATP-binding cassette transporters; ABCG2; BCR-ABL kinase; imatinib; nilotinib; P-glycoprotein; tyrosine kinase inhibitor; structure-activity relationship ID CANCER RESISTANCE PROTEIN; P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; IMATINIB MESYLATE; SELECTIVE INHIBITOR; 3D QSAR; ABCG2; ABCB1; MODULATORS; SUBSTRATE AB Nilotinib (Tasigna) is a tyrosine kinase inhibitor approved by the FDA to treat chronic phase chronic myeloid leukemia patients. It is also a transport substrate of the ATP-binding cassette (ABC) drug efflux transporters ABCB1 (P-glycoprotein, P-gp) and ABCG2 (BCRP), which may have an effect on the pharmacokinetics and toxicity of this drug. The goal of this study was to identify pharmacophoric features of nilotinib in order to potentially develop specific inhibitors of BCR-ABL kinase with minimal interactions with ABC drug transporters. Three-dimensional pharmacophore modeling and quantitative structure activity relationship (QSAR) studies were carried out on a series of nilotinib analogues to identify chemical features that contribute to inhibitory activity of nilotinib against BCR-ABL kinase activity, P-gp, and ABCG2. Twenty-five derivatives of nilotinib were synthesized and were then tested to measure their activity to inhibit BCR-ABL kinase and to inhibit the function of ABC drug transporters. A set of in vitro experiments including kinase activity and cell-based transport assays and photolabeling of P-gp and ABCG2 with a transport substrate, [I-125]-iodoarylazido-prazosin (IAAP), were carried out in isolated membranes to evaluate the potency of the derivatives to inhibit the function of ABC drug transporters and BCR-ABL kinase. Sixteen, fourteen, and ten compounds were selected as QSAR data sets, respectively, to generate PHASE v3.1 pharmacophore models for BCR-ABL kinase, ABCG2, and P-gp inhibitors. The IC50 values of these derivatives against P-gp, ABCG2, or BCR-ABL kinase were used to generate pharmacophore features required for optimal interactions with these targets. A seven-point pharmacophore (AADDRRR) for BCR-ABL kinase inhibitory activity, a six-point pharmacophore (ADHRRR) for ABCG2 inhibitory activity, and a seven-point pharmacophore (AADDRRR) for P-gp inhibitory activity were generated. The derived models clearly demonstrate high predictive power for test sets of BCR-ABL, ABCG2, and P-gp inhibitors. In aggregate, these results should aid in the development of specific inhibitors of BCR-ABL kinase that exhibit no or minimal interaction with ABC drug transporters. C1 [Shukla, Suneet; Kouanda, Abdul; Silverton, Latoya; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Talele, Tanaji T.] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research [ZIABC010030-13] FX We are grateful to Drs. A. P. Skoumbourdis, D. Y. Duveau, and C. J. Thomas (National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850) for synthesizing nilotinib and its derivatives. We thank Bhargav Patel (Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University) for help with Figure 3d and George Leiman for editing the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (Grant ZIABC010030-13). NR 37 TC 10 Z9 10 U1 2 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD JUL PY 2014 VL 11 IS 7 BP 2313 EP 2322 DI 10.1021/mp400762h PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AK9LI UT WOS:000338748200039 PM 24865254 ER PT J AU Meylan, F Hawley, ET Barron, L Barlow, JL Penumetcha, P Pelletier, M Sciume, G Richard, AC Hayes, ET Gomez-Rodriguez, J Chen, X Paul, WE Wynn, TA Mckenzie, ANJ Siegel, RM AF Meylan, F. Hawley, E. T. Barron, L. Barlow, J. L. Penumetcha, P. Pelletier, M. Sciume, G. Richard, A. C. Hayes, E. T. Gomez-Rodriguez, J. Chen, X. Paul, W. E. Wynn, T. A. Mckenzie, A. N. J. Siegel, R. M. TI The TNF-family cytokine TL1A promotes allergic immunopathology through group 2 innate lymphoid cells SO MUCOSAL IMMUNOLOGY LA English DT Article ID HELPER TYPE-2 RESPONSE; T-CELL; RHEUMATOID-ARTHRITIS; AIRWAY INFLAMMATION; LUNG INFLAMMATION; DEATH RECEPTOR-3; IMMUNITY; EXPRESSION; IL-13; DR3 AB The tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells and promotes diverse T cell-dependent models of autoimmune disease through its receptor DR3. TL1A polymorphisms also confer susceptibility to inflammatory bowel disease. Here, we find that allergic pathology driven by constitutive TL1A expression depends on interleukin-13 (IL-13), but not on T, NKT, mast cells, or commensal intestinal flora. Group 2 innate lymphoid cells (ILC2) express surface DR3 and produce IL-13 and other type 2 cytokines in response to TL1A. DR3 is required for ILC2 expansion and function in the setting of T cell-dependent and -independent models of allergic disease. By contrast, DR3-deficient ILC2 can still differentiate, expand, and produce IL-13 when stimulated by IL-25 or IL-33, and mediate expulsion of intestinal helminths. These data identify costimulation of ILC2 as a novel function of TL1A important for allergic lung disease, and suggest that TL1A may be a therapeutic target in these settings. C1 [Meylan, F.; Hawley, E. T.; Penumetcha, P.; Pelletier, M.; Richard, A. C.; Hayes, E. T.; Siegel, R. M.] NIAMS, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Barron, L.; Wynn, T. A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Barlow, J. L.; Mckenzie, A. N. J.] MRC Lab Mol Biol, Cambridge, England. [Sciume, G.] NIAMS, Lymphocyte Cell Biol Sect, Bethesda, MD USA. [Gomez-Rodriguez, J.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Chen, X.; Paul, W. E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Siegel, RM (reprint author), NIAMS, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. EM rsiegel@nih.gov RI Sciume, Giuseppe/K-8985-2016 OI Sciume, Giuseppe/0000-0003-0131-512X FU Intramural NIH HHS [ZIA AR041133-12]; Medical Research Council [MC_U105178805] NR 49 TC 27 Z9 29 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JUL PY 2014 VL 7 IS 4 BP 958 EP 968 DI 10.1038/mi.2013.114 PG 11 WC Immunology SC Immunology GA AK8UI UT WOS:000338703600019 PM 24368564 ER PT J AU Faraldo-Gomez, JD AF Faraldo-Gomez, Jose D. TI Channeling your inner energy SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID MITOCHONDRIAL OUTER-MEMBRANE; DEPENDENT ANION CHANNEL; VDAC; DYNAMICS; SIMULATIONS; TRANSPORT; PROTEINS AB ATP is continuously synthesized inside mitochondria and exported to the cytoplasm via transporter and channel proteins residing in the inner and outer mitochondrial membranes, respectively. In this issue of Nature Structural & Molecular Biology, a new crystal structure of the mitochondrial channel protein VDAC-1 provides the basis for a detailed simulation study that unravels the mechanism by which ATP diffuses across the outer mitochondrial membrane at a fast rate. C1 NHLBI, Theoret Mol Biophys Sect, NIH, Bethesda, MD 20892 USA. RP Faraldo-Gomez, JD (reprint author), NHLBI, Theoret Mol Biophys Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jose.faraldo@nih.gov RI Faraldo-Gomez, Jose/H-7127-2016 NR 23 TC 1 Z9 1 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUL PY 2014 VL 21 IS 7 BP 575 EP 577 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA AK8PH UT WOS:000338689800002 PM 24992223 ER PT J AU Divito, CB Underhill, SM AF Divito, Christopher B. Underhill, Suzanne M. TI Excitatory amino acid transporters: Roles in glutamatergic neurotransmission SO NEUROCHEMISTRY INTERNATIONAL LA English DT Review DE Glutamate; Transporters; Ion channels; Synapse; Receptors; Plasticity ID LONG-TERM POTENTIATION; SYNAPTICALLY RELEASED GLUTAMATE; CYSTEINE-ACCESSIBILITY METHOD; CLIMBING FIBER ACTIVATION; CEREBELLAR PURKINJE-CELLS; RETINAL GLIAL-CELLS; RAT-BRAIN; MEMBRANE-VESICLES; BINDING-SITE; BACILLUS-STEAROTHERMOPHILUS AB Excitatory amino acid transporters or EAATs are the major transport mechanism for extracellular glutamate in the nervous system. This family of five carriers not only displays an impressive ability to regulate ambient extracellular glu concentrations but also regulate the temporal and spatial profile of glu after vesicular release. This dynamic form of regulation mediates several characteristic of synaptic, perisynaptic, and spillover activation of ionotropic and metabotropic receptors. EAATs function through a secondary active, electrogenic process but also possess a thermodynamically uncoupled ligand gated anion channel activity, both of which have been demonstrated to play a role in regulation of cellular activity. This review will highlight the inception of EAATs as a focus of research, the transport and channel functionality of the carriers, and then describe how these properties are used to regulate glutamatergic neurotransmission. Published by Elsevier Ltd. C1 [Divito, Christopher B.] Univ Pittsburgh, Sch Med, Ctr Neurosci, Dept Neurobiol, Pittsburgh, PA 15261 USA. [Underhill, Suzanne M.] NIMH, Lab Cellular & Mol Neurosci, NIH, Bethesda, MD 20892 USA. RP Underhill, SM (reprint author), NIMH, Lab Cellular & Mol Neurosci, NIH, Bethesda, MD 20892 USA. EM suzanne.underhill@nih.gov FU NIMH Department of Intramural Research; NIH [MH080726] FX This work was supported by the NIMH Department of Intramural Research (S.M.U.) and NIH Grant MH080726 (C.B.D.). The authors would like to thank Jon W. Johnson for his thoughtful review and comments on the manuscript. NR 118 TC 7 Z9 7 U1 0 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 EI 1872-9754 J9 NEUROCHEM INT JI Neurochem. Int. PD JUL PY 2014 VL 73 SI SI BP 172 EP 180 DI 10.1016/j.neuint.2013.12.008 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AL0FW UT WOS:000338803800022 PM 24418112 ER PT J AU Srivanitchapoom, P Pandey, S Hallett, M AF Srivanitchapoom, Prachaya Pandey, Sanjay Hallett, Mark TI Restless legs syndrome and pregnancy: A review SO PARKINSONISM & RELATED DISORDERS LA English DT Review DE Restless legs syndrome; Pregnancy; Hormones; Iron ID LIMB MOVEMENT-DISORDER; PLACEBO-CONTROLLED TRIAL; OF-THE-LITERATURE; DOUBLE-BLIND; GENERAL-POPULATION; GABAPENTIN ENACARBIL; PARKINSONS-DISEASE; DOPAMINE RELEASE; SYNDROME RLS; RISK-FACTOR AB Restless legs syndrome (RLS) is a common sensorimotor neurological disorder that is diagnosed according to the revised criteria of the International RLS Study Group (IRLSSG). The pathophysiology of RLS is still unknown and its prevalence is influenced by ethnicity, age, and gender. RLS is divided into two types by etiology: primary or idiopathic and secondary. Primary RLS is strongly influenced by a genetic component while secondary RLS is caused by other associated conditions such as end-stage renal disease or peripheral neuropathy. Another common condition associated with RLS is pregnancy. The prevalence of RLS during pregnancy is two to three times higher than in the normal population and is influenced by the trimester and the number of parity. The main mechanisms that may contribute to the pathophysiology of RLS during pregnancy are hormonal changes and iron and folate status. Standard medications for treating RLS during pregnancy are not established. Most medications have been used according to the evidence from non-pregnant patients. Therefore, consideration of the medical treatment for treating RLS during pregnancy should be balanced between the benefit of relieving the symptoms and maternal and fetal risk. In general, the prognosis of RLS during pregnancy is good and symptoms are usually relieved after delivery. Published by Elsevier Ltd. C1 [Srivanitchapoom, Prachaya] Mahidol Univ, Siriraj Hosp, Fac Med, Div Neurol,Dept Med, Bangkok 10700, Thailand. [Srivanitchapoom, Prachaya; Pandey, Sanjay; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Pandey, Sanjay] Govind Ballabh Pant Hosp, New Delhi 110002, India. RP Hallett, M (reprint author), NINDS, NIH, 10 Ctr Dr,MSC 1428,Bldg 10,Room 7D37, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov FU NINDS Intramural Program FX NINDS Intramural Program. NR 82 TC 8 Z9 9 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD JUL PY 2014 VL 20 IS 7 BP 716 EP 722 DI 10.1016/j.parkreldis.2014.03.027 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AL0GL UT WOS:000338805300004 PM 24768121 ER PT J AU Schwieters, CD Clore, GM AF Schwieters, Charles D. Clore, G. Marius TI Using small angle solution scattering data in Xplor-NIH structure calculations SO PROGRESS IN NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY LA English DT Review DE Structure determination; SAXS; WAXS; SANS; NMR restraints ID X-RAY-SCATTERING; SUGAR PHOSPHOTRANSFERASE SYSTEM; RESIDUAL DIPOLAR COUPLINGS; ENZYME-I; BIOLOGICAL MACROMOLECULES; NMR STRUCTURES; DNA DODECAMER; CONFORMATIONAL DATABASE; STRUCTURE REFINEMENT; RESOLUTION STRUCTURE AB This contribution describes the use of small and wide angle X-ray and small angle neutron scattering for biomolecular structure calculation using the program Xplor-NIH, both with and without NMR data. The current algorithms used for calculating scattering curves are described, and the use of scattering data as a structural restraint is given concrete form as a fragment of an Xplor-NIH structure calculation script. We review five examples of the use of scattering data in structure calculation, including the treatment of single domain proteins, nucleic acids, structure determination of large proteins, and the use of ensemble representations to characterize small and large amplitude motions. Published by Elsevier B.V. C1 [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Clore, G. Marius] Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Schwieters, CD (reprint author), NIH, Div Computat Biosci, Ctr Informat Technol, Bldg 12A, Bethesda, MD 20892 USA. EM charles.schwieters@nih.gov; mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural Programs of the Center for Information Technology; NIDDK at the National Institutes of Health FX This work was supported by funds from the Intramural Programs of the Center for Information Technology (C.D.S.) and NIDDK (G.M.C.) at the National Institutes of Health. NR 45 TC 17 Z9 17 U1 4 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0079-6565 J9 PROG NUCL MAG RES SP JI Prog. Nucl. Magn. Reson. Spectrosc. PD JUL PY 2014 VL 80 BP 1 EP 11 DI 10.1016/j.pnmrs.2014.03.001 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Chemistry; Physics; Spectroscopy GA AL0MK UT WOS:000338820800001 PM 24924264 ER PT J AU Hamer, D AF Hamer, Dean TI Going Beyond the Lab SO SCIENTIST LA English DT Editorial Material C1 [Hamer, Dean] NIH, Bethesda, MD 20892 USA. [Hamer, Dean] NCI, Gene Struct & Regulat Sect, Bethesda, MD 20892 USA. RP Hamer, D (reprint author), NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LABX MEDIA GROUP PI MIDLAND PA PO BOX 216, 478 BAY ST, MIDLAND, ONTARIO L4R 1K9, CANADA SN 0890-3670 EI 1547-0806 J9 SCIENTIST JI Scientist PD JUL PY 2014 VL 28 IS 7 BP 22 EP 23 PG 2 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA AK9OZ UT WOS:000338757700006 ER PT J AU Tedbury, PR Freed, EO AF Tedbury, Philip R. Freed, Eric O. TI The role of matrix in HIV-1 envelope glycoprotein incorporation SO TRENDS IN MICROBIOLOGY LA English DT Review DE HIV-1; matrix; envelope; assembly; packaging ID VIRUS TYPE-1 MATRIX; GP41 CYTOPLASMIC TAIL; MURINE LEUKEMIA-VIRUS; MEMBRANE-LIPID RAFTS; PLASMA-MEMBRANE; GAG-PROTEINS; RETROVIRAL VECTOR; ENV INCORPORATION; ASSEMBLY SITES; MYOSIN VB AB Incorporation of the viral envelope (Env) glycoprotein is a critical requirement for the production of infectious HIV-1 particles. It has long been appreciated that the matrix (MA) domain of the Gag polyprotein and the cytoplasmic tail of Env are central players in the process of Env incorporation, but the precise mechanisms have been elusive. Several recent developments have thrown light on the contributions of both proteins, prompting a re-evaluation of the role of MA during Env incorporation. The two domains appear to play distinct but complementary roles, with the cytoplasmic tail of Env responsible for directing Env to the site of assembly and the matrix domain accommodating the cytoplasmic tail of Env in the Gag lattice. C1 [Tedbury, Philip R.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Tedbury, PR (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. EM philip.tedbury@nih.gov; efreed@nih.gov OI Tedbury, Philip/0000-0001-8151-4967 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Intramural AIDS Targeted Antiviral Program FX Research in the Freed laboratory is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the Intramural AIDS Targeted Antiviral Program. NR 53 TC 11 Z9 13 U1 2 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X EI 1878-4380 J9 TRENDS MICROBIOL JI Trends Microbiol. PD JUL PY 2014 VL 22 IS 7 BP 372 EP 378 DI 10.1016/j.tim.2014.04.012 PG 7 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AL1QJ UT WOS:000338900000004 PM 24933691 ER PT J AU Neuman, MG Cohen, L Zakhari, S Nanau, RM Mueller, S Schneider, M Parry, C Isip, R Seitz, HK AF Neuman, Manuela G. Cohen, Lawrence Zakhari, Samir Nanau, Radu M. Mueller, Sebastian Schneider, Michelle Parry, Charles Isip, Romina Seitz, Helmut K. TI Alcoholic Liver Disease: A Synopsis of the Charles Lieber's Memorial Symposia 2009-2012 SO ALCOHOL AND ALCOHOLISM LA English DT Article ID CHRONIC HEPATITIS-C; HISTAMINE-2 RECEPTOR ANTAGONISTS; VIRUS-COINFECTED PATIENTS; IN-VITRO; HUMAN-IMMUNODEFICIENCY; ETHANOL OXIDATION; ALDEHYDE DEHYDROGENASES; MEDIATED CARCINOGENESIS; ANTIRETROVIRAL THERAPY; GENETIC POLYMORPHISMS AB This paper is based upon the 'Charles Lieber Satellite Symposia' organized by Manuela G. Neuman at each of the 2009-2012 Research Society on Alcoholism (RSA) Annual Meetings. The presentations represent a broad spectrum dealing with alcoholic liver disease (ALD). In addition, a literature search (2008-2013) in the discussed area was performed in order to obtain updated data. The presentations are focused on genetic polymorphisms of ethanol metabolizing enzymes and the role of cytochrome P4502E1 (CYP2E1) in ALD. In addition, alcohol-mediated hepatocarcinogenesis, immune response to alcohol and fibrogenesis in alcoholic hepatitis as well as its co-morbidities with chronic viral hepatitis infections in the presence or absence of human deficiency virus are discussed. Finally, emphasis was led on alcohol and drug interactions as well as liver transplantation for end-stage ALD. C1 [Neuman, Manuela G.; Nanau, Radu M.; Isip, Romina] Univ Toronto, In Vitro Drug Safety & Biotechnol, Toronto, ON M5G 0A3, Canada. [Neuman, Manuela G.; Nanau, Radu M.; Isip, Romina] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5G 0A3, Canada. [Cohen, Lawrence] Univ Toronto, Fac Med, Dept Med, Div Gastroenterol,Sunnybrook Hlth Sci Ctr, Toronto, ON M5G 0A3, Canada. [Zakhari, Samir] NIAAA, Div Metab & Hlth Effects, NIH, Bethesda, MD USA. [Mueller, Sebastian; Seitz, Helmut K.] Heidelberg Univ, Ctr Alcohol Res, Heidelberg, Germany. [Mueller, Sebastian; Seitz, Helmut K.] Salem Med Ctr, Dept Med Gastroenterol & Hepatol, Heidelberg, Germany. [Schneider, Michelle; Parry, Charles] Univ Stellenbosch, MRC, Alcohol & Drug Abuse Res Unit, Cape Town, South Africa. [Parry, Charles] Univ Stellenbosch, Dept Psychiat, Cape Town, South Africa. RP Neuman, MG (reprint author), Univ Toronto, Dept Pharmacol & Toxicol, Banting Inst, In Vitro Drug Safety & Biotechnol, 100 Coll St,Lab 217, Toronto, ON M5G 0A3, Canada. EM manuela.neuman@utoronto.ca RI Parry, Charles/A-2906-2009 OI Parry, Charles/0000-0001-9787-2785 FU In Vitro Drug Safety and Biotechnology Inc., Toronto, Ontario, Canada FX The funding for the present paper was provided by In Vitro Drug Safety and Biotechnology Inc., Toronto, Ontario, Canada. The research presented is not NIH-funded. NR 99 TC 4 Z9 4 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 EI 1464-3502 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD JUL-AUG PY 2014 VL 49 IS 4 BP 373 EP 380 DI 10.1093/alcalc/agu021 PG 8 WC Substance Abuse SC Substance Abuse GA AK5YH UT WOS:000338502700001 PM 24816574 ER PT J AU Chiocca, EA Blair, D Mufson, RA AF Chiocca, E. Antonio Blair, Donald Mufson, R. Allan TI Oncolytic Viruses Targeting Tumor Stem Cells SO CANCER RESEARCH LA English DT Editorial Material AB A workshop "Targeting Oncolytic Viruses to Tumor Stem Cells," organized by the Division of Cancer Biology, NCI, NIH, was held on September 6, 2013 in Rockville, MD. Seventeen invited experts presented an overview of their current research in this area and discussed the state of current research on the use of oncolytic viruses targeted to stem cells as a potential cancer therapy. The goal was to evaluate the evidence that this approach might increase the efficacy of oncolytic virus therapy and to identify gaps in knowledge that have retarded progress in this area. (C)2014 AACR. C1 [Chiocca, E. Antonio] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02115 USA. [Blair, Donald; Mufson, R. Allan] NCI, Div Canc Biol, Bethesda, MD 20892 USA. RP Mufson, RA (reprint author), NCI, Bethesda, MD 20892 USA. EM mufsonr@mail.nih.gov NR 1 TC 5 Z9 5 U1 2 U2 10 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 JUL 1 PY 2014 VL 74 IS 13 BP 3396 EP 3398 DI 10.1158/0008-5472.CAN-14-0290 PG 3 WC Oncology SC Oncology GA AK3RF UT WOS:000338341700003 PM 24753541 ER PT J AU Xu, YP Li, FL Lv, L Li, TT Zhou, X Deng, CX Guan, KL Lei, QY Xiong, Y AF Xu, Yanping Li, Fulong Lv, Lei Li, Tingting Zhou, Xin Deng, Chu-Xia Guan, Kun-Liang Lei, Qun-Ying Xiong, Yue TI Oxidative Stress Activates SIRT2 to Deacetylate and Stimulate Phosphoglycerate Mutase SO CANCER RESEARCH LA English DT Article ID LYSINE ACETYLATION; METABOLIC ENZYMES; CRYSTAL-STRUCTURE; ENOLASE ACTIVITY; PHOSPHATASE; INHIBITION; GLYCOLYSIS; ISOENZYMES; CELLS AB Glycolytic enzyme phosphoglycerate mutase (PGAM) plays an important role in coordinating energy production with generation of reducing power and the biosynthesis of nucleotide precursors and amino acids. Inhibition of PGAM by small RNAi or small molecule attenuates cell proliferation and tumor growth. PGAM activity is commonly upregulated in tumor cells, but how PGAM activity is regulated in vivo remains poorly understood. Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. Increased levels of reactive oxygen species stimulate PGAM2 deacetylation and activity by promoting its interaction with SIRT2. Substitution of endogenous PGAM2 with an acetylation mimetic mutant K100Q reduces cellular NADPH production and inhibits cell proliferation and tumor growth. These results reveal a mechanism of PGAM2 regulation and NADPH homeostasis in response to oxidative stress that impacts cell proliferation and tumor growth. (C)2014 AACR. C1 [Lv, Lei; Guan, Kun-Liang; Lei, Qun-Ying; Xiong, Yue] Fudan Univ, Shanghai Med Coll, Minist Educ, Key Lab Mol Med, Shanghai 200433, Peoples R China. [Lv, Lei; Guan, Kun-Liang; Lei, Qun-Ying; Xiong, Yue] Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Shanghai 200433, Peoples R China. [Xu, Yanping; Li, Fulong; Lv, Lei; Li, Tingting; Zhou, Xin; Guan, Kun-Liang; Lei, Qun-Ying; Xiong, Yue] Fudan Univ, Inst Biomed Sci, Mol & Cell Biol Lab, Shanghai 200433, Peoples R China. [Xu, Yanping; Li, Fulong; Li, Tingting; Zhou, Xin] Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China. [Deng, Chu-Xia] Natl Inst Diabet Digest & Kidney Dis, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. [Guan, Kun-Liang] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Guan, Kun-Liang] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Xiong, Yue] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. RP Xiong, Y (reprint author), Univ N Carolina, 22-012 Lineberger Canc Ctr,CB 7295, Chapel Hill, NC 27599 USA. EM kuguan@ucsd.edu; qlei@fudan.edu.cn; yxiong@email.unc.edu RI deng, chuxia/N-6713-2016 FU NFC 973 [2011CB910600, 2009CB918401]; NSFC [31071192, 81225016]; Shanghai Key Basic Research Program [12JC1401100]; "100 Talents" Program of Shanghai Health [XBR2011041]; "Dawn" Program of Shanghai Education Commission; Shanghai Outstanding Academic Leader [13XD1400600]; 985 Program; Shanghai Leading Academic Discipline Project [B110]; Biomedical Core Facility; Fudan University; Fudan University Interdisciplinary Research Program of outstanding Ph.D. students Funds; NIH FX This work was supported by 973 (grant no. 2011CB910600, 2009CB918401), NSFC (grant no. 31071192, 81225016), Shanghai Key Basic Research Program (12JC1401100), "100 Talents" Program of Shanghai Health (grant no. XBR2011041), Scholar of "Dawn" Program of Shanghai Education Commission, and Shanghai Outstanding Academic Leader (grant no. 13XD1400600) to Q.-Y. Lei. This work was also supported by the 985 Program, the Shanghai Leading Academic Discipline Project (project number B110), Biomedical Core Facility, Fudan University; Fudan University Interdisciplinary Research Program of outstanding Ph.D. students Funds (Y. Xu), and NIH grants (Y. Xiong and K.-L. Guan). NR 27 TC 25 Z9 27 U1 5 U2 14 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 JUL 1 PY 2014 VL 74 IS 13 BP 3630 EP 3642 DI 10.1158/0008-5472.CAN-13-3615 PG 13 WC Oncology SC Oncology GA AK3RF UT WOS:000338341700024 PM 24786789 ER PT J AU Delitala, AP Pilia, MG Ferreli, L Loi, F Curreli, N Balaci, L Schlessinger, D Cucca, F AF Delitala, Alessandro P. Pilia, Maria Grazia Ferreli, Liana Loi, Francesco Curreli, Nicolo Balaci, Lenuta Schlessinger, David Cucca, Francesco TI Prevalence of unknown thyroid disorders in a Sardinian cohort SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; SUBCLINICAL HYPOTHYROIDISM; ENDEMIC GOITER; IODINE INTAKE; RISK-FACTORS; ALL-CAUSE; AUTOIMMUNE; AREA; HYPERTHYROIDISM; AUTOANTIBODIES AB Objective: To assess thyroid function, the presence of thyroid antibodies, as well as the presence of goiter and/or nodules in subjects without a prior diagnosis of thyroid disorders, in a region with mild to moderate iodine deficiency. Design and methods: This cross-sectional study is based on data obtained from first and third visits of participants in the Sardinian survey. We performed two different analyses. In one, we assessed the prevalence of unknown thyroid dysfunctions among 6252 subjects who had a medical examination and blood collection for assays of thyrotropin, free thyroxine, and antibodies against thyroperoxidase (AbTPO) and against thyroglobulin (AbTG). In a second analysis, we evaluated the frequency of undiagnosed goiter and nodules among 3377 subjects who had a thyroid ultrasound scan. Subjects were excluded if they had a previous history of thyroid disorders or presence of goiter and/or nodules, or thyroid surgery, or if they were taking drugs that could impair thyroid function. Results: We found a low prevalence of overt thyroid dysfunction (hyperthyroidism 0.4% and hypothyroidism 0.7%). The rates of subclinical hypothyroidism and hyperthyroidism were 4.7 and 2.4% respectively. Almost 16% of participants were positive for at least one antibody and 5.2% for both AbTG and AbTPO. Nodules were detected in 17.4% of subjects and the prevalence of goiter was 22.1%. Conclusions: Undiagnosed biochemical thyroid dysfunctions, unknown nodules, and goiter were common in subjects living in a mild to moderate iodine-deficient area. In this community, thyroid disorders often go undetected and screening could be reasonable in subjects at a higher risk. C1 [Delitala, Alessandro P.] Univ Sassari, Dept Clin & Expt Med, I-07100 Sassari, Italy. [Pilia, Maria Grazia; Ferreli, Liana; Loi, Francesco; Curreli, Nicolo; Balaci, Lenuta; Cucca, Francesco] Cittadella Univ Monserrato, Consiglio Nazl Ric, IRGB, Cagliari, Italy. [Schlessinger, David; Cucca, Francesco] NIA, Genet Lab, Baltimore, MD 21224 USA. [Cucca, Francesco] Univ Sassari, Dept Biochem Sci, I-07100 Sassari, Italy. RP Delitala, AP (reprint author), Univ Sassari, Dept Clin & Expt Med, Viale San Pietro 8, I-07100 Sassari, Italy. EM aledelitala@tiscali.it RI Delitala, Alessandro/L-3194-2016 OI Delitala, Alessandro/0000-0003-1729-8969 FU National Institute on Aging [NO1-AG-1-2109] FX This work was supported by the National Institute on Aging (contract NO1-AG-1-2109). NR 31 TC 7 Z9 9 U1 0 U2 6 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD JUL PY 2014 VL 171 IS 1 BP 143 EP 149 DI 10.1530/EJE-14-0182 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AK7AI UT WOS:000338578000023 PM 24917664 ER PT J AU Clyne, M Schully, SD Dotson, WD Douglas, MP Gwinn, M Kolor, K Wulf, A Bowen, MS Khoury, MJ AF Clyne, Mindy Schully, Sheri D. Dotson, W. David Douglas, Michael P. Gwinn, Marta Kolor, Katherine Wulf, Anja Bowen, M. Scott Khoury, Muin J. TI Horizon scanning for translational genomic research beyond bench to bedside SO GENETICS IN MEDICINE LA English DT Article DE genomic medicine; horizon scanning; public health; surveillance; translational research ID MEDICINE; PREVENTION; UTILITY; DISEASE; FUTURE; TESTS; CARE AB Purpose: The dizzying pace of genomic discoveries is leading to an increasing number of clinical applications. In this report, we provide a method for horizon scanning and 1 year data on translational research beyond bench to bedside to assess the validity, utility, implementation, and outcomes of such applications. Methods: We compiled cross-sectional results of ongoing horizon scanning of translational genomic research, conducted between 16 May 2012 and 15 May 2013, based on a weekly, systematic query of PubMed. A set of 505 beyond bench to bedside articles were collected and classified, including 312 original research articles; 123 systematic and other reviews; 38 clinical guidelines, policies, and recommendations; and 32 articles describing tools, decision support, and educational materials. Results: Most articles (62%) addressed a specific genomic test or other health application; almost half of these (n = 180) were related to cancer. We estimate that these publications account for 0.5% of reported human genomics and genetics research during the same time. Conclusion: These data provide baseline information to track the evolving knowledge base and gaps in genomic medicine. Continuous horizon scanning of the translational genomics literature is crucial for an evidence-based translation of genomics discoveries into improved health care and disease prevention. C1 [Clyne, Mindy] Kelly Serv, Troy, MI 48084 USA. [Clyne, Mindy; Schully, Sheri D.; Khoury, Muin J.] NCI, Epidemiol & Genom Res Program, Bethesda, MD 20892 USA. [Dotson, W. David; Douglas, Michael P.; Gwinn, Marta; Kolor, Katherine; Wulf, Anja; Bowen, M. Scott; Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Douglas, Michael P.; Gwinn, Marta] McKing Consulting Corp, Atlanta, GA USA. [Wulf, Anja] Cadence Grp, Atlanta, GA USA. RP Clyne, M (reprint author), Kelly Serv, Troy, MI 48084 USA. EM mindy.dyne@nih.gov OI Dotson, William David/0000-0002-9606-6594 FU Intramural NIH HHS [Z99 CA999999] NR 19 TC 8 Z9 8 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD JUL PY 2014 VL 16 IS 7 BP 535 EP 538 DI 10.1038/gim.2013.184 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA AK7IG UT WOS:000338601400007 PM 24406461 ER PT J AU Procino, G Milano, S Carmosino, M Barbieri, C Nicoletti, MC Li, JH Wess, J Svelto, M AF Procino, Giuseppe Milano, Serena Carmosino, Monica Barbieri, Claudia Nicoletti, Maria C. Li, Jian H. Wess, Juergen Svelto, Maria TI Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice SO KIDNEY INTERNATIONAL LA English DT Article DE cell and transport physiology; collecting ducts; diabetes insipidus; statins; vasopressin; water channels ID RENAL WATER REABSORPTION; VASOPRESSIN TYPE-2 RECEPTOR; BRATTLEBORO RATS; EPITHELIAL-CELLS; COLLECTING DUCT; AQUAPORIN-2; MEMBRANE; KIDNEY; AQP2; PHOSPHORYLATION AB X-linked nephrogenic diabetes insipidus (X-NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. Loss of V2R function prevents plasma membrane expression of the AQP2 water channel in the kidney collecting duct cells and impairs the kidney concentration ability. In an attempt to develop strategies to bypass V2R signaling in X-NDI, we evaluated the effects of secretin and fluvastatin, either alone or in combination, on kidney function in a mouse model of X-NDI. The secretin receptor was found to be functionally expressed in the kidney collecting duct cells. Based on this, X-NDI mice were infused with secretin for 14 days but urinary parameters were not altered by the infusion. Interestingly, secretin significantly increased AQP2 levels in the collecting duct but the protein primarily accumulated in the cytosol. Since we previously reported that fluvastatin treatment increased AQP2 plasma membrane expression in wild-type mice, secretin-infused X-NDI mice received a single injection of fluvastatin. Interestingly, urine production by X-NDI mice treated with secretin plus fluvastatin was reduced by nearly 90% and the urine osmolality was doubled. Immunostaining showed that secretin increased intracellular stores of AQP2 and the addition of fluvastatin promoted AQP2 trafficking to the plasma membrane. Taken together, these findings open new perspectives for the pharmacological treatment of X-NDI. C1 [Procino, Giuseppe; Milano, Serena; Carmosino, Monica; Barbieri, Claudia; Nicoletti, Maria C.; Svelto, Maria] Univ Bari, Dept Biosci Biotechnol & Biopharmaceut, I-70126 Bari, Italy. [Procino, Giuseppe; Svelto, Maria] Ctr Eccellenza Genom Campo Biomed & Agr CEGBA, Bari, Italy. [Li, Jian H.; Wess, Juergen] NIDDK, NIH, Bethesda, MD USA. RP Procino, G (reprint author), Univ Bari, Dept Biosci Biotechnol & Biopharmaceut, Via Orabona 4, I-70126 Bari, Italy. EM giuseppe.procino@uniba.it RI Carmosino, Monica/O-2594-2014; OI Carmosino, Monica/0000-0001-7600-8816; Procino, Giuseppe/0000-0002-0043-7523; Svelto, Maria/0000-0002-5584-9541 FU Fondazione Telethon [GGP12040]; Agenzia Italiana del Farmaco (AIFA) [MRAR08P011]; PRIN (Research Program of National Interest) projects [2009J53ALK]; Fondo per gli Investimenti della Ricerca di Base-Rete Nazionale di Proteomica [RBRN07BMCT_009]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIH, Bethesda, MD) FX This work has been funded by grants from Fondazione Telethon No GGP12040 to MS, Agenzia Italiana del Farmaco (AIFA) MRAR08P011 to MS, from PRIN (Research Program of National Interest) projects to MS (2009J53ALK), and from Fondo per gli Investimenti della Ricerca di Base-Rete Nazionale di Proteomica (RBRN07BMCT_009). JW and JHL were supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIH, Bethesda, MD). We are grateful to Professor Hayo Castrop and Dr Katharina Mederle for sharing their expertise on GFR measurements in conscious mice and to G Devito for animal care. NR 42 TC 16 Z9 17 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2014 VL 86 IS 1 BP 127 EP 138 DI 10.1038/ki.2014.10 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA AK7IJ UT WOS:000338601700020 PM 24522493 ER PT J AU Dogan, I Kawabata, S Bergbower, E Gills, JJ Ekmekci, A Wilson, W Rudin, CM Dennis, PA AF Dogan, Irem Kawabata, Shigeru Bergbower, Emily Gills, Joell J. Ekmekci, Abdullah Wilson, Willie, III Rudin, Charles M. Dennis, Phillip A. TI SOX2 expression is an early event in a murine model of EGFR mutant lung cancer and promotes proliferation of a subset of EGFR mutant lung adenocarcinoma cell lines SO LUNG CANCER LA English DT Article DE SOX2; Non-small cell lung cancer; EGFR; Akt; Erlotinib; H1975; HCC827 ID PLURIPOTENT STEM-CELLS; SELF-RENEWAL; TUMOR; IDENTIFICATION; SENSITIVITY; RESISTANCE; GEFITINIB; CHEMOTHERAPY; CARCINOMAS; MUTATIONS AB Objectives: Primary and acquired resistance to EGFR TKIs in EGFR mutant lung cancer occurs primarily through secondary mutations in EGFR or Met amplification. Drug resistance can also be mediated by expression of pluripotency transcription factors, such as OCT4, SOX2 and NANOG that decrease terminal differentiation. In this study, we investigated the expression and role of SOX2 in model systems of EGFR mutant tumors. Materials and methods: Immunoblotting or immunohistochemistry was used to assess expression of pluripotency transcription factors in lungs of transgenic mice or in human NSCLC cell lines. Expression of SOX2 was reduced by shRNA knockdown, and response to erlotinib and cellular proliferation were assessed. Results and conclusion: Induction of mutant EGFR in transgenic CCSP-rtTA/TetO-EGFR(L858R/T790M) mice correlated with increased OCT4 and SOX2 expression in lung tissue prior to tumor development. Established lung tumors retained SOX2 expression. To assess a role for SOX2 in tumorigenesis, a panel of NSCLC cell lines with activating EGFR mutations was assessed for SOX2 expression. Two of six cell lines with mutant EGFR showed detectable SOX2 levels, suggesting SOX2 expression did not correlate with EGFR mutation status. To assess the role of SOX2 in these cell lines, HCC827 and H1975 cells were infected with lentivirus containing SOX2 shRNA. Knockdown of SOX2 decreased proliferation in both cell lines and increased sensitivity to erlotinib in HCC827 cells. Because constitutive activation of the PI3K/Akt pathway is associated with EGFR TKI resistance, cells were treated with PI3K/AKT inhibitors and expression of SOX2 was examined. PI3K/Akt inhibitors decreased SOX2 expression in a time-dependent manner. These data suggest targeting SOX2 may provide therapeutic benefit in the subset of EGFR-mutant tumors with high constitutive levels of SOX2, and that until more direct means of inhibiting SOX2 are developed, PI3K/Akt inhibitors might be useful to inhibit SOX2 in EGFR TKI resistant tumors. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Dogan, Irem; Wilson, Willie, III] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Dogan, Irem; Ekmekci, Abdullah] Gazi Univ, Fac Med, Dept Med Biol & Genet, Ankara, Turkey. [Kawabata, Shigeru; Bergbower, Emily; Gills, Joell J.; Rudin, Charles M.; Dennis, Phillip A.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Dennis, PA (reprint author), Johns Hopkins Bayview Med Ctr, Dept Oncol, 4940 Eastern Ave 301-4500, Baltimore, MD 21224 USA. EM pdennis@jhmi.edu FU Intramural Program of the National Cancer Institute [ZIA SC010292] FX This work was supported by the Intramural Program of the National Cancer Institute [ZIA SC010292]. NR 41 TC 7 Z9 8 U1 0 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD JUL PY 2014 VL 85 IS 1 BP 1 EP 6 DI 10.1016/j.lungcan.2014.03.021 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AK7OH UT WOS:000338617100001 PM 24746758 ER PT J AU Groninger, H Vijayan, J AF Groninger, Hunter Vijayan, Jaya TI Pharmacologic Management of Pain at the End of Life SO AMERICAN FAMILY PHYSICIAN LA English DT Article ID CANCER PAIN; CLINICAL-PRACTICE; ANALGESIC LADDER; NEUROPATHIC PAIN; OPIOID USE; GUIDELINES; PREVALENCE; VALIDATION; STRATEGIES; CONSENSUS AB Although many patients experience debilitating pain at the end of life, there are many options to improve analgesia and quality of life. Pain assessment using a validated tool, with attention to patient function and specific goals, helps tailor individual treatment plans. The World Health Organization pain ladder offers a stepwise guideline for approaching pain management. However, for many patients with terminal illness, strong opioids are necessary for efficient and effective analgesia. Equianalgesic dosing tables and expert guidelines aid in initiating, monitoring, and adjusting doses of oral and parenteral opioids. Clinicians should feel comfortable administering a repeat dose after the time to peak analgesic effect if the patient is still in pain. In patients with constant pain, using scheduled long-acting opioids may significantly improve pain control. Among pain subtypes, visceral pain management usually requires multiple drugs. Neuropathic pain responds well to adjuvant pharmacotherapies, such as anticonvulsants or antidepressants, in addition to opioids. Opioid-induced hyperalgesia can occur with any dose of an opioid, but is more common with higher doses of parenteral morphine and hydromorphone. With appropriate counseling, most patients with a history of substance abuse will comply with a pain treatment plan. Copyright (C) 2014 American Academy of Family Physicians. C1 [Groninger, Hunter] NIH, Ctr Clin, Dept Pain & Palliat Care, Bethesda, MD 20892 USA. [Vijayan, Jaya] Holy Cross Hosp, Silver Spring, MD USA. [Vijayan, Jaya] Holy Cross Hosp, Div Qual Care & Management, Silver Spring, MD USA. RP Groninger, H (reprint author), NIH, Ctr Clin, Bldg 10,Rm 2-1733, Bethesda, MD 20892 USA. EM hunter.groninger@nih.gov NR 54 TC 4 Z9 4 U1 0 U2 4 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X EI 1532-0650 J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD JUL 1 PY 2014 VL 90 IS 1 BP 26 EP 32 PG 7 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA AK2TY UT WOS:000338273600008 PM 25077499 ER PT J AU Petr, EJ Ayers, CR Pandey, A de Lemos, JA Powell-Wiley, TM Khera, A Lloyd-Jones, DM Berry, JD AF Petr, Elisabeth Joye Ayers, Colby R. Pandey, Ambarish de Lemos, James A. Powell-Wiley, Tiffany M. Khera, Amit Lloyd-Jones, Donald M. Berry, Jarett D. TI Perceived Lifetime Risk for Cardiovascular Disease (from the Dallas Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY RISK; PREVENTIVE ACTION; FAMILY-HISTORY; FACTOR BURDEN; CHECK-UP; HEALTH; ASSOCIATION; ADULTS; WOMEN; PERCEPTIONS AB Lifetime risk estimation for cardiovascular disease (CVD) has been proposed as a useful strategy to improve risk communication in the primary prevention setting. However, the perception of lifetime risk for CVD is unknown. We included 2,998 subjects from the Dallas Heart Study. Lifetime risk for developing CVD was classified as high (>= 39%) versus low (<39%) according to risk factor burden as described in our previously published algorithm. Perception of lifetime risk for myocardial infarction was assessed by way of a 5-point scale. Baseline characteristics were compared across levels of perceived lifetime risk. Multivariable logistic regression analyses were performed to determine the association of participant characteristics with level of perceived lifetime risk for CVD and with correctness of perceptions. Of the 2,998 participants, 64.8% (n = 1,942) were classified as having high predicted lifetime risk for CVD. There was significant discordance between perceived and predicted lifetime risk. After multivariable adjustment, family history of premature myocardial infarction, high self-reported stress, and low perceived health were all strongly associated with high perceived lifetime risk (odds ratio [OR] 2.37, 95% confidence interval [CI] 1.72 to 3.27; OR 2.17, 95% CI 1.66 to 2.83; and OR 2.71, 95% CI 2.09 to 3.53; respectively). However, the association between traditional CVD risk factors and high perceived lifetime risk was more modest. In conclusion, misperception of lifetime risk for CVD is common and frequently reflects the influence of factors other than traditional risk factor levels. These findings highlight the importance of effectively communicating the significance of traditional risk factors in determining the lifetime risk for CVD. (C) 2014 Elsevier Inc. All rights reserved. C1 [Petr, Elisabeth Joye; Pandey, Ambarish] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Ayers, Colby R.; de Lemos, James A.; Khera, Amit; Berry, Jarett D.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Cardiol, Dallas, TX 75390 USA. [Powell-Wiley, Tiffany M.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Lloyd-Jones, Donald M.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Lloyd-Jones, Donald M.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. RP Berry, JD (reprint author), Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Cardiol, Dallas, TX 75390 USA. EM jarett.berry@utsouthwestern.edu OI Powell-Wiley, Tiffany/0000-0001-9488-4131 FU Dedman Family Scholar in Clinical Care endowment at the University of Texas Southwestern Medical Center (Dallas, Texas); National Heart, Lung, and Blood Institute (NHLBI, Bethesda, Maryland) [K23 HL092229]; American Heart Association (Dallas, Texas) [13GRNT14560079]; Merck; Division of Intramural Research of the National Heart, Lung, and Blood Institute of the National Institutes of Health; AstraZeneca; Janssen Pharmaceuticals FX Dr. Berry receives funding from (1) the Dedman Family Scholar in Clinical Care endowment at the University of Texas Southwestern Medical Center (Dallas, Texas), (2) grant K23 HL092229 from the National Heart, Lung, and Blood Institute (NHLBI, Bethesda, Maryland), and (3) grant 13GRNT14560079 from the American Heart Association (Dallas, Texas). Dr. Berry also reports receiving financial compensation from Merck in the form of speaker's bureau fees. Dr. Powell-Wiley is funded by the Division of Intramural Research of the National Heart, Lung, and Blood Institute of the National Institutes of Health. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. Dr. de Lemos reports receiving speaker honoraria and consulting income from AstraZeneca and consulting income from Janssen Pharmaceuticals. No other authors report relevant financial disclosures. NR 23 TC 9 Z9 9 U1 1 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 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 1 PY 2014 VL 114 IS 1 BP 53 EP 58 DI 10.1016/j.amjcard.2014.04.006 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AK5QQ UT WOS:000338481500009 PM 24834788 ER PT J AU Gibson, TM Engels, EA Clarke, CA Lynch, CF Weisenburger, DD Morton, LM AF Gibson, Todd M. Engels, Eric A. Clarke, Christina A. Lynch, Charles F. Weisenburger, Dennis D. Morton, Lindsay M. TI Risk of diffuse large B-cell lymphoma after solid organ transplantation in the United States SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS; NON-HODGKIN-LYMPHOMA; EPSTEIN-BARR-VIRUS; KIDNEY-TRANSPLANTATION; CANCER-RISK; RECIPIENTS; IMMUNOSUPPRESSION; PTLD; EPIDEMIOLOGY; SEROSTATUS AB Non-Hodgkin lymphoma arising in the context of immunosuppression is an important adverse outcome after solid organ transplantation. Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed subtype of post-transplantation non-Hodgkin lymphoma, but few studies of transplant recipients have examined subtype-specific risks. Therefore, we examined DLBCL risk in the Transplant Cancer Match Study, including registry-based cancer ascertainment among 96,615 solid organ transplants performed from 2000 to 2008. We determined standardized incidence ratios (SIRs) and 95% confidence intervals comparing DLBCL risk in transplant recipients with that in the general population, and used multivariable Poisson regression models to assess the impact of potential risk factors. We identified 321 incident cases of DLBCL, over 12 times more than expected based on general population rates (SIR = 12.6, 95% confidence interval = 11.2-14.0). SIRs were highest in young recipients and those receiving a lung or pancreas/kidney-pancreas transplant, and were greatly elevated for extranodal DLBCLs at the site of the transplantation compared with other sites. DLBCL risk was highest in the first year following transplantation, and SIRs for early-onset DLBCL risk were elevated in association with Epstein-Barr virus-negative serostatus and use of polyclonal antibody induction therapy. In conclusion, associations between recipient and transplant factors and post-transplantation DLBCL risk suggest a complicated interrelationship among multiple risk factors and timing of disease. (C) 2014 Wiley Periodicals, Inc. C1 [Gibson, Todd M.; Engels, Eric A.; Morton, Lindsay M.] NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Bethesda, MD 20892 USA. [Gibson, Todd M.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, US Dept HHS,NIH, Bethesda, MD 20892 USA. [Clarke, Christina A.] Canc Prevent Inst Calif, Fremont, CA USA. [Clarke, Christina A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy & Med, Stanford, CA 94305 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Weisenburger, Dennis D.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. RP Gibson, TM (reprint author), 262 Danny Thomas Pl,Mail Stop 735, Memphis, TN 38105 USA. EM Todd.Gibson@stjude.org RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU Intramural Research Program of the National Cancer Institute; Arbor Research Collaborative for Health (Ann Arbor, MI) [HHSH234200537009C]; Minneapolis Medical Research Foundation (Minneapolis, MN) [HHSH250201000018C]; National Program of Cancer Registry of the Center for Disease Control and Prevention: California [1U58 DP000807-01]; National Program of Cancer Registry of the Center for Disease Control and Prevention: Colorado [U58 DP000848-04]; National Program of Cancer Registry of the Center for Disease Control and Prevention: Georgia [5U58DP003875-01]; National Program of Cancer Registry of the Center for Disease Control and Prevention: Illinois [5658DP000805-04]; National Program of Cancer Registry of the Center for Disease Control and Prevention: Michigan [5U58DP000812-03]; National Program of Cancer Registry of the Center for Disease Control and Prevention: New Jersey [1US58/DP0039311-01]; National Program of Cancer Registry of the Center for Disease Control and Prevention: New York [U58DP0038789]; National Program of Cancer Registry of the Center for Disease Control and Prevention: North Carolina [U58DP000832]; National Program of Cancer Registry of the Center for Disease Control and Prevention: Texas [5U58DP000824-04]; SEER Program of the National Cancer Institute (California) [HHSN261201000036C, HHSN261201000035C, HHSN261201000034C]; SEER Program of the National Cancer Institute (Connecticut) [HHSN261201000024C]; SEER Program of the National Cancer Institute (Hawaii) [HHSN261201000037C, N01-PC-35137, N01-PC-35139]; SEER Program of the National Cancer Institute (Iowa) [HSN261201000032C, N01-PC-35143]; SEER Program of the National Cancer Institute (New Jersey) [HHSN261201000027C, N01-PC-2010-0027]; SEER Program of the National Cancer Institute (Seattle-Puget Sound) [N01-PC-35142]; SEER Program of the National Cancer Institute (Utah) [HHSN261201000026C]; Cancer Surveillance Improvement Initiative (California) [14-2491]; Cancer Surveillance Improvement Initiative (Colorado) [14-2491]; Cancer Surveillance Improvement Initiative (Connecticut) [14-2491]; Cancer Surveillance Improvement Initiative (Illinois) [14-2491]; Cancer Surveillance Improvement Initiative (Iowa) [14-2491]; Cancer Surveillance Improvement Initiative (New Jersey) [14-2491]; Cancer Surveillance Improvement Initiative (New York) [14-2491]; Cancer Surveillance Improvement Initiative (Texas) [14-2491]; Cancer Surveillance Improvement Initiative (Washington) [14-2491]; Fred Hutchinson Cancer Research Center in Seattle, WA FX Contract grant sponsor: Intramural Research Program of the National Cancer Institute.; Contract grant sponsor: Arbor Research Collaborative for Health (Ann Arbor, MI); Contract grant number: HHSH234200537009C.; Contract grant sponsor: Minneapolis Medical Research Foundation (Minneapolis, MN); Contract grant number: HHSH250201000018C.; Contract grant sponsor: National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP003875-01), Illinois (5658DP000805-04), Michigan (5U58DP000812-03), New Jersey (1US58/DP0039311-01), New York (U58DP0038789), North Carolina (U58DP000832), and Texas (5U58DP000824-04).; Contract grant sponsor: SEER Program of the National Cancer Institute (California); Contract grant numbers: HHSN261201000036C; HHSN261201000035C; HHSN261201000034C.; Contract grant sponsor: SEER Program of the National Cancer Institute (Connecticut); Contract grant number: HHSN261201000024C.; Contract grant sponsor: SEER Program of the National Cancer Institute (Hawaii); Contract grant numbers: HHSN261201000037C; N01-PC-35137; N01-PC-35139.; Contract grant sponsor: SEER Program of the National Cancer Institute (Iowa); Contract grant numbers: HSN261201000032C; N01-PC-35143.; Contract grant sponsor: SEER Program of the National Cancer Institute (New Jersey); Contract grant numbers: HHSN261201000027C; N01-PC-2010-0027.; Contract grant sponsor: SEER Program of the National Cancer Institute (Seattle-Puget Sound); Contract grant number: N01-PC-35142.; Contract grant sponsor: SEER Program of the National Cancer Institute (Utah); Contract grant number: HHSN261201000026C.; Contract grant sponsor: Cancer Surveillance Improvement Initiative 14-2491 (California, Colorado, Connecticut, Illinois, Iowa, New Jersey, New York, Texas, and Washington).; Contract grant sponsor: Fred Hutchinson Cancer Research Center in Seattle, WA. NR 40 TC 10 Z9 10 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD JUL PY 2014 VL 89 IS 7 BP 714 EP 720 DI 10.1002/ajh.23726 PG 7 WC Hematology SC Hematology GA AJ9KO UT WOS:000338029300009 PM 24753070 ER PT J AU El-Chemaly, S Pacheco-Rodriguez, G Malide, D Meza-Carmen, V Kato, J Cui, Y Padilla, PI Samidurai, A Gochuico, BR Moss, J AF El-Chemaly, Souheil Pacheco-Rodriguez, Gustavo Malide, Daniela Meza-Carmen, Victor Kato, Jiro Cui, Ye Padilla, Philip I. Samidurai, Arun Gochuico, Bernadette R. Moss, Joel TI Nuclear Localization of Vascular Endothelial Growth Factor-D and Regulation of c-Myc-Dependent Transcripts in Human Lung Fibroblasts SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE vascular endothelial growth factor-D; nuclei; fibroblast; idiopathic pulmonary fibrosis; c-Myc ID VEGF-D; PULMONARY-FIBROSIS; FACTOR FAMILY; RECEPTOR; KNOT; STABILITY; CYTOKINES; PROTEIN AB Lymphangiogenesis and angiogenesis are processes that are, in part, regulated by vascular endothelial growth factor (VEGF)-D. The formation of lymphatic structures has been implicated in multiple lung diseases, including pulmonary fibrosis. VEGF-D is a secreted protein produced by fibroblasts and macrophages, which induces lymphangiogenesis by signaling via VEGF receptor-3, and angiogenesis through VEGF receptor-2. VEGF-D contains a central VEGF homology domain, which is the biologically active domain, with flanking N- and C-terminal propeptides. Full-length VEGF-D (similar to 50 kD) is proteolytically processed in the extracellular space, to generate VEGF homology domain that contains the VEGF-D receptor-binding sites. Here, we report that, independent of its cell surface receptors, full-length VEGF-D accumulated in nuclei of fibroblasts, and that this process appears to increase with cell density. In nuclei, full-length VEGF-D associated with RNA polymerase II and c-Myc. In cells depleted of VEGF-D, the transcriptionally regulated genes appear to be modulated by c-Myc. These findings have potential clinical implications, as VEGF-D was found in fibroblast nuclei in idiopathic pulmonary fibrosis, a disease characterized by fibroblast proliferation. These findings are consistent with actions of full-length VEGF-D in cellular homeostasis in health and disease, independent of its receptors. C1 [El-Chemaly, Souheil; Pacheco-Rodriguez, Gustavo; Meza-Carmen, Victor; Kato, Jiro; Padilla, Philip I.; Samidurai, Arun; Moss, Joel] NHGRI, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. [Malide, Daniela] NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. [Gochuico, Bernadette R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [El-Chemaly, Souheil; Cui, Ye] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. RP Moss, J (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, 10 Ctr Dr,Room 6D05,Bldg 10, Bethesda, MD 20892 USA. EM sel-chemaly@partners.org; mossj@nhlbi.nih.gov RI Samidurai, Arun/K-9800-2015; Samidurai, Arun/D-7896-2015; OI Samidurai, Arun/0000-0002-5360-2553; MEZA-CARMEN, VICTOR/0000-0003-2838-7211 FU Intramural Research Programs; National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI); NIH/National Human Genome Research Institute; NIH [1K22HL092223]; NHLBI FX This work was supported in part by the Intramural Research Programs, National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), and NIH/National Human Genome Research Institute, and NIH grant 1K22HL092223, NHLBI (S.E.-C.). NR 37 TC 2 Z9 2 U1 3 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD JUL PY 2014 VL 51 IS 1 BP 34 EP 42 DI 10.1165/rcmb.2013-0417OC PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA AK3LK UT WOS:000338325300004 PM 24450584 ER PT J AU Hagman, BT Cohn, AM Schonfeld, L Moore, K Barrett, B AF Hagman, Brett T. Cohn, Amy M. Schonfeld, Lawrence Moore, Kathleen Barrett, Blake TI College Students Who Endorse a Sub-Threshold Number of DSM-5 Alcohol Use Disorder Criteria: Alcohol, Tobacco, and Illicit Drug Use in DSM-5 Diagnostic Orphans SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID RESPONSE THEORY ANALYSIS; DEPENDENCE SYMPTOMS; ABUSE; ADOLESCENTS; DRINKING; SAMPLE; UTILITY AB Objectives: Diagnostic orphans (DOs) represent a group of individuals with no formal diagnosis, despite endorsing some criteria of an alcohol use disorder (AUD). Prior research has indicated that rates of DSM-IV DOs in college are high and closely resemble those with an alcohol abuse diagnosis across pertinent alcohol use risk factors. However, significant changes to the DSM-IV AUD criteria have been made for the current DSM-5 manual, which may impact how DOs are classified. This study examined the unique alcohol and illicit drug use characteristics of a group of 2,620 DSM-5 DOs in college and tested whether DOs differed from those with and without a DSM-5 AUD across pertinent alcohol and drug use risk factors. Methods: Participants were 2,620 DSM-5 DO undergraduate college students, between the ages of 18 and 30, recruited from three public universities in the Southeastern, United States. Results: Diagnostic orphans represented 19.6% (n = 506) of the sample; with the most frequently endorsed criteria being tolerance and consuming alcohol in hazardous situations. DOs reported significantly greater alcohol consumption, alcohol and drug related problems, and illicit drug use compared to those with no DSM-5 AUD diagnosis. Alternatively, DOs reported significantly lower alcohol use and illicit drug use compared to those with a DSM-5 AUD. Conclusion: The present findings indicate that DSM-5 DOs in college represent a distinct group of drinkers relative to those with and without a DSM-5 AUD. Current screening initiatives should target this group to prevent future escalation of problem drinking. C1 [Hagman, Brett T.] NIAAA, Div Treatment & Recovery Res, Bethesda, MD 20892 USA. [Cohn, Amy M.; Schonfeld, Lawrence; Moore, Kathleen; Barrett, Blake] Univ S Florida, Dept Mental Hlth Law & Policy, Tempa, FL USA. RP Hagman, BT (reprint author), NIAAA, Div Treatment & Recovery Res, Bethesda, MD 20892 USA. EM brett.hagman@nih.gov NR 30 TC 4 Z9 4 U1 3 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD JUL-AUG PY 2014 VL 23 IS 4 BP 378 EP 385 DI 10.1111/j.1521-0391.2014.12120.x PG 8 WC Substance Abuse SC Substance Abuse GA AK0PM UT WOS:000338116600009 PM 24628662 ER PT J AU Machado, MJC Stone, OA Carter, JG Lin, PC Paleolog, E Emanueli, C Bates, DO AF Machado, Maria J. C. Stone, Oliver A. Carter, James G. Lin, P. Charles Paleolog, Ewa Emanueli, Costanza Bates, David O. TI Differential regulation of neovascularisation and mural cell recruitment by VEGF and angiopoietin signaling SO ANGIOGENESIS LA English DT Meeting Abstract C1 [Machado, Maria J. C.; Stone, Oliver A.; Carter, James G.; Bates, David O.] Univ Bristol, Sch Physiol & Pharmacol, Bristol Heart Inst, Microvasc Res Labs, Bristol BS8 1TH, Avon, England. [Lin, P. Charles] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Paleolog, Ewa] Univ Oxford, Kennedy Inst Rheumatol, London, England. [Emanueli, Costanza] Univ Bristol, Sch Clin Sci, Bristol Heart Inst, Bristol, Avon, England. [Machado, Maria J. C.] Univ Nottingham, Queens Med Ctr, Sch Clin Sci, Div Oncol, Nottingham NG7 2RD, England. FU British Heart Foundation [PG/11/67/29067] NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0969-6970 EI 1573-7209 J9 ANGIOGENESIS JI Angiogenesis PD JUL PY 2014 VL 17 IS 3 MA P-87 BP 759 EP 759 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AK1XU UT WOS:000338213400147 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI The origins of cellular life SO ANTONIE VAN LEEUWENHOEK INTERNATIONAL JOURNAL OF GENERAL AND MOLECULAR MICROBIOLOGY LA English DT Review DE RNA World; Viruses; Selfish elements; Membrane evolution; Cellular organization ID UNIVERSAL COMMON ANCESTOR; HORIZONTAL GENE-TRANSFER; ANOXIC GEOTHERMAL FIELDS; RNA WORLD HYPOTHESIS; COMPARATIVE GENOMICS; PROTEIN EVOLUTION; TRANSMEMBRANE HELICES; PHYLOGENETIC FOREST; MOLECULAR EVOLUTION; REPLICATOR SYSTEMS AB All life on earth can be naturally classified into cellular life forms and virus-like selfish elements, the latter being fully dependent on the former for their reproduction. Cells are reproducers that not only replicate their genome but also reproduce the cellular organization that depends on semipermeable, energy-transforming membranes and cannot be recovered from the genome alone, under the famous dictum of Rudolf Virchow, Omnis cellula e cellula. In contrast, simple selfish elements are replicators that can complete their life cycles within the host cell starting from genomic RNA or DNA alone. The origin of the cellular organization is the central and perhaps the hardest problem of evolutionary biology. I argue that the origin of cells can be understood only in conjunction with the origin and evolution of selfish genetic elements. A scenario of precellular evolution is presented that involves cohesion of the genomes of the emerging cellular life forms from primordial pools of small genetic elements that eventually segregated into hosts and parasites. I further present a model of the coevolution of primordial membranes and membrane proteins, discuss protocellular and non-cellular models of early evolution, and examine the habitats on the primordial earth that could have been conducive to precellular evolution and the origin of cells. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Resources FX Eugene V. Koonin is supported by intramural funds of the US Department of Health and Human Resources (to the National Library of Medicine, NIH). NR 154 TC 5 Z9 7 U1 9 U2 96 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0003-6072 EI 1572-9699 J9 ANTON LEEUW INT J G JI Antonie Van Leeuwenhoek PD JUL PY 2014 VL 106 IS 1 SI SI BP 27 EP 41 DI 10.1007/s10482-014-0169-5 PG 15 WC Microbiology SC Microbiology GA AK3KG UT WOS:000338321700003 PM 24756907 ER PT J AU van den Berg, SM de Moor, MHM McGue, M Pettersson, E Terracciano, A Verweij, KJH Amin, N Derringer, J Esko, T van Grootheest, G Hansell, NK Huffman, J Konte, B Lahti, J Luciano, M Matteson, LK Viktorin, A Wouda, J Agrawal, A Allik, J Bierut, L Broms, U Campbell, H Smith, GD Eriksson, JG Ferrucci, L Franke, B Fox, JP de Geus, EJC Giegling, I Gow, AJ Grucza, R Hartmann, AM Heath, AC Heikkila, K Iacono, W Janzing, J Jokela, M Kiemeney, L Lehtimaki, T Madden, PAF Magnusson, PKE Northstone, K Nutile, T Ouwens, KG Palotie, A Pattie, A Pesonen, AK Polasek, O Pulkkinen, L Pulkki-Raback, L Raitakari, OT Realo, A Rose, RJ Ruggiero, D Seppala, I Slutske, WS Smyth, DC Sorice, R Starr, JM Sutin, AR Tanaka, T Verhagen, J Vermeulen, S Vuoksimaa, E Widen, E Willemsen, G Wright, M Zgaga, L Rujescu, D Metspalu, A Wilson, JF Ciullo, M Hayward, C Rudan, I Deary, IJ Raikkonen, K Vasquez, AA Costa, PT Keltikangas-Jarvinen, L van Duijn, CM Penninx, BWJH Krueger, RF Evans, DM Kaprio, J Pedersen, NL Martin, NG Boomsma, DI AF van den Berg, Stephanie M. de Moor, Marleen H. M. McGue, Matt Pettersson, Erik Terracciano, Antonio Verweij, Karin J. H. Amin, Najaf Derringer, Jaime Esko, Tonu van Grootheest, Gerard Hansell, Narelle K. Huffman, Jennifer Konte, Bettina Lahti, Jari Luciano, Michelle Matteson, Lindsay K. Viktorin, Alexander Wouda, Jasper Agrawal, Arpana Allik, Jueri Bierut, Laura Broms, Ulla Campbell, Harry Smith, George Davey Eriksson, Johan G. Ferrucci, Luigi Franke, Barbera Fox, Jean-Paul de Geus, Eco J. C. Giegling, Ina Gow, Alan J. Grucza, Richard Hartmann, Annette M. Heath, Andrew C. Heikkilae, Kauko Iacono, William G. Janzing, Joost Jokela, Markus Kiemeney, Lambertus Lehtimaki, Terho Madden, Pamela A. F. Magnusson, Patrik K. E. Northstone, Kate Nutile, Teresa Ouwens, Klaasjan G. Palotie, Aarno Pattie, Alison Pesonen, Anu-Katriina Polasek, Ozren Pulkkinen, Lea Pulkki-Raback, Laura Raitakari, Olli T. Realo, Anu Rose, Richard J. Ruggiero, Daniela Seppala, Ilkka Slutske, Wendy S. Smyth, David C. Sorice, Rossella Starr, John M. Sutin, Angelina R. Tanaka, Toshiko Verhagen, Josine Vermeulen, Sita Vuoksimaa, Eero Widen, Elisabeth Willemsen, Gonneke Wright, Margaret J. Zgaga, Lina Rujescu, Dan Metspalu, Andres Wilson, James F. Ciullo, Marina Hayward, Caroline Rudan, Igor Deary, Ian J. Raikkonen, Katri Vasquez, Alejandro Arias Costa, Paul T. Keltikangas-Jarvinen, Liisa van Duijn, Cornelia M. Penninx, Brenda W. J. H. Krueger, Robert F. Evans, David M. Kaprio, Jaakko Pedersen, Nancy L. Martin, Nicholas G. Boomsma, Dorret I. TI Harmonization of Neuroticism and Extraversion phenotypes across inventories and cohorts in the Genetics of Personality Consortium: an application of Item Response Theory SO BEHAVIOR GENETICS LA English DT Article DE Personality; Item-Response Theory; Measurement; Genome-wide association studies; Consortium; Meta-analysis ID GENOME-WIDE METAANALYSIS; 5-FACTOR MODEL; MEASUREMENT INVARIANCE; NEO-PI; ASSOCIATION; TEMPERAMENT; CLONINGERS; REPLICATION; DIMENSIONS; DISORDERS AB Mega- or meta-analytic studies (e.g. genome-wide association studies) are increasingly used in behavior genetics. An issue in such studies is that phenotypes are often measured by different instruments across study cohorts, requiring harmonization of measures so that more powerful fixed effect meta-analyses can be employed. Within the Genetics of Personality Consortium, we demonstrate for two clinically relevant personality traits, Neuroticism and Extraversion, how Item-Response Theory (IRT) can be applied to map item data from different inventories to the same underlying constructs. Personality item data were analyzed in > 160,000 individuals from 23 cohorts across Europe, USA and Australia in which Neuroticism and Extraversion were assessed by nine different personality inventories. Results showed that harmonization was very successful for most personality inventories and moderately successful for some. Neuroticism and Extraversion inventories were largely measurement invariant across cohorts, in particular when comparing cohorts from countries where the same language is spoken. The IRT-based scores for Neuroticism and Extraversion were heritable (48 and 49 %, respectively, based on a meta-analysis of six twin cohorts, total N = 29,496 and 29,501 twin pairs, respectively) with a significant part of the heritability due to non-additive genetic factors. For Extraversion, these genetic factors qualitatively differ across sexes. We showed that our IRT method can lead to a large increase in sample size and therefore statistical power. The IRT approach may be applied to any mega- or meta-analytic study in which item-based behavioral measures need to be harmonized. C1 [van den Berg, Stephanie M.; Fox, Jean-Paul] Univ Twente, Dept Res Methodol Measurement & Data Anal, NL-7500 AE Enschede, Netherlands. [van den Berg, Stephanie M.] Univ Twente, Dept Behav Sci, OMD, NL-7500 AE Enschede, Netherlands. [de Moor, Marleen H. M.; Wouda, Jasper; de Geus, Eco J. C.; Ouwens, Klaasjan G.; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [McGue, Matt; Matteson, Lindsay K.; Iacono, William G.; Krueger, Robert F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [McGue, Matt] Univ Southern Denmark, Inst Publ Hlth, Odense, Denmark. [Pettersson, Erik; Viktorin, Alexander; Magnusson, Patrik K. E.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Terracciano, Antonio; Ferrucci, Luigi; Sutin, Angelina R.; Tanaka, Toshiko] NIA, NIH, Baltimore, MD 21224 USA. [Terracciano, Antonio; Sutin, Angelina R.] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Verweij, Karin J. H.; Hansell, Narelle K.; Smyth, David C.; Wright, Margaret J.; Martin, Nicholas G.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Verweij, Karin J. H.] Vrije Univ Amsterdam, Dept Dev Psychol, Amsterdam, Netherlands. [Verweij, Karin J. H.] Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Amin, Najaf; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Derringer, Jaime] Univ Illinois, Dept Psychol, Champaign, IL USA. [Esko, Tonu; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [van Grootheest, Gerard; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr Amsterdam, EMGO Inst, Dept Psychiat, Amsterdam, Netherlands. [Huffman, Jennifer; Hayward, Caroline] Univ Edinburgh, Western Gen Hosp, MRC IGMM, MRC Human Genet, Edinburgh, Midlothian, Scotland. [Konte, Bettina; Giegling, Ina; Hartmann, Annette M.; Rujescu, Dan] Univ Halle, Dept Psychiat, Halle, Germany. [Lahti, Jari; Jokela, Markus; Pesonen, Anu-Katriina; Pulkki-Raback, Laura; Raikkonen, Katri; Keltikangas-Jarvinen, Liisa] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Lahti, Jari; Eriksson, Johan G.; Raikkonen, Katri] Folkhalsan Res Ctr, Helsinki, Finland. [Luciano, Michelle; Pattie, Alison; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [Luciano, Michelle; Pattie, Alison; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Agrawal, Arpana; Bierut, Laura; Grucza, Richard; Heath, Andrew C.; Madden, Pamela A. F.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Allik, Jueri; Realo, Anu] Univ Tartu, Dept Psychol, EE-50090 Tartu, Estonia. [Allik, Jueri; Metspalu, Andres] Estonian Acad Sci, EE-200103 Tallinn, Estonia. [Broms, Ulla; Heikkilae, Kauko; Vuoksimaa, Eero; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Broms, Ulla; Eriksson, Johan G.; Raikkonen, Katri; Kaprio, Jaakko] Natl Inst Hlth & Welf THL, Helsinki, Finland. [Campbell, Harry; Zgaga, Lina; Wilson, James F.; Rudan, Igor] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Smith, George Davey; Northstone, Kate; Evans, David M.] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol, Avon, England. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Franke, Barbera; Vasquez, Alejandro Arias] Radboud Univ Nijmegen, Donders Inst Cognit Neurosci, NL-6525 ED Nijmegen, Netherlands. [Franke, Barbera; Janzing, Joost; Vasquez, Alejandro Arias] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 ED Nijmegen, Netherlands. [Franke, Barbera; Vermeulen, Sita; Vasquez, Alejandro Arias] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Gow, Alan J.] Heriot Watt Univ, Dept Psychol, Sch Life Sci, Edinburgh, Midlothian, Scotland. [Jokela, Markus; Lehtimaki, Terho; Seppala, Ilkka] Univ Tampere, Fimlab Labs, Dept Clin Chem, FIN-33101 Tampere, Finland. [Jokela, Markus; Lehtimaki, Terho; Seppala, Ilkka] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Kiemeney, Lambertus; Vermeulen, Sita] Radboud Univ Nijmegen, Dept Hlth Evidence, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Kiemeney, Lambertus] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Nutile, Teresa; Ruggiero, Daniela; Sorice, Rossella; Ciullo, Marina] CNR, Inst Genet & Biophys A Buzzati Traverso, I-80125 Naples, Italy. [Palotie, Aarno] Wellcome Trust Sanger Inst, Cambridge, England. [Palotie, Aarno; Widen, Elisabeth; Kaprio, Jaakko] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Polasek, Ozren] Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia. [Pulkkinen, Lea] Univ Jyvaskyla, Dept Psychol, Jyvaskyla, Finland. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Rose, Richard J.] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA. [Slutske, Wendy S.] Univ Missouri, Dept Psychol Sci, Columbia, MO USA. [Slutske, Wendy S.] Univ Missouri, Missouri Alcoholism Res Ctr, Columbia, MO USA. [Verhagen, Josine] Univ Amsterdam, Dept Psychol Methods, Amsterdam, Netherlands. [Vuoksimaa, Eero] Univ Calif, Dept Psychiat, La Jolla, CA USA. [Zgaga, Lina] Trinity Coll Dublin, Dept Publ Hlth & Primary Care, Dublin, Ireland. [Vasquez, Alejandro Arias] Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, NL-6525 ED Nijmegen, Netherlands. [Costa, Paul T.] Duke Univ, Sch Med, Behav Med Res Ctr, Durham, NC USA. RP van den Berg, SM (reprint author), Univ Twente, Dept Behav Sci, OMD, POB 217, NL-7500 AE Enschede, Netherlands. EM stephanie.vandenberg@utwente.nl RI Jokela, Markus/A-4669-2009; Wright, Margaret/A-4560-2016; Arias Vasquez, Alejandro/E-4762-2012; Vermeulen, H.H.M./L-4716-2015; van Grootheest, Gerard/C-6942-2014; Franke, Barbara/D-4836-2009; Gow, Alan/A-6070-2009; Kiemeney, Lambertus/D-3357-2009; Allik, Juri/D-5609-2009; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Janzing, J.G.E./L-4413-2015; Hansell, Narelle/A-4553-2016; Rudan, Igor/I-1467-2012; ruggiero, daniela/K-5638-2016; Hayward, Caroline/M-8818-2016; Realo, Anu/M-9524-2016; Luciano, Michelle/F-7277-2010; Davey Smith, George/A-7407-2013; Northstone, Kate/A-8165-2011; Magnusson, Patrik/C-4458-2017; OI de Geus, Eco/0000-0001-6022-2666; Martin, Nicholas/0000-0003-4069-8020; Ouwens, Klaasjan/0000-0002-3864-7710; Jokela, Markus/0000-0003-0117-0012; Wright, Margaret/0000-0001-7133-4970; Arias Vasquez, Alejandro/0000-0002-4786-0169; van Grootheest, Gerard/0000-0003-4350-6661; Franke, Barbara/0000-0003-4375-6572; Gow, Alan/0000-0002-3320-4531; Kiemeney, Lambertus/0000-0002-2368-1326; Allik, Juri/0000-0002-8358-4747; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Hansell, Narelle/0000-0002-8229-9741; Rudan, Igor/0000-0001-6993-6884; ruggiero, daniela/0000-0003-3898-7827; Hayward, Caroline/0000-0002-9405-9550; Luciano, Michelle/0000-0003-0935-7682; Davey Smith, George/0000-0002-1407-8314; Northstone, Kate/0000-0002-0602-1983; Derringer, Jaime/0000-0002-7352-9859; Grucza, Richard/0000-0002-8191-6875; Esko, Tonu/0000-0003-1982-6569; Zgaga, Lina/0000-0003-4089-9703; NUTILE, TERESA/0000-0001-7062-8352; Viktorin, Alexander/0000-0003-2141-2816; Evans, David/0000-0003-0663-4621; Lahti, Jari/0000-0002-4310-5297 FU European Network of Genomic and Genetic Epidemiology (ENGAGE); Wellcome Trust [092731]; Intramural Research Program of the National Institutes of Health, National Institute on Aging; Fondazione CON IL SUD [2011-PDR-13]; Fondazione Banco di Napoli; NIH Genes, Environment and Health Initiative [GEI] [U01 HG004422]; Gene Environment Association Studies (GENEVA) under GEI; NIH from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) [U10AA008401]; National Institute on Drug Abuse (NIDA); NIH from the National Cancer Institute [P01 CA089392]; NIDA [HHSN271200477451C]; Estonian Government [SF0180142s08]; Center of Excellence in Genomics (EXCEGEN); University of Tartu (SP1GVARENG); European Commission FP6 STRP [018947 (LSHG-CT-2006-01947)]; European Community's Seventh Framework Programme (FP7) by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme [HEALTH-F4-2007-201413, QLG2-CT-2002-01254]; NIH [DA12854, AA-12502, AA-00145, AA-09203, AA15416, AA07728, AA10248, AA07580, AA11998, AA13320, AA13321, AA13326, DA019951, AA014041, AA07535, MH66206, AGO4954, GM30250]; Academy of Finland [118555, 141054, 265240, 263278, 264146, 126925, 121584, 124282, 129378, 117787, 265869, 258711, 41071]; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Medical Research Council (UK); European Commission Framework 6 project EUROSPAN [LSHG-CT-2006-018947]; Republic of Croatia Ministry of Science, Education and Sports [108-1080315-0302]; Lifelong Health and Wellbeing initiative [G0700704/84698]; Scottish Executive Chief Scientist Office [CZG/3/2/79]; BBSRC [15/SAG09977]; Research into Ageing [251]; Age UK (Disconnected Mind grant); National Institutes of Health [R37DA005147, R01AA009367, R01AA011886, R01DA013240, R01MH066140]; Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMW) [10-000-1002]; VU University Medical Center; GGZ inGeest; Leiden University Medical Center; GGZ Rivierduinen; University Medical Center Groningen; Lentis; GGZ Friesland; GGZ Drenthe; Netherlands Institute of Mental Health and Addiction; Netherlands Organization for Scientific Research (NWO) [575-25-006, 480-04-004, 904-61-090, 904-61-193, 400-05-717, 311-60008]; Spinozapremie SPI [56-464-14192]; European Research Council [ERC 230374]; NWO VENI [016-115-035]; Chief Scientist Office of the Scottish Government; Royal Society; MRC Human Genetics Unit; Arthritis Research UK; European Union framework program 6 EUROSPAN project [LSHG-CT-2006-018947]; Australian Research Council [A79600334, A79906588, A79801419, DP0212016, DP0343921, DP0664638, DP1093900]; Beyond Blue; Borderline Personality Disorder Research Foundation; Australian National Health and Medical Research Council; Gemini Genomics Plc; Australian Associated Brewers; ADAMHA [AA06781, MH40828]; American Cancer Society [IRG-58-010-50]; Swedish Ministry for Higher Education; TwinGene; Swedish Research Council [M-2005-1112, 2011-3060, K2006-71X-14676-04-2, 2008-54 x 20638-01-3]; GenomEUtwin [QLG2-CT-2002-01254, EU/QLRT-2001-01254]; NIH DK [U01-066134]; Swedish Foundation for Strategic Research (SSF); Heart and Lung foundation [20070481. STOPPA]; Strategic Research Program in Epidemiology at Karolinska Institutet; Swedish Asthma and Allergy Association; Stockholm County Council; Karolinska Institutet. CATSS; Swedish Council for Working Life and Social Research [2004-0174, 2007-0231]; System-bolaget; National Board of Forensic Medicine; Swedish Prison and Probation Service; Bank of Sweden Tercentenary Foundation; Soderstrom-Konigska foundation; Karolinska Institutet Center of Neurodevelopmental Disorders (KIND). BIRTH; Swedish Cancer Society [4594-B01-01XAC, 4594-B04-04XAB]; European Union [FP6036894]; Social Insurance Institution of Finland; Kuopio, Tampere, and Turku University Hospital Medical Funds [9M048, 9N035]; Juho Vainio Foundation; Paavo Nurmi Foundation; Signe and Ane Gyllenberg's Foundation; Finnish Foundation of Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation FX Phenotype harmonization was financially supported by the European Network of Genomic and Genetic Epidemiology (ENGAGE).; ALSPAC thanks all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (Grant ref: 092731) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and DME, KN and GDS will serve as guarantors for the contents of this paper.; The BLSA was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging.; Cilento give special thanks to the Cilento populations for their participation in the study, acknowledge Dr. Maria Enza Amendola for the test administration and thank the personnel working in the organization of the study in the villages. This work was supported by grants from the Fondazione CON IL SUD (2011-PDR-13) and the Fondazione Banco di Napoli to MC.; Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422). SAGE is one of the GWA studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401) and the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392).; The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut, includes ten different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, A. Goate, J. Rice, K. Bucholz); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield); Texas Biomedical Research Institute (L. Almasy), Howard University (R. Taylor) and Virginia Commonwealth University (D. Dick). Other COGA collaborators include: L. Bauer (University of Connecticut); D. Koller, S. O'Connor, L. Wetherill, X. Xuei (Indiana University); Grace Chan (University of Iowa); S. Kang, N. Manz, M. Rangaswamy (SUNY Downstate); J. Rohrbaugh, J-C Wang (Washington University in St. Louis); A. Brooks (Rutgers University); and F. Aliev (Virginia Commonwealth University). A. Parsian and M. Reilly are the NIAAA Staff Collaborators. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA).; The Collaborative Genetic Study of Nicotine Dependence (COGEND) project is a collaborative research group and part of the NIDA Genetics Consortium. Subject collection was supported by NIH grant P01 CA089392 (L.J. Bierut) from the National Cancer Institute. Phenotypic and genotypic data are stored in the NIDA Center for Genetic Studies (NCGS) at http://zork.wustl.edu/under NIDA Contract HHSN271200477451C (J. Tischfield and J. Rice).; EGCUT received targeted financing from Estonian Government SF0180142s08, Center of Excellence in Genomics (EXCEGEN) and University of Tartu (SP1GVARENG). We acknowledge EGCUT technical personnel.; The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002-01254). We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection.; The Finnish Twin Cohort acknowledges NIH grants DA12854 to P A F Madden; AA-12502, AA-00145, and AA-09203 to R J Rose; AA15416 to D M Dick; and Academy of Finland grants 118555, 141054, 265240, 263278, and 264146 to J Kaprio.; HBCS thanks all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhalsan Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation.; The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to I. R. (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the people of Korcula.; LBC1921 and LBC1936 phenotype collection was carried out within the Centre for Cognitive Ageing and Cognitive Epidemiology funded by a Lifelong Health and Wellbeing initiative (G0700704/84698). LBC1921 also acknowledge financial support from the Scottish Executive Chief Scientist Office (CZG/3/2/79) and BBSRC (15/SAG09977). LBC1936 also acknowledge financial support from Research into Ageing (Grant No. 251) and Age UK (Disconnected Mind grant).; MCTFR acknowledges support by the National Institutes of Health under award numbers R37DA005147, R01AA009367, R01AA011886, R01DA013240, and R01MH066140.; NESDA acknowledges financial support from the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMW, grant number 10-000-1002) and participating institutes (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Netherlands Institute of Mental Health and Addiction).; NTR acknowledges financial support from the Netherlands Organization for Scientific Research (NWO) Grants No. 575-25-006, 480-04-004, 904-61-090; 904-61-193, 400-05-717, 311-60008 and Spinozapremie SPI 56-464-14192 and the European Research Council (ERC 230374). MHMdeM is financially supported by NWO VENI Grant No. 016-115-035.; ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney.; QIMR adolescents We acknowledge financial support from the Australian Research Council (A79600334, A79906588, A79801419, DP0212016, DP0343921, DP0664638, DP1093900), Beyond Blue, and the Borderline Personality Disorder Research Foundation.; QIMR adults We acknowledge financial support from NIH (DA12854, AA07728, AA10248, AA07580, AA11998, AA13320, AA13321, AA13326, DA019951, AA014041, AA07535, MH66206, AGO4954 and GM30250), the Australian National Health and Medical Research Council, Gemini Genomics Plc, the Borderline Personality Disorder Research Foundation, the Australian Associated Brewers, ADAMHA (AA06781 and MH40828), and the American Cancer Society (IRG-58-010-50).; The STR is financially supported by the Swedish Ministry for Higher Education For the various projects financial support has been provided by: TwinGene; the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), NIH DK U01-066134, The Swedish Foundation for Strategic Research (SSF), the Heart and Lung foundation no. 20070481. STOPPA; the Strategic Research Program in Epidemiology at Karolinska Institutet, the Swedish Research Council (grant number 2011-3060), the Swedish Asthma and Allergy Association and the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet. CATSS; support was provided by the Swedish Council for Working Life and Social Research, the Swedish Research Council, System-bolaget, the National Board of Forensic Medicine, the Swedish Prison and Probation Service, Bank of Sweden Tercentenary Foundation, the Soderstrom-Konigska foundation, and the Karolinska Institutet Center of Neurodevelopmental Disorders (KIND). BIRTH; supported by the Swedish Council for Working Life and Social Research (2004-0174 and 2007-0231), the Swedish Research Council (K2006-71X-14676-04-2 and 2008-54 x 20638-01-3), the Swedish Cancer Society (4594-B01-01XAC and 4594-B04-04XAB), and the European Union-funded Network of Excellence Lifespan (FP6036894).; The Cardiovascular Risk in Young Finns Study acknowledges financial support from the Academy of Finland (grants 126925, 121584, 124282, 129378 [Salve], 117787 [Gendi], 265869 (MIND), 258711 and 41071 [Skidi]); the Social Insurance Institution of Finland; the Kuopio, Tampere, and Turku University Hospital Medical Funds (grant 9M048 and 9N035 for Dr. Lehtimaki); the Juho Vainio Foundation; the Paavo Nurmi Foundation; Signe and Ane Gyllenberg's Foundation, the Finnish Foundation of Cardiovascular Research; the Finnish Cultural Foundation; as well as the Tampere Tuberculosis Foundation and the Emil Aaltonen Foundation (Dr. Lehtimaki). The expert technical assistance in data management and statistical analyses by Irina Lisinen and Ville Aalto is gratefully acknowledged. NR 46 TC 19 Z9 19 U1 4 U2 27 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 EI 1573-3297 J9 BEHAV GENET JI Behav. Genet. PD JUL PY 2014 VL 44 IS 4 BP 295 EP 313 DI 10.1007/s10519-014-9654-x PG 19 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA AK0PO UT WOS:000338116800001 PM 24828478 ER PT J AU Liu, S Yan, B Lai, WW Chen, L Xiao, DS Xi, SC Jiang, YQ Dong, X An, J Chen, X Cao, Y Tao, YG AF Liu, Shuang Yan, Bin Lai, Weiwei Chen, Ling Xiao, Desheng Xi, Sichuan Jiang, Yiqun Dong, Xin An, Jing Chen, Xiang Cao, Ya Tao, Yongguang TI As a novel p53 direct target, bidirectional gene HspB2/alpha B-crystallin regulates the ROS level and Warburg effect SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Article DE Bidirectional promoter; p53; HspB2; alpha B-crystallin; Warburg effect; Renal cell carcinoma ID ALPHA-B-CRYSTALLIN; RENAL-CELL CARCINOMA; HUMAN GENOME; CYCLE ARREST; METABOLISM; TRANSCRIPTION; PROMOTERS; CANCER; EXPRESSION; IDENTIFICATION AB Many mammalian genes are composed of bidirectional gene pairs with the two genes separated by less than 1.0 kb. The transcriptional regulation and function of these bidirectional genes remain largely unclear. Here, we report that bidirectional gene pair HspB2/alpha B-crystallin, both of which are members of the small heat shock protein gene family, is a novel direct target gene of p53. Two potential binding sites of p53 are present in the intergenic region of HspB2/alpha B-crystallin. p53 up-regulated the bidirectional promoter activities of HspB2/alpha B-crystallin. Actinomycin D (ActD), an activator of p53, induces the promoter and protein activities of HspB2/alpha B-crystallin. p53 binds to two p53 binding sites in the intergenic region of HspB2/alpha B-crystallin in vitro and in vivo. Moreover, the products of bidirectional gene pair HspB2/alpha B-crystallin regulate glucose metabolism, intracellular reactive oxygen species (ROS) level and the Warburg effect by affecting metabolic genes, including the synthesis of cytochrome c oxidase 2 (SCO2), hexokinase II (HK2), and TP53-induced glycolysis and apoptosis regulator (TIGAR). The ROS level and the Warburg effect are affected after the depletion of p53, HspB2 and alpha B-crystallin respectively. Finally, we show that both HspB2 and alpha B-crystallin are linked with human renal carcinogenesis. These findings provide novel insights into the role of p53 as a regulator of bidirectional gene pair HspB2/alpha B-crystallin-mediated ROS and the Warburg effect. (C) 2014 Elsevier B.V. All rights reserved. C1 [Liu, Shuang] Cent S Univ, Xiangya Hosp, Med Res Ctr, Changsha 410008, Hunan, Peoples R China. [Liu, Shuang; Yan, Bin; Lai, Weiwei; Chen, Ling; Jiang, Yiqun; Dong, Xin; Cao, Ya; Tao, Yongguang] Cent S Univ, Canc Res Inst, Changsha 410078, Hunan, Peoples R China. [Liu, Shuang; Chen, Xiang] Cent S Univ, Xiangya Hosp, Dept Dermatol, Changsha 410008, Hunan, Peoples R China. [Yan, Bin; Lai, Weiwei; Chen, Ling; Jiang, Yiqun; Dong, Xin; Cao, Ya; Tao, Yongguang] Cent S Univ, Ctr Mol Imaging, Changsha 410078, Hunan, Peoples R China. [Yan, Bin; Lai, Weiwei; Chen, Ling; Jiang, Yiqun; Dong, Xin; Cao, Ya; Tao, Yongguang] Minist Educ, Key Lab Carcinogenesis & Canc Invas, Changsha 410078, Hunan, Peoples R China. [Yan, Bin; Lai, Weiwei; Chen, Ling; Jiang, Yiqun; Dong, Xin; Cao, Ya; Tao, Yongguang] Minist Hlth, Key Lab Carcinogenesis, Changsha 410078, Hunan, Peoples R China. [Xiao, Desheng] Cent S Univ, Xiangya Hosp, Dept Pathol, Changsha 410078, Hunan, Peoples R China. [Xi, Sichuan] NCI, Ctr Canc Res, Thorac Oncol Sect, Surg Branch, Bethesda, MD 20892 USA. [An, Jing] Cent S Univ, State Key Lab Med Genet, Changsha 410078, Hunan, Peoples R China. RP Tao, YG (reprint author), Cent S Univ, Ctr Mol Imaging, Changsha 410078, Hunan, Peoples R China. EM taoyong@csu.edu.cn FU China Postdoctoral Science Foundation [2012M511422]; Hunan Natural Science Foundation of China [12JJ1013]; National Basic Research Program of China [2011CB504300]; Fundamental Research Funds for the Central Universities [2011JQ019]; National Natural Science Foundation of China [81171881, 81271763] FX We would like to thank Dr. Lunquan Sun (Center for Molecular Medicine of Central South University) for the critical reading and suggestion, and the members of the lab for the critical discussions of this manuscript. This work was supported by the China Postdoctoral Science Foundation [2012M511422 (S.L.)]; the Hunan Natural Science Foundation of China [12JJ1013 (Y.T.)]; the National Basic Research Program of China [2011CB504300 (Y.T.)]; the Fundamental Research Funds for the Central Universities [2011JQ019 (Y.T.)]; and the National Natural Science Foundation of China [81171881 (Y.T.), 81271763 (S.L.)]. NR 65 TC 6 Z9 6 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 EI 0006-3002 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD JUL PY 2014 VL 1839 IS 7 BP 592 EP 603 DI 10.1016/j.bbagrm.2014.05.017 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AK7GW UT WOS:000338597700006 PM 24859470 ER PT J AU Kang, JH Hassan, SA Zhao, P Tsai-Morris, CH Dufau, ML AF Kang, J. -H. Hassan, S. A. Zhao, P. Tsai-Morris, C. H. Dufau, M. L. TI Impact of subdomain D1 of the short form S1b of the human prolactin receptor on its inhibitory action on the function of the long form of the receptor induced by prolactin SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE Human prolactin receptor; Short and long form; Subdomain D1; Structure/function ID BREAST-CANCER; PROMOTER UTILIZATION; WSXWS MOTIF; ACTIVATION; GENE; SIMULATIONS; VARIANTS; PATHWAY; CELLS; PRL AB Background: Long-form (LF) homodimers of the human prolactin receptor (PRLR) mediate prolactin's diverse actions. Short form S1b inhibits the LF function through heterodimerization. Reduced S1b/LF-ratio in breast cancer could contribute to tumor development/progression. Current work defines the structural and functional relevance of the D1 domain of S1b on its inhibitory function on prolactin-induced LF function. Methods: Studies were conducted using mutagenesis, promoter/signaling analyses, bioluminescence resonance energy transfer (BRET) and molecular modeling approaches. Results: Mutation of E69 in D1 S1b or adjacent residues at the receptor surface near to the binding pocket (S) causes loss of its inhibitory effect while mutations away from this region (A) or in the D2 domain display inhibitory action as the wild-type. All S1b mutants preserved prolactin-induced Jak2 activation. BRET reveals an increased affinity in D-1 mutated S1b (S) homodimers in transfected cells stably expressing LF. In contrast, affinity in S1b homodimers with either D1 (A) or D2 mutations remained unchanged. This favors LF mediated signaling induced by prolactin. Molecular dynamics simulations show that mutations (S) elicit major conformational changes that propagate downward to the Dl/D2 interface and change their relative orientation in the dimers. Conclusions: These findings demonstrate the essential role of D1 on the S1b structure and its inhibitory action on prolactin-induced LF-mediated function. General significance: Major changes in receptor conformation and dimerization affinity are triggered by single mutations in critical regions of Dl. Our structure-function/simulation studies provide a basis for modeling and design of small molecules to enhance inhibition of LF activation for potential use in breast cancer treatment. Published by Elsevier B.V. C1 [Kang, J. -H.; Zhao, P.; Tsai-Morris, C. H.; Dufau, M. L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Endocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Hassan, S. A.] NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NIH, MSC, Bldg 49,Rm 6A-28,49 Convent Dr, Bethesda, MD 20892 USA. EM dufaum@mail.nih.gov FU NIH Intramural Research Program through the Eunice Kennedy Shriver National Institute of Child Health and Human Development; Center for Information Technology FX This work was supported by the NIH Intramural Research Program through the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Center for Information Technology. The study utilized the high performance computer capabilities of the Biowulf PC/Linux cluster at the NIH. NR 25 TC 1 Z9 1 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 EI 1872-8006 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD JUL PY 2014 VL 1840 IS 7 BP 2272 EP 2280 DI 10.1016/j.bbagen.2014.04.006 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AK4NW UT WOS:000338402400018 PM 24735798 ER PT J AU Jayanthi, S McCoy, MT Chen, B Britt, JP Kourrich, S Yau, HJ Ladenheim, B Krasnova, IN Bonci, A Cadet, JL AF Jayanthi, Subramaniam McCoy, Michael T. Chen, Billy Britt, Jonathan P. Kourrich, Said Yau, Hau-Jie Ladenheim, Bruce Krasnova, Irina N. Bonci, Antonello Cadet, Jean Lud TI Methamphetamine Downregulates Striatal Glutamate Receptors via Diverse Epigenetic Mechanisms SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Addiction; AMPAR; CoREST; HDAC2; MeCP2; NMDAR; REST; valproic acid ID CPG-BINDING PROTEIN; CELL FATE DECISIONS; HISTONE DEACETYLASE; SYNAPTIC PLASTICITY; DNA METHYLATION; NUCLEUS-ACCUMBENS; GENE-EXPRESSION; IN-VIVO; TRANSCRIPTIONAL REPRESSION; NEUROPSYCHIATRIC DISORDERS AB Background: Chronic methamphetamine (METH) exposure causes neuroadaptations at glutamatergic synapses. Methods: To identify the METH-induced epigenetic underpinnings of these neuroadaptations, we injected increasing METH doses to rats for 2 weeks and measured striatal glutamate receptor expression. We then quantified the effects of METH exposure on histone acetylation. We also measured METH-induced changes in DNA methylation and DNA hydroxymethylation. Results: Chronic METH decreased transcript and protein expression of GluA1 and GluA2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and GluN1 N-methyl-D-aspartate receptor subunits. These changes were associated with altered electrophysiological glutamatergic responses in striatal neurons. Chromatin immunoprecipitation-polymerase chain reaction revealed that METH decreased enrichment of acetylated histone H4 on GluA1, GluA2, and GluN1 promoters. Methamphetamine exposure also increased repressor element-1 silencing transcription factor (REST) corepressor 1, methylated CpG binding protein 2, and histone deacetylase 2 enrichment, but not of sirtuin 1 or sirtuin 2, onto GluA1 and GluA2 gene sequences. Moreover, METH caused interactions of REST corepressor 1 and methylated CpG binding protein 2 with histone deacetylase 2 and of REST with histone deacetylase 1. Surprisingly, methylated DNA immunoprecipitation and hydroxymethylated DNA immunoprecipitation-polymerase chain reaction revealed METH-induced decreased enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at GluA1 and GluA2 promoter sequences. Importantly, the histone deacetylase inhibitor, valproic acid, blocked METH-induced decreased expression of AMPAR and N-methyl-D-aspartate receptor subunits. Finally, valproic acid also attenuated METH-induced decrease H4K16Ac recruitment on AMPAR gene sequences. Conclusions: These observations suggest that histone H4 hypoacetylation may be the main determinant of METH-induced decreased striatal glutamate receptor expression. C1 [Jayanthi, Subramaniam; McCoy, Michael T.; Chen, Billy; Krasnova, Irina N.; Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, US Dept Hlth & Human Serv, NIH,Intramural Res Program, Baltimore, MD 21224 USA. [Chen, Billy; Britt, Jonathan P.; Kourrich, Said; Yau, Hau-Jie; Bonci, Antonello] NIDA, Synapt Plast Sect, US Dept Hlth & Human Serv, NIH,Intramural Res Program, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Res Branch, NIH, US Dept Hlth & Human Serv, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov RI kourrich, said/M-3916-2014; Britt, Jonathan/D-8877-2011; OI Britt, Jonathan/0000-0003-3044-9565; YAU, HAU-JIE/0000-0001-7454-7971 FU US Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse FX This work was supported by funds of the Intramural Research Program of the US Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse. NR 103 TC 37 Z9 39 U1 5 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 1 PY 2014 VL 76 IS 1 BP 47 EP 56 DI 10.1016/j.biopsych.2013.09.034 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AK2WD UT WOS:000338279500009 PM 24239129 ER PT J AU Zimmerberg, J Blank, PS AF Zimmerberg, Joshua Blank, Paul S. TI It's What's Inside that Matters SO BIOPHYSICAL JOURNAL LA English DT News Item ID FUSION PORE; EXOCYTOSIS; MEMBRANE; PROTEIN; RETENTION; GRANULES C1 [Zimmerberg, Joshua; Blank, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM zimmerbj@mail.nih.gov FU Intramural NIH HHS NR 15 TC 0 Z9 0 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JUL 1 PY 2014 VL 107 IS 1 BP 5 EP 7 DI 10.1016/j.bpj.2014.05.032 PG 3 WC Biophysics SC Biophysics GA AK4RK UT WOS:000338411600003 PM 24988334 ER PT J AU Venable, RM Sodt, AJ Rogaski, B Rui, H Hatcher, E MacKerell, AD Pastor, RW Klauda, JB AF Venable, Richard M. Sodt, Alexander J. Rogaski, Brent Rui, Huan Hatcher, Elizabeth MacKerell, Alexander D., Jr. Pastor, Richard W. Klauda, Jeffery B. TI CHARMM All-Atom Additive Force Field for Sphingomyelin: Elucidation of Hydrogen Bonding and of Positive Curvature SO BIOPHYSICAL JOURNAL LA English DT Article ID MOLECULAR-DYNAMICS SIMULATION; BENDING ELASTICITY; LIPID-BILAYERS; CONFORMATIONAL-ANALYSIS; COMPUTER-SIMULATION; MAGNETIC-RESONANCE; MEMBRANE CURVATURE; CHAIN-LENGTH; FREE-ENERGY; CHOLESTEROL AB The C36 CHARMM lipid force field has been extended to include sphingolipids, via a combination of high-level quantum mechanical calculations on small molecule fragments, and validation by extensive molecular dynamics simulations on N-palmitoyl and N-stearoyl sphingomyelin. NMR data on these two molecules from several studies in bilayers and micelles played a strong role in the development and testing of the force field parameters. Most previous force fields for sphingomyelins were developed before the availability of the detailed NMR data and relied on x-ray diffraction of bilayers alone for the validation;. these are shown to be too dense in the bilayer plane based on published chain order parameter data from simulations and experiments. The present simulations reveal O-H ::: O-P intralipid hydrogen bonding occurs 99% of the time, and interlipid N-H ::: O=C (26-29%, depending on the lipid) and N-H ::: O-H (17-19%). The interlipid hydrogen bonds are long lived, showing decay times of 50 ns, and forming strings of lipids, and leading to reorientational correlation time of nearly 100 ns. The spontaneous radius of curvature for pure N-palmitoyl sphingomyelin bilayers is estimated to be 43-100 angstrom, depending on the assumptions made in assigning a bending constant; this unusual positive curvature for a two-tailed neutral lipid is likely associated with hydrogen bond networks involving the NH of the sphingosine group. C1 [Venable, Richard M.; Sodt, Alexander J.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Rogaski, Brent; Klauda, Jeffery B.] Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. [Rui, Huan] Univ Kansas, Ctr Bioinformat, Lawrence, KS 66045 USA. [Rui, Huan] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA. [Hatcher, Elizabeth; MacKerell, Alexander D., Jr.] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. RP MacKerell, AD (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. EM alex@outerbanks.umaryland.edu; pastorr@nhlbi.nih.gov; jbklauda@umd.edu OI MacKerell, Alex/0000-0001-8287-6804 FU National Institutes of Health (NIH); National Heart, Lung and Blood Institute; National Science Foundation [DBI-1145652, MCB-1149187]; NIH [GM070855, GM072558]; National Center for Multiscale Modeling of Biological Systems (MMBioS) from the NIH [P41GM103712-S1]; Pittsburgh Supercomputing Center (PSC) [PSCA12035P] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Heart, Lung and Blood Institute (to R.W.P., R.M.V., A.J.S., and B.R.), institutional support from the University of Maryland (to B.R.), National Science Foundation (DBI-1145652 and MCB-1149187) to J.B.K. and by NIH GM070855 and GM072558 to A.D.M. The computational research was performed in part with Anton computer time, which was provided by the National Center for Multiscale Modeling of Biological Systems (MMBioS) through grant P41GM103712-S1 from the NIH and the Pittsburgh Supercomputing Center (PSC) under grant No. PSCA12035P. The Anton machine at PSC was generously made available by D. E. Shaw Research (33). Additional computational time was used on the High Performance Computing Cluster at the University of Maryland and also used the high-performance computational capabilities at the National Institutes of Health, Bethesda, MD (NHLBI LoBoS cluster). NR 63 TC 36 Z9 36 U1 2 U2 41 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD JUL 1 PY 2014 VL 107 IS 1 BP 134 EP 145 DI 10.1016/j.bpj.2014.05.034 PG 12 WC Biophysics SC Biophysics GA AK4RK UT WOS:000338411600017 PM 24988348 ER PT J AU Ghantous, A Saffery, R Cros, MP Ponsonby, AL Hirschfeld, S Kasten, C Dwyer, T Herceg, Z Hernandez-Vargas, H AF Ghantous, Akram Saffery, Richard Cros, Marie-Pierre Ponsonby, Anne-Louise Hirschfeld, Steven Kasten, Carol Dwyer, Terence Herceg, Zdenko Hernandez-Vargas, Hector TI Optimized DNA extraction from neonatal dried blood spots: application in methylome profiling SO BMC BIOTECHNOLOGY LA English DT Article DE Blood spot; DNA extraction; Epigenetics; Methylome; HM450; Pyrosequencing; Whole bisulfitome amplification; QIAamp; GenSolve; NucleoSpin ID MICROARRAY ANALYSIS; HIGH-QUALITY; LUNG-CANCER; METHYLATION; ARRAY; SAMPLES; FRESH; BIRTH AB Background: Neonatal dried blood spots (DBS) represent an inexpensive method for long-term biobanking worldwide and are considered gold mines for research for several human diseases, including those of metabolic, infectious, genetic and epigenetic origin. However, the utility of DBS is restricted by the limited amount and quality of extractable biomolecules (including DNA), especially for genome wide profiling. Degradation of DNA in DBS often occurs during storage and extraction. Moreover, amplifying small quantities of DNA often leads to a bias in subsequent data, particularly in methylome profiles. Thus it is important to develop methodologies that maximize both the yield and quality of DNA from DBS for downstream analyses. Results: Using combinations of in-house-derived and modified commercial extraction kits, we developed a robust and efficient protocol, compatible with methylome studies, many of which require stringent bisulfite conversion steps. Several parameters were tested in a step-wise manner, including blood extraction, cell lysis, protein digestion, and DNA precipitation, purification and elution. DNA quality was assessed based on spectrophotometric measurements, DNA detectability by PCR, and DNA integrity by gel electrophoresis and bioanalyzer analyses. Genome scale Infinium HumanMethylation450 and locus-specific pyrosequencing data generated using the refined DBS extraction protocol were of high quality, reproducible and consistent. Conclusions: This study may prove useful to meet the increased demand for research on prenatal, particularly epigenetic, origins of human diseases and for newborn screening programs, all of which are often based on DNA extracted from DBS. C1 [Ghantous, Akram; Cros, Marie-Pierre; Herceg, Zdenko; Hernandez-Vargas, Hector] Int Agcy Res Canc, Epigenet Grp, F-69008 Lyon, France. [Saffery, Richard; Ponsonby, Anne-Louise; Dwyer, Terence] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Ponsonby, Anne-Louise; Dwyer, Terence] Univ Tasmania, Menzies Res Inst, Hobart, Tas 7000, Australia. [Hirschfeld, Steven; Kasten, Carol] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, Natl Childrens Study, Natl Inst Hlth US, Bethesda, MD 20892 USA. RP Hernandez-Vargas, H (reprint author), Int Agcy Res Canc, Epigenet Grp, 150 Rue Albert Thomas, F-69008 Lyon, France. EM vargash@iarc.fr RI Hirschfeld, Steven/E-2987-2016; GHANTOUS, Akram/C-1689-2017 OI Hirschfeld, Steven/0000-0003-0627-7249; GHANTOUS, Akram/0000-0002-2582-6402 FU IARC Postdoctoral Fellowship; Marie Curie Actions-People-COFUND; NICHD [HHSN275200503414C, HHSN275200503411C, HHSN275200603416C, HHSN275200503415C, HHSN275200503413C, HHSN275200503410C, HHSN275200503396C, HHSN275201000121U, HHSN275200900010C] FX We thank Dr. Florence Le Calvez-Kelm and Mr. Geoffroy Durand for helping in the HM450 experimental process and bioanalyzer measurements. This work was partially supported by the Association pour le Recherche Contre le Cancer (l'ARC). AG is supported by the IARC Postdoctoral Fellowship and Marie Curie Actions-People-COFUND. We thank the International Childhood Cancer Cohort Consortium for contributing to the coordination between participating cohorts.; The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Children's Study, National Institutes of Health, or U.S. Department of Health and Human Services. Supported in part by NICHD Contracts HHSN275200503414C, HHSN275200503411C, HHSN275200603416C, HHSN275200503415C, HHSN275200503413C, HHSN275200503410C, HHSN275200503396C, HHSN275201000121U, and HHSN275200900010C. NR 29 TC 6 Z9 7 U1 0 U2 28 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6750 J9 BMC BIOTECHNOL JI BMC Biotechnol. PD JUL 1 PY 2014 VL 14 AR 60 DI 10.1186/1472-6750-14-60 PG 13 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AK6VZ UT WOS:000338566700001 PM 24980254 ER PT J AU Jin, LJ Lim, M Zhao, SP Sano, Y Simone, BA Savage, JE Wickstrom, E Camphausen, K Pestell, RG Simone, NL AF Jin, Lianjin Lim, Meng Zhao, Shuping Sano, Yuri Simone, Brittany A. Savage, Jason E. Wickstrom, Eric Camphausen, Kevin Pestell, Richard G. Simone, Nicole L. TI The metastatic potential of triple-negative breast cancer is decreased via caloric restriction-mediated reduction of the miR-17 similar to 92 cluster SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Caloric restriction; Triple-negative breast cancer; microRNA; miR-17 similar to 92 cluster; Radiation ID TGF-BETA; EXPRESSION; MICRORNA; CELLS; DISEASE; TUMORS; HETEROGENEITY; INHIBITION; EFFICACY; MATRIX AB Caloric restriction (CR) has been shown to cause tumor regression in models of triple-negative breast cancer (TNBC), and the regression is augmented when coupled with ionizing radiation (IR). In this study, we sought to determine if the molecular interaction between CR and IR could be mediated by microRNA (miR). miR arrays revealed 3 miRs in the miR-17 similar to 92 cluster as most significantly down regulated when CR is combined with IR. In vivo, CR and IR down regulated miR-17/20 in 2 TNBC models. To elucidate the mechanism by which this cluster regulates the response to CR, cDNA arrays were performed and the top 5 statistically significant gene ontology terms with high fold changes were all associated with extracellular matrix (ECM) and metastases. In silico analysis revealed 4 potential targets of the miR-17 similar to 92 cluster related to ECM: collagen 4 alpha 3, laminin alpha 3, and metallopeptidase inhibitors 2 and 3, which were confirmed by luciferase assays. The overexpression or silencing of miR-17/20a demonstrated that those miRs directly affected the ECM proteins. Furthermore, we found that CR-mediated inhibition of miR-17/20a can regulate the expression of ECM proteins. Functionally, we demonstrate that CR decreases the metastatic potential of cells which further demonstrates the importance of the ECM. In conclusion, CR can be used as a potential treatment for cancer because it may alter many molecular targets concurrently and decrease metastatic potential for TNBC. C1 [Jin, Lianjin; Lim, Meng; Sano, Yuri; Simone, Brittany A.; Simone, Nicole L.] Thomas Jefferson Univ, Dept Radiat Oncol, Philadelphia, PA 19107 USA. [Zhao, Shuping; Savage, Jason E.; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wickstrom, Eric] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Phiadelphia, PA 19107 USA. [Pestell, Richard G.] Thomas Jefferson Univ, Dept Canc Biol, Phiadelphia, PA 19107 USA. RP Simone, NL (reprint author), Thomas Jefferson Univ, Dept Radiat Oncol, Philadelphia, PA 19107 USA. EM nicole.simone@jeffersonhospital.org FU NCI Cancer Center Support Grant [P30-CA56036] FX The study was funded by the NCI Cancer Center Support Grant P30-CA56036 for the Kimmel Cancer Center. NR 38 TC 6 Z9 6 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2014 VL 146 IS 1 BP 41 EP 50 DI 10.1007/s10549-014-2978-7 PG 10 WC Oncology SC Oncology GA AK1ZW UT WOS:000338219300005 PM 24863696 ER PT J AU Bharti, SK Khan, I Banerjee, T Sommers, JA Wu, YL Brosh, RM AF Bharti, Sanjay Kumar Khan, Irfan Banerjee, Taraswi Sommers, Joshua A. Wu, Yuliang Brosh, Robert M., Jr. TI Molecular functions and cellular roles of the ChlR1 (DDX11) helicase defective in the rare cohesinopathy Warsaw breakage syndrome SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE ChlR1; DDX11; Warsaw breakage syndrome; Cohesinopathy; Helicase; Genomic instability; Genetic disease ID SISTER-CHROMATID COHESION; DNA-DAMAGE RESPONSE; ANEMIA GROUP J; G-QUADRUPLEX STRUCTURES; REPLICATION PROTEIN-A; IRON-SULFUR CLUSTER; CROSS-LINK REPAIR; FANCONI-ANEMIA; CAENORHABDITIS-ELEGANS; DYSKERATOSIS-CONGENITA AB In 2010, a new recessive cohesinopathy disorder, designated Warsaw breakage syndrome (WABS), was described. The individual with WABS displayed microcephaly, pre- and postnatal growth retardation, and abnormal skin pigmentation. Cytogenetic analysis revealed mitomycin C (MMC)-induced chromosomal breakage; however, an additional sister chromatid cohesion defect was also observed. WABS is genetically linked to bi-allelic mutations in the ChlR1/DDX11 gene which encodes a protein of the conserved family of Iron-Sulfur (Fe-S) cluster DNA helicases. Mutations in the budding yeast ortholog of ChlR1, known as Chl1, were known to cause sister chromatid cohesion defects, indicating a conserved function of the gene. In 2012, three affected siblings were identified with similar symptoms to the original WABS case, and found to have a homozygous mutation in the conserved Fe-S domain of ChlR1, confirming the genetic linkage. Significantly, the clinically relevant mutations perturbed ChlR1 DNA unwinding activity. In addition to its genetic importance in human disease, ChlR1 is implicated in papillomavirus genome maintenance and cancer. Although its precise functions in genome homeostasis are still not well understood, ongoing molecular studies of ChlR1 suggest the helicase plays a critically important role in cellular replication and/or DNA repair. C1 [Bharti, Sanjay Kumar; Khan, Irfan; Banerjee, Taraswi; Sommers, Joshua A.; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Wu, Yuliang] Univ Saskatchewan, Dept Biochem, Saskatoon, SK S7N 5E5, Canada. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU National Institutes of Health (NIH); National Institute on Aging (NIA); Saskatchewan Health Research Foundation (SHRF); Natural Sciences and Engineering Research Council of Canada (NSERC) FX This work is funded in part by the National Institutes of Health (NIH) and the National Institute on Aging (NIA) (R.M.B.), and by the Saskatchewan Health Research Foundation (SHRF) and the Natural Sciences and Engineering Research Council of Canada (NSERC) (Y.W.). We thank Drs. H. Vallabhaneni and J. Yin (NIA-NIH) for critically reading the manuscript. We wish to dedicate this paper to the memory of Dr. Johan P. de Winter, an outstanding scientist who led efforts in understanding the molecular-genetic basis of Warsaw breakage syndrome, Fanconi anemia, and other genetic disorders. NR 94 TC 13 Z9 13 U1 0 U2 5 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JUL PY 2014 VL 71 IS 14 BP 2625 EP 2639 DI 10.1007/s00018-014-1569-4 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AK0SW UT WOS:000338126600003 PM 24487782 ER PT J AU Fram, S King, H Sacks, DB Wells, CM AF Fram, Sally King, Helen Sacks, David B. Wells, Claire M. TI A PAK6-IQGAP1 complex promotes disassembly of cell-cell adhesions SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE PAK6; IQGAP; Cell junctions; Cell motility; HGF ID SMALL GTPASE RAC; E-CADHERIN; P21-ACTIVATED KINASE; EPITHELIAL-CELLS; PROSTATE-CANCER; ALPHA-CATENIN; BETA-CATENIN; IQGAP1; CDC42; ACTIVATION AB p-21 activated 6 (PAK6), first identified as interacting with the androgen receptor (AR), is over-expressed in multiple cancer tissues and has been linked to the progression of prostate cancer, however little is known about PAK6 function in the absence of AR signaling. We report here that PAK6 is specifically required for carcinoma cell-cell dissociation downstream of hepatocyte growth factor (HGF) for both DU145 prostate cancer and HT29 colon cancer cells. Moreover, PAK6 overexpression can drive cells to escape from adhesive colonies in the absence of stimulation. We have localized PAK6 to cell-cell junctions and have detected a direct interaction between the kinase domain of PAK6 and the junctional protein IQGAP1. Co-expression of IQGAP1 and PAK6 increases cell colony escape and leads to elevated PAK6 activation. Further studies have identified a PAK6/E-cadherin/IQGAP1 complex downstream of HGF. Moreover, we find that beta-catenin is also localized with PAK6 in cell-cell junctions and is a novel PAK6 substrate. We propose a unique role for PAK6, independent of AR signaling, where PAK6 drives junction disassembly during HGF-driven cell-cell dissociation via an IQGAP1/E-cadherin complex that leads to the phosphorylation of beta-catenin and the disruption of cell-cell adhesions. C1 [Fram, Sally; King, Helen; Wells, Claire M.] Kings Coll London, Div Canc Studies, London SE1 1UL, England. [Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Wells, CM (reprint author), Kings Coll London, Div Canc Studies, New Hunts House,Guys Campus, London SE1 1UL, England. EM claire.wells@kcl.ac.uk OI Sacks, David/0000-0003-3100-0735 FU Guys and St. Thomas Charity; Medical Research Council; Cancer and Polio Research Fund; Pancreatic Cancer Research Fund; Intramural Program of the National Institutes of Health FX This work was supported by Guys and St. Thomas Charity (to CMW) the Medical Research Council (to SF) the Cancer and Polio Research Fund (to CMW) the Pancreatic Cancer Research Fund (to HK) and the Intramural Program of the National Institutes of Health (to DBS). NR 54 TC 10 Z9 10 U1 0 U2 7 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JUL PY 2014 VL 71 IS 14 BP 2759 EP 2773 DI 10.1007/s00018-013-1528-5 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AK0SW UT WOS:000338126600013 PM 24352566 ER PT J AU Williams, JS Kunkel, TA AF Williams, Jessica S. Kunkel, Thomas A. TI Ribonucleotides in DNA: Origins, repair and consequences SO DNA REPAIR LA English DT Article DE DNA polymerase; DNA replication; Ribonucleotides; Genome instability; DNA repair ID YEAST REPLICATIVE POLYMERASES; MAINTAIN GENOME INTEGRITY; AFFECT TELOMERE-LENGTH; SACCHAROMYCES-CEREVISIAE; RNASE H2; ESCHERICHIA-COLI; TOPOISOMERASE-I; EXCISION-REPAIR; STRAND DNA; MITOCHONDRIAL-DNA AB While primordial life is thought to have been RNA-based (Cech, Cold Spring Harbor Perspect. Biol. 4 (2012) a006742), all living organisms store genetic information in DNA, which is chemically more stable. Distinctions between the RNA and DNA worlds and our views of "DNA" synthesis continue to evolve as new details emerge on the incorporation, repair and biological effects of ribonucleotides in DNA genomes of organisms from bacteria through humans. Published by Elsevier B.V. C1 [Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Division of Intramural Research of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) [Z01 ES065070] FX This work was supported by Project Z01 ES065070 to T.A.K. from the Division of Intramural Research of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). NR 105 TC 44 Z9 44 U1 2 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JUL PY 2014 VL 19 SI SI BP 27 EP 37 DI 10.1016/j.dnarep.2014.03.029 PG 11 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA AK4QC UT WOS:000338408200004 PM 24794402 ER PT J AU Pommier, Y Huang, SYN Gao, R Das, BB Murai, J Marchand, C AF Pommier, Yves Huang, Shar-yin N. Gao, Rui Das, Benu Brata Murai, Junko Marchand, Christophe TI Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2) SO DNA REPAIR LA English DT Article DE Topoisomerases; Poly(ADPribose) polymerases (PARP); Homologous Recombination (HR); Non-homologous end joining (NHEJ); Chemotherapy ID TOPOISOMERASE-I CLEAVAGE; DOUBLE-STRAND BREAKS; DIOL EPOXIDE ADDUCTS; RECEPTOR-ASSOCIATED FACTORS; DEPENDENT PROTEIN-KINASE; BASE EXCISION-REPAIR; SINGLE-STRAND; COVALENT COMPLEXES; POLY(ADP-RIBOSE) POLYMERASE; SPINOCEREBELLAR ATAXIA AB TDP1 and TDP2 were discovered and named based on the fact they process 3'- and 5'-DNA ends by excising irreversible protein tyrosyl-DNA complexes involving topoisomerases I and II, respectively. Yet, both enzymes have an extended spectrum of activities. TDP1 not only excises trapped topoisomerases I (Top1 in the nucleus and Top1mt in mitochondria), but also repairs oxidative damage-induced 3'-phosphoglycolates and alkylation damage-induced DNA breaks, and excises chain terminating anticancer and antiviral nucleosides in the nucleus and mitochondria. The repair function of TDP2 is devoted to the excision of topoisomerase II- and potentially topoisomerases III-DNA adducts. TDP2 is also essential for the life cycle of picornaviruses (important human and bovine pathogens) as it unlinks VPg proteins from the 5'-end of the viral RNA genome. Moreover, TDP2 has been involved in signal transduction (under the former names of TTRAP or EAPII). The DNA repair partners of TDP1 include PARP1, XRCC1, ligase III and PNKP from the base excision repair (BER) pathway. By contrast, TDP2 repair functions are coordinated with Ku and ligase IV in the non-homologous end joining pathway (NHEJ). This article summarizes and compares the biochemistry, functions, and post-translational regulation of TDP1 and TDP2, as well as the relevance of TDP1 and TDP2 as determinants of response to anticancer agents. We discuss the rationale for developing TDP inhibitors for combinations with topoisomerase inhibitors (topotecan, irinotecan, doxorubicin, etoposide, mitoxantrone) and DNA damaging agents (temozolomide, bleomycin, cytarabine, and ionizing radiation), and as novel antiviral agents. Published by Elsevier B.V. C1 [Pommier, Yves; Huang, Shar-yin N.; Gao, Rui; Das, Benu Brata; Murai, Junko; Marchand, Christophe] NCI, Dev Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Pommier, Yves; Huang, Shar-yin N.; Gao, Rui; Das, Benu Brata; Murai, Junko; Marchand, Christophe] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Das, Benu Brata] Indian Assoc Cultivat Sci, Mol Biol Lab, Kolkata 700032, India. [Murai, Junko] Kyoto Univ, Grad Sch Med, Dept Radiat Genet, Sakyo Ku, Kyoto 6068501, Japan. RP Pommier, Y (reprint author), NCI, Dev Therapeut Branch, NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Mendez, Pedro /J-8955-2016 OI Mendez, Pedro /0000-0001-6713-7907 FU Center for Cancer Research, National Cancer Institute [Z01 BC 006150] FX Our studies are supported by the Center for Cancer Research, Intramural Program of the National Cancer Institute (Z01 BC 006150). NR 202 TC 50 Z9 51 U1 3 U2 38 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JUL PY 2014 VL 19 SI SI BP 114 EP 129 DI 10.1016/j.dnarep.2014.03.020 PG 16 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA AK4QC UT WOS:000338408200013 PM 24856239 ER PT J AU Copeland, WC Longley, MJ AF Copeland, William C. Longley, Matthew J. TI Mitochondrial genome maintenance in health and disease SO DNA REPAIR LA English DT Article DE POLG; Mitochondrial DNA replication; mtDNA; Mitochondrial disease; Mutagenesis ID DNA-POLYMERASE-GAMMA; PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; BASE EXCISION-REPAIR; P55 ACCESSORY SUBUNIT; MTDNA MUTATOR MICE; SACCHAROMYCES-CEREVISIAE; POINT MUTATIONS; POLG MUTATIONS; MAMMALIAN MITOCHONDRIA; OXIDATIVE STRESS AB Human mitochondria harbor an essential, high copy number, 16,569 base pair, circular DNA genome that encodes 13 gene products required for electron transport and oxidative phosphorylation. Mutation of this genome can compromise cellular respiration, ultimately resulting in a variety of progressive metabolic diseases collectively known as 'mitochondrial diseases'. Mutagenesis of mtDNA and the persistence of mtDNA mutations in cells and tissues is a complex topic, involving the interplay of DNA replication, DNA damage and repair, purifying selection, organelle dynamics, mitophagy, and aging. We briefly review these general elements that affect maintenance of mtDNA, and we focus on nuclear genes encoding the mtDNA replication machinery that can perturb the genetic integrity of the mitochondrial genome. Published by Elsevier B.V. C1 [Copeland, William C.; Longley, Matthew J.] NIEHS, Mol Genet Lab, NIH, Durham, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, NIH, Durham, NC 27709 USA. EM copelan1@niehs.nih.gov FU NIH, NIEHS [ES 065078, ES 065080] FX This work was supported by the Intramural Research Program of the NIH, NIEHS (ES 065078 and ES 065080). NR 132 TC 29 Z9 29 U1 3 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD JUL PY 2014 VL 19 SI SI BP 190 EP 198 DI 10.1016/j.dnarep.2014.03.010 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA AK4QC UT WOS:000338408200022 PM 24780559 ER PT J AU Taylor, SM Antonia, AL Harrington, WE Goheen, MM Mwapasa, V Chaluluka, E Fried, M Kabyemela, E Madanitsa, M Khairallah, C Kalilani-Phiri, L Tshefu, AK Rogerson, SJ ter Kuile, FO Duffy, PE Meshnick, SR AF Taylor, Steve M. Antonia, Alejandro L. Harrington, Whitney E. Goheen, Morgan M. Mwapasa, Victor Chaluluka, Ebbie Fried, Michal Kabyemela, Edward Madanitsa, Mwayi Khairallah, Carole Kalilani-Phiri, Linda Tshefu, Antoinette K. Rogerson, Stephen J. ter Kuile, Feiko O. Duffy, Patrick E. Meshnick, Steven R. TI Independent Lineages of Highly Sulfadoxine-Resistant Plasmodium falciparum Haplotypes, Eastern Africa SO EMERGING INFECTIOUS DISEASES LA English DT Article ID PREGNANCY-ASSOCIATED MALARIA; POPULATION-STRUCTURE; PREVENTIVE TREATMENT; PYRIMETHAMINE; SOFTWARE; QUEERPAM; OUTCOMES; ALLELES; SPREAD AB Sulfadoxine-resistant Plasmodium falciparum undermines malaria prevention with sulfadoxine/pyrimethamine. Parasites with a highly resistant mutant dihydropteroate synthase (dhps) haplotype have recently emerged in eastern Africa; they negated preventive benefits of sulfadoxine/pyrimethamine, and might exacerbate placental malaria. We explored emerging lineages of dhps mutant haplotypes in Malawi, the Democratic Republic of the Congo, and Tanzania by using analyses of genetic microsatellites flanking the dhps locus. In Malawi, a triple-mutant dhps SGEG (mutant amino acids are underlined) haplotype emerged in 2010 that was closely related to pre-existing double-mutant SGEA haplotypes, suggesting local origination in Malawi. When we compared mutant strains with parasites from the Democratic Republic of the Congo and Tanzania by multiple independent analyses, we found that SGEG parasites were partitioned into separate lineages by country. These findings support a model of local origination of SGEG dhps haplotypes, rather than geographic diffusion, and have implications for investigations of emergence and effects of parasite drug resistance. C1 [Taylor, Steve M.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Taylor, Steve M.; Antonia, Alejandro L.; Goheen, Morgan M.; Meshnick, Steven R.] Univ N Carolina, Chapel Hill, NC USA. [Harrington, Whitney E.] Univ Washington, Sch Med, Seattle Childrens Hosp, Seattle, WA USA. [Mwapasa, Victor; Chaluluka, Ebbie; Madanitsa, Mwayi; Kalilani-Phiri, Linda] Coll Med, Blantyre, Malawi. [Fried, Michal; Duffy, Patrick E.] NIH, Bethesda, MD 20892 USA. [Kabyemela, Edward] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Khairallah, Carole; ter Kuile, Feiko O.] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. [Tshefu, Antoinette K.] Univ Kinshasa, Kinshasha, Congo. [Rogerson, Stephen J.] Univ Melbourne, Melbourne, Vic, Australia. [ter Kuile, Feiko O.] Univ Amsterdam, Amsterdam, Netherlands. RP Taylor, SM (reprint author), Duke Univ, Med Ctr, Dept Med, Div Infect Dis & Int Hlth, Box 102359, Durham, NC 27710 USA. EM steve.taylor@duke.edu OI Rogerson, Stephen/0000-0003-4287-1982; ter Kuile, Feiko/0000-0003-3663-5617 FU National Institute of Allergy and Infectious Diseases, National Instituted of Health FX M.F. and P.E.D. were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Instituted of Health. NR 33 TC 6 Z9 6 U1 0 U2 0 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JUL PY 2014 VL 20 IS 7 BP 1140 EP 1148 DI 10.3201/eid2007.131720 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AK4JB UT WOS:000338389900006 PM 24960247 ER PT J AU Marthaler, D Rossow, K Culhane, M Goyal, S Collins, J Matthijnssens, J Nelson, M Ciarlet, M AF Marthaler, Douglas Rossow, Kurt Culhane, Marie Goyal, Sagar Collins, Jim Matthijnssens, Jelle Nelson, Martha Ciarlet, Max TI Widespread Rotavirus H in Domesticated Pigs, United States SO EMERGING INFECTIOUS DISEASES LA English DT Article ID GROUP-B; ADULT DIARRHEA; CLASSIFICATION; CHINA AB We investigated the presence in US pigs of rotavirus H (RVH), identified in pigs in Japan and Brazil. From 204 samples collected during 2006-2009, we identified RVH in 15% of fecal samples from 10 US states, suggesting that RVH has circulated in the United States since 2002, but probably longer. C1 [Marthaler, Douglas; Rossow, Kurt; Culhane, Marie; Goyal, Sagar; Collins, Jim] Univ Minnesota, Vet Diagnost Lab, St Paul, MN 55108 USA. [Matthijnssens, Jelle] Univ Leuven, Leuven, Belgium. [Nelson, Martha] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Ciarlet, Max] Novartis Vaccines & Diagnost Inc, Cambridge, MA USA. RP Marthaler, D (reprint author), Univ Minnesota, Coll Vet Med, Vet Diagnost Lab, 1333 Gortner Ave, St Paul, MN 55108 USA. EM marth027@umn.edu RI Matthijnssens, Jelle/A-6770-2015; Matthijnssens, Jelle/B-8634-2016 FU University of Minnesota Veterinary Diagnostic Laboratory FX The research project was funded by the University of Minnesota Veterinary Diagnostic Laboratory. NR 11 TC 11 Z9 11 U1 0 U2 2 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JUL PY 2014 VL 20 IS 7 BP 1195 EP 1198 DI 10.3201/eid2007.140034 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AK4JB UT WOS:000338389900014 PM 24960190 ER PT J AU Chowell, G Towers, S Viboud, C Fuentes, R Sotomayor, V AF Chowell, Gerardo Towers, Sherry Viboud, Cecile Fuentes, Rodrigo Sotomayor, Viviana TI Rates of Influenza-like Illness and Winter School Breaks, Chile, 2004-2010 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID CLOSURE; TRANSMISSION AB To determine effects of school breaks on influenza virus transmission in the Southern Hemisphere, we analyzed 2004-2010 influenza-like illness surveillance data from Chile. Winter breaks were significantly associated with a two-thirds temporary incidence reduction among schoolchildren, which supports use of school closure to temporarily reduce illness, especially among schoolchildren, in the Southern Hemisphere. C1 [Chowell, Gerardo; Towers, Sherry] Arizona State Univ, Tempe, AZ 85282 USA. [Chowell, Gerardo; Viboud, Cecile] NIH, Bethesda, MD 20892 USA. [Fuentes, Rodrigo; Sotomayor, Viviana] Minist Salud, Santiago, Chile. RP Chowell, G (reprint author), Arizona State Univ, Box 872402, Tempe, AZ 85282 USA. EM gchowell@asu.edu FU Office of Global Affairs, International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services FX This research was conducted in the context of the Multinational Influenza Seasonal Mortality Study, an ongoing international collaborative effort to understand influenza epidemiological and evolutionary patterns led by the Fogarty International Center, National Institutes of Health (http://www.origem.info/misms/index.php). Funding for this project came in part from the Office of Global Affairs, International Influenza Unit, in the Office of the Secretary of the Department of Health and Human Services. NR 15 TC 3 Z9 3 U1 0 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JUL PY 2014 VL 20 IS 7 BP 1203 EP 1207 DI 10.3201/eid2007.130967 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AK4JB UT WOS:000338389900016 PM 24963800 ER PT J AU van Doremalen, N Bushmaker, T Karesh, WB Munster, VJ AF van Doremalen, Neeltje Bushmaker, Trenton Karesh, William B. Munster, Vincent J. TI Stability of Middle East Respiratory Syndrome Coronavirus in Milk SO EMERGING INFECTIOUS DISEASES LA English DT Letter C1 [van Doremalen, Neeltje; Bushmaker, Trenton; Munster, Vincent J.] NIAID, NIH, Hamilton, MT 59840 USA. [Karesh, William B.] EcoHlth Alliance, New York, NY USA. RP Munster, VJ (reprint author), NIAID, Rocky Mt Labs, 903 South 4th St, Hamilton, MT 59840 USA. EM vincent.munster@nih.gov OI Munster, Vincent/0000-0002-2288-3196 FU Intramural NIH HHS NR 10 TC 15 Z9 15 U1 1 U2 15 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JUL PY 2014 VL 20 IS 7 BP 1263 EP 1264 DI 10.3201/eid2007.140500 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AK4JB UT WOS:000338389900039 PM 24960335 ER PT J AU Fann, DYW Santro, T Manzanero, S Widiapradja, A Cheng, YL Lee, SY Chunduri, P Jo, DG Stranahan, AM Mattson, MP Arumugam, TV AF Fann, David Yang-Wei Santro, Tomislav Manzanero, Silvia Widiapradja, Alexander Cheng, Yi-Lin Lee, Seung-Yoon Chunduri, Prasad Jo, Dong-Gyu Stranahan, Alexis M. Mattson, Mark P. Arumugam, Thiruma V. TI Intermittent fasting attenuates inflammasome activity in ischemic stroke SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Intermittent fasting; Inflammasomes; Ischemic stroke; NLRP1; NLRP3 ID NF-KAPPA-B; GLYCATION END-PRODUCTS; NEURONAL CELL-DEATH; CALORIC RESTRICTION; NLRP3 INFLAMMASOME; DIETARY RESTRICTION; BRAIN-DAMAGE; MOUSE MODEL; ACTIVATION; CASPASE-1 AB Recent findings have revealed a novel inflammatory mechanism that contributes to tissue injury in cerebral ischemia mediated by multi-protein complexes termed inflammasomes. Intermittent fasting (IF) can decrease the levels of pro-inflammatory cytokines in the periphery and brain. Here we investigated the impact of IF (16 h of food deprivation daily) for 4 months on NLRP1 and NLRP3 inflammasome activities following cerebral ischemia. Ischemic stroke was induced in C578L/6J mice by middle cerebral artery occlusion, followed by reperfusion (I/R). IF decreased the activation of NF-kappa B and MAPK signaling pathways, the expression of NLRPI and NLRP3 inflammasome proteins, and both IL-1 beta and IL-18 in the ischemic brain tissue. These findings demonstrate that IF can attenuate the inflammatory response and tissue damage following ischemic stroke by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. (C) 2014 Elsevier Inc. All rights reserved. C1 [Fann, David Yang-Wei; Widiapradja, Alexander; Cheng, Yi-Lin; Arumugam, Thiruma V.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117595, Singapore. [Jo, Dong-Gyu; Arumugam, Thiruma V.] Sungkyunkwan Univ, Sch Pharm, Suwon, South Korea. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Stranahan, Alexis M.] Georgia Hlth Sci Univ, Dept Physiol, Augusta, GA USA. [Fann, David Yang-Wei; Santro, Tomislav; Manzanero, Silvia; Widiapradja, Alexander; Cheng, Yi-Lin; Lee, Seung-Yoon; Chunduri, Prasad; Arumugam, Thiruma V.] Univ Queensland, Sch Biomed Sci, St Lucia, Qld, Australia. RP Arumugam, TV (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117595, Singapore. EM phstva@nus.edu.sg RI Chunduri, Prasad/J-2141-2014; Arumugam, Thiruma/B-4898-2011; OI Manzanero, Silvia/0000-0002-5294-7082; Chunduri, Prasad/0000-0001-7297-7580 FU ARC Future Fellowship [FT100100427]; National Institute on Aging Intramural Research Program FX The ARC Future Fellowship (FT100100427) awarded to TVA, and the National Institute on Aging Intramural Research Program supported this work. NR 45 TC 21 Z9 22 U1 4 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD JUL PY 2014 VL 257 BP 114 EP 119 DI 10.1016/j.expneurol.2014.04.017 PG 6 WC Neurosciences SC Neurosciences & Neurology GA AK1MU UT WOS:000338180000013 PM 24805069 ER PT J AU Camargo, MC Freedman, ND Hollenbeck, AR Abnet, CC Rabkin, CS AF Camargo, M. Constanza Freedman, Neal D. Hollenbeck, Albert R. Abnet, Christian C. Rabkin, Charles S. TI Height, weight, and body mass index associations with gastric cancer subsites SO GASTRIC CANCER LA English DT Article DE BMI; Cardia; Gastric cancer; Height; Noncardia; Weight ID HELICOBACTER-PYLORI INFECTION; US ADULTS; PROSPECTIVE COHORT; RISK-FACTORS; ADENOCARCINOMA; ESOPHAGEAL; STOMACH; GROWTH; METAANALYSIS; HEALTH AB Although excess body weight has been associated with cancers of the gastric cardia, relationships with gastric cancer at other anatomic subsites are not well defined. Furthermore, subsite-specific associations with attained height have not been fully assessed. In 1995-1996, 483,700 Whites enrolling in the multi-state NIH-AARP Diet and Health Study self-reported height and weight. Gastric cancers occurring through 31 December 2006 were ascertained from regional population-based registries. We used Cox regression models to estimate cancer hazard ratios (HRs) for sex-specific tertiles of height and weight and for body mass index (BMI) categories of the World Health Organization. One thousand incident cancers (48 % localized to the cardia, 4 % fundus, 6 % corpus, 3 % greater curvature, 6 % lesser curvature, 10 % antrum, 2 % pylorus, 5 % overlapping lesion, and 16 % unspecified) occurred an average of 5.4 years after enrollment. After controlling for effects of age, sex, education, and smoking, we found an inverse association between height and total noncardia cancers (i.e., fundus, corpus, greater and lesser curvatures, antrum, and pylorus), with HRs vs. tertile 1 of 0.65 and 0.71 for tertiles 2 and 3, respectively (p trend = 0.016). Trends were consistent for individual noncardia subsites. In contrast, although weight and BMI were each associated with risk of cardia cancer, neither was associated with total noncardia cancer nor individual subsites. Noncardia gastric cancer is associated with short stature but not with high body weight or obesity. The excess risk for shorter adults would be consistent with the known association of chronic H. pylori infection with growth retardation during childhood. C1 [Camargo, M. Constanza; Freedman, Neal D.; Abnet, Christian C.; Rabkin, Charles S.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Camargo, MC (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,BG 9609-6E206, Rockville, MD 20850 USA. EM camargomc@mail.nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; Camargo, M. Constanza/R-9891-2016 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. Specific to NIH-AARP: 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. We also thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for outcomes ascertainment and study management and Nathan Arpel at Information Management Services for data support and analysis. The NIH-AARP Diet and Health Study is registered at clinicaltrials.gov as NCT00340015. NR 32 TC 5 Z9 6 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1436-3291 EI 1436-3305 J9 GASTRIC CANCER JI Gastric Cancer PD JUL PY 2014 VL 17 IS 3 BP 463 EP 468 DI 10.1007/s10120-013-0312-4 PG 6 WC Oncology; Gastroenterology & Hepatology SC Oncology; Gastroenterology & Hepatology GA AK5VK UT WOS:000338494400008 PM 24174008 ER PT J AU Fontana, RJ Hayashi, PH Gu, JZ Reddy, KR Barnhart, H Watkins, PB Serrano, J Lee, WM Chalasani, N Stolz, A Davern, T Talwakar, JA AF Fontana, Robert J. Hayashi, Paul H. Gu, Jiezhun Reddy, K. Rajender Barnhart, Huiman Watkins, Paul B. Serrano, Jose Lee, William M. Chalasani, Naga Stolz, Andrew Davern, Timothy Talwakar, Jayant A. CA DILIN Network TI Idiosyncratic Drug-Induced Liver Injury Is Associated With Substantial Morbidity and Mortality Within 6 Months From Onset SO GASTROENTEROLOGY LA English DT Article DE Hepatotoxicity; Acute Liver Failure; Transplantation; Causality ID TERM-FOLLOW-UP; UNITED-STATES; CAUSALITY ASSESSMENT; HEPATOTOXICITY; FAILURE; DISEASE; HEPATITIS; JAUNDICE; REGISTRY AB BACKGROUND & AIMS: Little is known about the incidence of drug-induced liver injury (DILI) and risk factors for adverse outcomes. We evaluated short-term outcomes of a large cohort of patients with DILI enrolled in an ongoing multicenter prospective study. METHODS: Data were collected from 660 adults with definite, highly likely, or probable DILI. Regression methods were used to identify risk factors for early liver-related death or liver transplantation and chronic liver injury. RESULTS: Patients' median age was 51.4 years; 59.5% were female and 59.1% required hospitalization. Within 6 months of DILI onset, 30 patients received liver transplants (4.5%; 95% confidence interval [CI], 3.0%-6.1%) and 32 died (5%; 95% CI, 3.2%-6.5%); 53% of the deaths were liver related. Asian race, absence of itching, lung disease, low serum albumin levels, low platelet counts, and high serum levels of alanine aminotransferase and total bilirubin at presentation were independent risk factors for reduced times to liver-related death or liver transplantation (C-statistic = 0.87). At 6 months after DILI onset, 18.9% of the 598 evaluable subjects had persistent liver damage. African-American race, higher serum levels of alkaline phosphatase, and prior heart disease or malignancy requiring treatment were independent risk factors for chronic DILI (C-statistic = 0.71). CONCLUSIONS: Nearly 1 in 10 patients die or undergo liver transplantation within 6 months of DILI onset and nearly 1 in 5 of the remaining patients have evidence of persistent liver injury at 6 months. The profile of liver injury at presentation, initial severity, patient's race, and medical comorbidities are important determinants of the likelihood of death/transplantation or persistent liver injury within 6 months. C1 [Fontana, Robert J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Hayashi, Paul H.; Watkins, Paul B.] Univ N Carolina, Chapel Hill, NC USA. [Gu, Jiezhun; Barnhart, Huiman] Duke Clin Res Inst, Durham, NC USA. [Reddy, K. Rajender] Univ Penn, Div Gastroenterol & Hepatol, Philadelphia, PA 19104 USA. [Serrano, Jose] NIDDKD, Liver Dis Res Branch, NIH, Bethesda, MD USA. [Lee, William M.] Univ Texas SW Med Ctr Dallas, Div Digest & Liver Dis, Dallas, TX 75390 USA. [Chalasani, Naga] Indiana Univ, Dept Med, Indianapolis, IN USA. [Stolz, Andrew] Univ So Calif, Los Angeles, CA USA. [Davern, Timothy] Calif Pacific Med Ctr, San Francisco, CA USA. [Talwakar, Jayant A.] Mayo Clin, Rochester, MN USA. RP Fontana, RJ (reprint author), Univ Michigan, Dept Internal Med, Taubman Ctr 3912, Ann Arbor, MI 48109 USA. EM rfontana@med.umich.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [2U01-DK065176-06, 2U01-DK065201-06, 2U01-DK065184-06, 2U01-DK065211-06, 5U01DK065193-04, 5U01-DK065238-08, 1U01-DK083023-01, 1U01-DK083027-01, 1U01-DK082992-01, 1U01-DK083020-01]; Clinical and Translational Science Awards grants [UL1 RR025761, UL1TR000083, UL1 RR024134, UL1 RR024986, UL1 RR024982, UL1 RR024150]; Intramural Research Program of the National Institutes of Health, National Cancer Institute FX The DILIN Network is structured as a U01 cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases under grants: 2U01-DK065176-06 (Duke University), 2U01-DK065201-06 (University of North Carolina), 2U01-DK065184-06 (University of Michigan), 2U01-DK065211-06 (Indiana University), 5U01DK065193-04 (University of Connecticut), 5U01-DK065238-08 (University of California, San Francisco/California Pacific Medical Center), 1U01-DK083023-01 (University of Texas Southwestern), 1U01-DK083027-01 (Thomas Jefferson Hospital/University of Pennsylvania), 1U01-DK082992-01 (Mayo Clinic), 1U01-DK083020-01 (University of Southern California). Additional funding is provided by Clinical and Translational Science Awards grants: UL1 RR025761 (Indiana University), UL1TR000083 (University of North Carolina), UL1 RR024134 (University of Pennsylvania), UL1 RR024986 (University of Michigan), UL1 RR024982 (University of Texas Southwestern), UL1 RR024150 (Mayo Clinic), and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 23 TC 30 Z9 35 U1 2 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2014 VL 147 IS 1 BP 96 EP U189 DI 10.1053/j.gastro.2014.03.045 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AK4DE UT WOS:000338373400026 PM 24681128 ER PT J AU Serti, E Werner, JM Chattergoon, M Cox, AL Lohmann, V Rehermann, B AF Serti, Elisavet Werner, Jens M. Chattergoon, Michael Cox, Andrea L. Lohmann, Volker Rehermann, Barbara TI Monocytes Activate Natural Killer Cells via Inflammasome-Induced Interleukin 18 in Response to Hepatitis C Virus Replication SO GASTROENTEROLOGY LA English DT Article DE Immune Response; Cytokine Production; Hepatocyte; Viral Replication ID CD8(+) T-CELLS; INFECTED-CELLS; ENVELOPE PROTEIN; NK CELLS; INTERFERON; INHIBITION; IMMUNITY; RELEASE; VIRIONS; CULTURE AB BACKGROUND & AIMS: Production of interferon (IFN)-gamma by natural killer (NK) cells is attenuated during chronic infection with hepatitis C virus (HCV). We investigated whether this is due to intrinsic or extrinsic mechanisms of NK cells. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from patients with chronic HCV infection or uninfected blood donors (controls); NK cells and monocytes were isolated or eliminated. We cultured hepatoma cells that express luciferase-tagged subgenomic HCV replicons (Huh7/HCV replicon cells) or their HCV-negative counterparts (Huh7) with NK cells in the presence or absence of other populations of PBMCs. Antiviral activity, cytotoxicity, and cytokine production were assessed. RESULTS: NK cells produced greater amounts of IFN-gamma when PBMC were cocultured with Huh7/HCV replicon cells than with Huh7 cells; NK cells and PBMCs from controls suppressed HCV replication to a greater extent than those from patients with chronic HCV infection. This antiviral effect was predominantly mediated by tumor necrosis factor (TNF)-alpha and IFN-gamma. The antiviral activity of NK cells and their production of IFN-gamma were reduced when they were used in coculture alone (rather than with PBMC), or after depletion of CD14(+) monocytes, after knockdown of the inflammasome in monocytes, or after neutralization of interleukin-18, which is regulated by the inflammasome. These findings indicate a role for monocytes in NK cell activation. Compared with control monocytes, monocytes from patients with chronic HCV infection had reduced TNF-alpha-mediated (direct) and reduced NK cell-mediated (indirect) antiviral effects. Control monocytes increased the antiviral effects of NK cells from patients with chronic HCV infection and their production of IFN-gamma. CONCLUSIONS: Monocytes sense cells that contain replicating HCV and respond by producing interleukin-18 via the inflammasome and by activating NK cells. Patients with chronic HCV infection have reduced monocyte function, attenuating NK cell IFN-gamma-mediated responses. C1 [Serti, Elisavet; Werner, Jens M.; Rehermann, Barbara] NIDDKD, Immunol Sect, Liver Dis Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Chattergoon, Michael; Cox, Andrea L.] Johns Hopkins Sch Med, Div Infect Dis, Baltimore, MD USA. [Lohmann, Volker] Heidelberg Univ, Dept Infect Dis, Heidelberg, Germany. RP Rehermann, B (reprint author), NIDDKD, Immunol Sect, Liver Dis Branch, NIH,Dept Hlth & Human Serv, 10 Ctr Dr,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. EM rehermann@nih.gov OI Lohmann, Volker/0000-0001-8719-7608; Werner, Jens/0000-0001-7156-4370 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health intramural research program; Deutsche Forschungsgemeinschaft (Bonn, Germany) [We-4675/1-1] FX Supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health intramural research program. J.M.W. was supported by grant We-4675/1-1 from the Deutsche Forschungsgemeinschaft (Bonn, Germany). NR 29 TC 17 Z9 18 U1 2 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2014 VL 147 IS 1 BP 209 EP U343 DI 10.1053/j.gastro.2014.03.046 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AK4DE UT WOS:000338373400036 PM 24685721 ER PT J AU Chen, ZX Sturgill, D Qu, JX Jiang, HY Park, S Boley, N Suzuki, AM Fletcher, AR Plachetzki, DC FitzGerald, PC Artieri, CG Atallah, J Barmina, O Brown, JB Blankenburg, KP Clough, E Dasgupta, A Gubbala, S Han, Y Jayaseelan, JC Kalra, D Kim, YA Kovar, CL Lee, SL Li, MM Malley, JD Malone, JH Mathew, T Mattiuzzo, NR Munidasa, M Muzny, DM Ongeri, F Perales, L Przytycka, TM Pu, LL Robinson, G Thornton, RL Saada, N Scherer, SE Smith, HE Vinson, C Warner, CB Worley, KC Wu, YQ Zou, XY Cherbas, P Kellis, M Eisen, MB Piano, F Kionte, K Fitch, DH Sternberg, PW Cutter, AD Duff, MO Hoskins, RA Graveley, BR Gibbs, RA Bickel, PJ Kopp, A Carninci, P Celniker, SE Oliver, B Richards, S AF Chen, Zhen-Xia Sturgill, David Qu, Jiaxin Jiang, Huaiyang Park, Soo Boley, Nathan Suzuki, Ana Maria Fletcher, Anthony R. Plachetzki, David C. FitzGerald, Peter C. Artieri, Carlo G. Atallah, Joel Barmina, Olga Brown, James B. Blankenburg, Kerstin P. Clough, Emily Dasgupta, Abhijit Gubbala, Sai Han, Yi Jayaseelan, Joy C. Kalra, Divya Kim, Yoo-Ah Kovar, Christie L. Lee, Sandra L. Li, Mingmei Malley, James D. Malone, John H. Mathew, Tittu Mattiuzzo, Nicolas R. Munidasa, Mala Muzny, Donna M. Ongeri, Fiona Perales, Lora Przytycka, Teresa M. Pu, Ling-Ling Robinson, Garrett Thornton, Rebecca L. Saada, Nehad Scherer, Steven E. Smith, Harold E. Vinson, Charles Warner, Crystal B. Worley, Kim C. Wu, Yuan-Qing Zou, Xiaoyan Cherbas, Peter Kellis, Manolis Eisen, Michael B. Piano, Fabio Kionte, Karin Fitch, David H. Sternberg, Paul W. Cutter, Asher D. Duff, Michael O. Hoskins, Roger A. Graveley, Brenton R. Gibbs, Richard A. Bickel, Peter J. Kopp, Artyom Carninci, Piero Celniker, Susan E. Oliver, Brian Richards, Stephen TI Comparative validation of the D. melanogaster modENCODE transcriptome annotation SO GENOME RESEARCH LA English DT Article ID DROSOPHILA-MELANOGASTER; GENE-EXPRESSION; HUMAN GENOME; JUNK DNA; EVOLUTIONARY DYNAMICS; RNA-POLYMERASE; CAP-ANALYSIS; START SITE; ENCODE; SEQUENCE AB Accurate gene model annotation of reference genomes is critical for making them useful. The modENCODE project has improved the D. melanogaster genome annotation by using deep and diverse high-throughput data. Since transcriptional activity that has been evolutionarily conserved is likely to have an advantageous function, we have performed large-scale interspecific comparisons to increase confidence in predicted annotations. To support comparative genomics, we filled in divergence gaps in the Drosophila phylogeny by generating draft genomes for eight new species. For comparative transcriptome analysis, we generated mRNA expression profiles on 81 samples from multiple tissues and developmental stages of 15 Drosophila species, and we performed cap analysis of gene expression in D. melanogaster and D. pseudoobscura. We also describe conservation of four distinct core promoter structures composed of combinations of elements at three positions. Overall, each type of genomic feature shows a characteristic divergence rate relative to neutral models, highlighting the value of multispecies alignment in annotating a target genome that should prove useful in the annotation of other high priority genomes, especially human and other mammalian genomes that are rich in noncoding sequences. We report that the vast majority of elements in the annotation are evolutionarily conserved, indicating that the annotation will be an important springboard for functional genetic testing by the Drosophila community. C1 [Chen, Zhen-Xia; Sturgill, David; Artieri, Carlo G.; Clough, Emily; Malone, John H.; Mattiuzzo, Nicolas R.; Smith, Harold E.; Oliver, Brian] NIDDK, NIH, Bethesda, MD 20892 USA. [Qu, Jiaxin; Jiang, Huaiyang; Blankenburg, Kerstin P.; Gubbala, Sai; Han, Yi; Jayaseelan, Joy C.; Kalra, Divya; Kovar, Christie L.; Lee, Sandra L.; Li, Mingmei; Mathew, Tittu; Munidasa, Mala; Muzny, Donna M.; Ongeri, Fiona; Perales, Lora; Pu, Ling-Ling; Thornton, Rebecca L.; Saada, Nehad; Scherer, Steven E.; Warner, Crystal B.; Worley, Kim C.; Wu, Yuan-Qing; Zou, Xiaoyan; Gibbs, Richard A.; Richards, Stephen] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Park, Soo; Hoskins, Roger A.; Celniker, Susan E.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Dept Genome Dynam, Div Life Sci, Berkeley, CA 94720 USA. [Boley, Nathan; Brown, James B.; Robinson, Garrett; Bickel, Peter J.] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. [Suzuki, Ana Maria; Carninci, Piero] RIKEN Omics Sci Ctr, Technol Dev Grp, Yokohama, Kanagawa 2300045, Japan. [Suzuki, Ana Maria; Carninci, Piero] RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa 2300045, Japan. [Fletcher, Anthony R.; Malley, James D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20814 USA. [Plachetzki, David C.; Atallah, Joel; Barmina, Olga; Kopp, Artyom] Univ Calif Davis, Dept Ecol & Evolut, Davis, CA 95616 USA. [FitzGerald, Peter C.; Vinson, Charles] NCI, NIH, Bethesda, MD 20892 USA. [Dasgupta, Abhijit] NIAMSD, Clin Trials & Outcomes Branch, NIH, Bethesda, MD 20892 USA. [Kim, Yoo-Ah; Przytycka, Teresa M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Cherbas, Peter] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Eisen, Michael B.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Piano, Fabio; Kionte, Karin; Fitch, David H.] New York Univ, Dept Biol, New York, NY 10003 USA. [Sternberg, Paul W.] CALTECH, HHMI, Pasadena, CA 91125 USA. [Sternberg, Paul W.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Cutter, Asher D.] Univ Toronto, Dept Ecol & Evolutionary Biol, Toronto, ON M5S 3B2, Canada. [Duff, Michael O.; Graveley, Brenton R.] Univ Connecticut, Inst Syst Genom, Dept Genet & Dev Biol, Ctr Hlth, Farmington, CT 06030 USA. RP Oliver, B (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM briano@helix.nih.gov RI Cutter, Asher/A-5647-2009; Carninci, Piero/K-1568-2014; Kalra, Divya/N-5453-2014; JAYASEELAN, JOY CHRISTINA/F-9824-2015; Brown, James/H-2971-2015; OI Carninci, Piero/0000-0001-7202-7243; JAYASEELAN, JOY CHRISTINA/0000-0002-7759-0139; Graveley, Brenton/0000-0001-5777-5892 FU Intramural Research Programs of the National Institutes of Health, NIDDK [DK015600-18]; extramural National Institutes of Health program [1ROIGM082843, U01HB004271] FX We thank modENCODE and laboratory members for discussion. This research was supported by the Intramural Research Programs of the National Institutes of Health, NIDDK (DK015600-18 to B.O.) and by the extramural National Institutes of Health program (1ROIGM082843 to A. K.; U01HB004271 to S. E. C.). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland (http://biowulf.nih.gov). NR 65 TC 33 Z9 33 U1 1 U2 18 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD JUL PY 2014 VL 24 IS 7 BP 1209 EP 1223 DI 10.1101/gr.159384.113 PG 15 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA AK1OS UT WOS:000338185000014 PM 24985915 ER PT J AU Simons-Morton, BG Bingham, CR Falk, EB Li, KG Pradhan, AK Ouimet, MC Almani, F Shope, JT AF Simons-Morton, Bruce G. Bingham, C. Raymond Falk, Emily B. Li, Kaigang Pradhan, Anuj K. Ouimet, Marie Claude Almani, Farideh Shope, Jean T. TI Experimental Effects of Injunctive Norms on Simulated Risky Driving Among Teenage Males SO HEALTH PSYCHOLOGY LA English DT Article DE social norms; social influence; risk behavior; adolescents; randomized trial ID PEER INFLUENCE; DECISION-MAKING; DRIVERS; PASSENGERS; ADOLESCENT; CRASHES; BEHAVIORS; DRINKING; FRIENDS AB Objective: Teenage passengers affect teenage driving performance, possibly by social influence. To examine the effect of social norms on driving behavior, male teenagers were randomly assigned to drive in a simulator with a peer-aged confederate to whom participants were primed to attribute either risk-accepting or risk-averse social norms. It was hypothesized that teenage drivers would engage in more risky driving behavior in the presence of peer passengers than no passengers, and with a risk-accepting compared with a risk-averse passenger. Method: 66 male participants aged 16 to 18 years holding a provisional driver license were randomized to drive with a risk-accepting or risk-averse passenger in a simulator. Failure to Stop at a red light and percent Time in Red (light) were measured as primary risk-relevant outcomes of interest at 18 intersections, while driving once alone and once with their assigned passenger. Results: The effect of passenger presence on risky driving was moderated by passenger type for Failed to Stop in a generalized linear mixed model (OR = 1.84, 95% CI [1.19, 2.86], p < .001), and percent Time in Red in a mixed model (B = 7.71, 95% CI [1.54, 13.87], p < .05). Conclusions: Exposure of teenage males to a risk-accepting confederate peer increased teenage males' risky simulated driving behavior compared with exposure to a risk-averse confederate peer. These results indicate that variability in teenage risky driving could be partially explained by social norms. C1 [Simons-Morton, Bruce G.; Li, Kaigang] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, Bethesda, MD 20892 USA. [Bingham, C. Raymond; Falk, Emily B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Pradhan, Anuj K.; Almani, Farideh; Shope, Jean T.] Univ Michigan, Transportat Res Inst, Ann Arbor, MI 48109 USA. [Ouimet, Marie Claude] Univ Sherbrooke, Fac Med & Hlth Sci, Sherbrooke, PQ J1K 2R1, Canada. RP Simons-Morton, BG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd,Room 7B13M, Bethesda, MD 20892 USA. EM Mortonb@mail.nih.gov OI Pradhan, Anuj/0000-0002-7612-4208; Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275201000007C] FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, contract # HHSN275201000007C. NR 39 TC 12 Z9 12 U1 4 U2 24 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD JUL PY 2014 VL 33 IS 7 BP 616 EP 627 DI 10.1037/a0034837 PG 12 WC Psychology, Clinical; Psychology SC Psychology GA AK5CS UT WOS:000338442500005 PM 24467258 ER PT J AU Phillips, KA Epstein, DH Vahabzadeh, M Mezghanni, M Lin, JL Preston, KL AF Phillips, Karran A. Epstein, David H. Vahabzadeh, Massoud Mezghanni, Mustapha Lin, Jia-Ling Preston, Kenzie L. TI Substance Use and Hepatitis C: An Ecological Momentary Assessment Study SO HEALTH PSYCHOLOGY LA English DT Article DE hepatitis C; ecological momentary assessment; craving; triggers; mood ID INJECTING DRUG-USERS; HUMAN-IMMUNODEFICIENCY-VIRUS; SEVERE MENTAL-ILLNESS; METHADONE-MAINTENANCE; RISK BEHAVIORS; DAILY-LIFE; HIV RISK; INFECTION; PREVALENCE; ABUSE AB Objective: The objective of this study was to assess craving and mood related to opioid and cocaine use among asymptomatic hepatitis C virus (HCV)+ and HCV-methadone patients who have not started antiviral treatment. Methods: In this 28-week prospective ecological momentary assessment (EMA) study, 114 methadone-maintained, heroin-and cocaine-abusing individuals reported from the field in real time on their mood, craving, exposure to drug-use triggers, and drug use via handheld computers. Results: Sixty-one percent were HCV+; none were overtly symptomatic or receiving HCV treatment. HCV status was not associated with age, sex, race, or past-30-day or lifetime heroin or cocaine use. In event-contingent EMA entries, HCV+ individuals more often attributed use to having been bored, worried, or sad; feeling uncomfortable; or others being critical of them compared with HCV-participants. In randomly prompted EMA entries, HCV+ participants reported significantly more exposure to drug-use triggers, including handling >=$10, seeing cocaine or heroin, seeing someone being offered/use cocaine or heroin, being tempted to use cocaine, and wanting to see what would happen if they used just a little cocaine or heroin. Conclusions: HCV+ individuals experienced more negative moods and more often cited these negative moods as causes for drug use. HCV+ individuals reported greater exposure to environmental drug-use triggers, but they did not more frequently cite these as causes for drug use. The EMA data reported here suggest that HCV+ intravenous drug users may experience more labile mood and more reactivity to mood than HCV-intravenous drug users. The reason for the difference is not clear, but HCV status may be relevant to tailoring of treatment. C1 [Phillips, Karran A.; Epstein, David H.; Vahabzadeh, Massoud; Lin, Jia-Ling; Preston, Kenzie L.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Mezghanni, Mustapha] Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. RP Phillips, KA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd,BRC Bldg,Suite 200, Baltimore, MD 21224 USA. EM phillipsk@nida.nih.gov FU Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health. These data were presented at the College on Problems of Drug Dependence meeting in June 2011 and the Association of Medical Education and Research in Substance Abuse meeting in November 2011. NR 63 TC 1 Z9 1 U1 0 U2 12 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD JUL PY 2014 VL 33 IS 7 BP 710 EP 719 DI 10.1037/hea0000087 PG 10 WC Psychology, Clinical; Psychology SC Psychology GA AK5CS UT WOS:000338442500017 PM 24977312 ER PT J AU Harris, PR Brearley, I Sheeran, P Barker, M Klein, WMP Creswell, JD Levine, JM Bond, R AF Harris, Peter R. Brearley, Irina Sheeran, Paschal Barker, Margo Klein, William M. P. Creswell, J. David Levine, John M. Bond, Rod TI Combining Self-Affirmation With Implementation Intentions to Promote Fruit and Vegetable Consumption SO HEALTH PSYCHOLOGY LA English DT Article DE health behavior change; healthy eating; implementation intentions; motivation; self-affirmation ID HEALTH BEHAVIOR-CHANGE; RANDOMIZED CONTROLLED-TRIAL; POSITIVE-AFFECT; PHYSICAL-ACTIVITY; RISK INFORMATION; MODERATING ROLE; HEART-DISEASE; INTERVENTION; METAANALYSIS; ADULTS AB Objective: The current study tested whether self-affirmation in the context of a threatening health message helps promote a health behavior (fruit and vegetable consumption) over a 3-month period, and whether adding a manipulation to support the translation of intentions into behavior (an implementation intentions induction) enhances the impact of self-affirmation. Methods: Participants (N = 332, 71% women) reported their baseline consumption and were randomly assigned to condition in a 2 (selfaffirmation: yes, no) X 2 (implementation intentions: formed, not formed) between-subjects factorial design. They completed a self-affirmation/control task and then read a health communication advising eating at least 5 portions of fruit and vegetables daily. Next participants reported intentions for behavior change, after which they formed/did not form relevant implementation intentions. Consumption was measured again 7 days and 3 months postintervention. Results: Self-affirmed (vs. nonaffirmed) participants reported eating more fruit and vegetables at both follow-ups. Forming (vs. not forming) implementation intentions was also beneficial for consumption. At 7 days, there was also a significant self-affirmation X implementation intentions interaction: consumption was highest when self-affirmed participants also formed implementation intentions. Conclusions: The present study offers new evidence concerning the impact and durability of self-affirmation on health behaviors and the role of implementation intentions in enhancing the impact of self-affirmation. C1 [Harris, Peter R.; Brearley, Irina; Sheeran, Paschal] Univ Sheffield, Dept Psychol, Sheffield S10 2TN, S Yorkshire, England. [Barker, Margo] Univ Sheffield, Dept Oncol, Sheffield S10 2TN, S Yorkshire, England. [Klein, William M. P.] NCI, Bethesda, MD 20892 USA. [Klein, William M. P.; Levine, John M.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Creswell, J. David] Carnegie Mellon Univ, Dept Psychol, Pittsburgh, PA 15213 USA. [Bond, Rod] Univ Sussex, Sch Psychol, Falmer BN1 9QN, Sussex, England. RP Harris, PR (reprint author), Univ Sussex, Sch Psychol, Pevensey Bldg, Falmer BN1 9QN, Sussex, England. EM p.r.harris@sussex.ac.uk FU National Science Foundation [BCS-0924387] FX We thank Kerry Fox for assistance with coding the implementation intention plans. This material is based upon work supported by the National Science Foundation under Grant BCS-0924387. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. NR 38 TC 18 Z9 18 U1 7 U2 36 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD JUL PY 2014 VL 33 IS 7 BP 729 EP 736 DI 10.1037/hea0000065 PG 8 WC Psychology, Clinical; Psychology SC Psychology GA AK5CS UT WOS:000338442500019 PM 24490648 ER PT J AU Battiwalla, M Fakhrejahani, F Jain, NA Klotz, JK Pophali, PA Draper, D Haggerty, J McIver, Z Jelinek, J Chawla, K Ito, S Barrett, J AF Battiwalla, Minoo Fakhrejahani, Farhad Jain, Natasha A. Klotz, Jeffrey K. Pophali, Priyanka A. Draper, Debbie Haggerty, Janice McIver, Zachariah Jelinek, James Chawla, Kamna Ito, Sawa Barrett, John TI Radiation exposure from diagnostic procedures following allogeneic stem cell transplantation - How much is acceptable? SO HEMATOLOGY LA English DT Article DE HSCT; Diagnostic; Radiation; CT; Outcome ID ATOMIC-BOMB SURVIVORS; IONIZING-RADIATION; CANCER-RISKS; SOLID CANCERS; CHILDREN; ADULTS AB Background: Frequent diagnostic radiology procedures in allogeneic stem cell transplantation (SCT) recipients raise concern about the potential harm from incidental radiation. Objectives: To determine the cumulative radiation dose from diagnostic studies in allogeneic SCT and its impact on clinical outcome. Patients and methods: This retrospective cohort study was conducted to determine the cumulative radiation dose from diagnostic studies following SCT. Sixty-four consecutive patients with hematological malignancies in a single tertiary care institution underwent total body irradiation (TBI)-based myeloablative conditioning followed by six of six human leukocyte antigen (HLA)-identical sibling allogeneic SCT. The median follow-up was 3 years. The cumulative effective dose in mSv from diagnostic radiological studies in the peritransplant period from day -30 to day +200 was calculated for each patient and its impact on overall survival and non-relapse mortality was determined. Results: The median cumulative radiation exposure from diagnostic radiological procedures was 92 mSv (range 1.2-300), representing about 30x the normal annual background radiation for the population and 10% of the 1200 cGy TBI dose used in conditioning. Sixty-five percent of the cumulative radiation exposure was delivered between day +1 and day 100 and computed tomography scans contributed 88%. In multivariate analysis, diagnostic procedures did not significantly impact clinical outcomes. Conclusions: While radiation exposure from diagnostic procedures did not impact clinical outcomes the risk of secondary cancers in long-term survivors is likely to be increased. Our results indicate that patients who are acutely ill for prolonged periods can receive clinically significant radiation doses during their hospital care. Our findings should prompt attempts to limit radiation exposure from diagnostic procedures in post-SCT recipients C1 [Battiwalla, Minoo; Fakhrejahani, Farhad; Jain, Natasha A.; Klotz, Jeffrey K.; Pophali, Priyanka A.; Draper, Debbie; Haggerty, Janice; McIver, Zachariah; Chawla, Kamna; Ito, Sawa; Barrett, John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Jelinek, James] Washington Hosp Ctr, Dept Radiol, Washington, DC 20010 USA. RP Battiwalla, M (reprint author), NHLBI, Hematol Branch, NIH, Room 5-3581,Bldg 10 CRC,10 Ctr Dr, Bethesda, MD 20892 USA. EM minoo.battiwalla@nih.gov RI Pophali, Priyanka/P-8646-2016 FU Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 22 TC 0 Z9 0 U1 0 U2 0 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1024-5332 EI 1607-8454 J9 HEMATOLOGY JI Hematology PD JUL PY 2014 VL 19 IS 5 BP 275 EP 279 DI 10.1179/1607845413Y.0000000131 PG 5 WC Hematology SC Hematology GA AK3SU UT WOS:000338345800004 PM 24094072 ER PT J AU Louis, GMB AF Louis, Germaine M. Buck TI Male fecundity and its implications for health and disease across the lifespan SO HUMAN REPRODUCTION LA English DT Editorial Material ID SEMEN QUALITY C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. EM louisg@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490 NR 12 TC 1 Z9 2 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD JUL PY 2014 VL 29 IS 7 BP 1351 EP 1352 DI 10.1093/humrep/deu108 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AK0SV UT WOS:000338126500002 PM 24838702 ER PT J AU Waller, AS Yamada, T Kristensen, DM Kultima, JR Sunagawa, S Koonin, EV Bork, P AF Waller, Alison S. Yamada, Takuji Kristensen, David M. Kultima, Jens Roat Sunagawa, Shinichi Koonin, Eugene V. Bork, Peer TI Classification and quantification of bacteriophage taxa in human gut metagenomes SO ISME JOURNAL LA English DT Article DE human gut; metagenomics; phage ID OCEAN SAMPLING EXPEDITION; HUMAN FECES; BACTERIAL PATHOGENS; FECAL MICROBIOTA; VIRAL COMMUNITY; VIRUSES; DIVERSITY; PHAGES; EVOLUTION; DISEASE AB Bacteriophages have key roles in microbial communities, to a large extent shaping the taxonomic and functional composition of the microbiome, but data on the connections between phage diversity and the composition of communities are scarce. Using taxon-specific marker genes, we identified and monitored 20 viral taxa in 252 human gut metagenomic samples, mostly at the level of genera. On average, five phage taxa were identified in each sample, with up to three of these being highly abundant. The abundances of most phage taxa vary by up to four orders of magnitude between the samples, and several taxa that are highly abundant in some samples are absent in others. Significant correlations exist between the abundances of some phage taxa and human host metadata: for example, 'Group 936 lactococcal phages' are more prevalent and abundant in Danish samples than in samples from Spain or the United States of America. Quantification of phages that exist as integrated prophages revealed that the abundance profiles of prophages are highly individual-specific and remain unique to an individual over a 1-year time period, and prediction of prophage lysis across the samples identified hundreds of prophages that are apparently active in the gut and vary across the samples, in terms of presence and lytic state. Finally, a prophage-host network of the human gut was established and includes numerous novel host-phage associations. C1 [Waller, Alison S.; Kultima, Jens Roat; Sunagawa, Shinichi; Bork, Peer] European Mol Biol Lab, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany. [Yamada, Takuji] Tokyo Inst Technol, Dept Biol Informat, Grad Sch Biosci & Biotechnol, Yokohama, Kanagawa 227, Japan. [Kristensen, David M.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Bork, P (reprint author), European Mol Biol Lab, Struct & Computat Biol Unit, Meyerhofstr 1, D-69117 Heidelberg, Germany. EM bork@embl.de RI Sunagawa, Shinichi/D-9715-2011; Bork, Peer/F-1813-2013 OI Sunagawa, Shinichi/0000-0003-3065-0314; Bork, Peer/0000-0002-2627-833X FU International Human Microbiome Consortium (IHMS); US Department of Health and Human Services FX ASW was supported by a grant from the International Human Microbiome Consortium (IHMS). DMK and EVK are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine, NIH). NR 59 TC 24 Z9 24 U1 8 U2 58 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1751-7362 EI 1751-7370 J9 ISME J JI ISME J. PD JUL PY 2014 VL 8 IS 7 BP 1391 EP 1402 DI 10.1038/ismej.2014.30 PG 12 WC Ecology; Microbiology SC Environmental Sciences & Ecology; Microbiology GA AK1XZ UT WOS:000338213900005 PM 24621522 ER PT J AU Madkour, AS de Looze, M Ma, P Halpern, CT Farhat, T ter Bogt, TFM Ehlinger, V Gabhainn, SN Currie, C Godeau, E AF Madkour, Aubrey Spriggs de Looze, Margaretha Ma, Ping Halpern, Carolyn Tucker Farhat, Tilda ter Bogt, Tom F. M. Ehlinger, Virginie Gabhainn, Saoirse Nic Currie, Candace Godeau, Emmanuelle TI Macro-Level Age Norms for the Timing of Sexual Initiation and Adolescents' Early Sexual Initiation in 17 European Countries SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Europe; Adolescents; Sexual behavior; Cross-national comparison; Culture; Multilevel modeling ID URBAN MINORITY YOUTH; AFRICAN-AMERICAN; PROBLEM BEHAVIOR; UNITED-STATES; 5 NATIONS; INTERCOURSE; HEALTH; DEBUT; YOUNG; ADULTHOOD AB Purpose: To examine the relationship between country-level age norms for sexual initiation timing and early sexual initiation (ESI) among adolescent boys and girls. Methods: Nationally representative data from 17 countries that participated in the 2006/2007 European Social Survey (ESS-3, n = 33,092) and the 2005/2006 Health Behaviour in School-Aged Children Study (HBSC, n = 27,702) were analyzed. Age norms were measured as the average country-level response to an item asking the age at which ESS respondents believed someone is too young to have sexual intercourse. HBSC respondents (aged 14-16 years) self-reported age at sexual initiation, which we defined as early (<15 years) or not early (>= 15 years or no initiation). Control variables included age, family affluence, perceived socioeconomic status, family living arrangement, substance use, school attachment, and country-level legal age of consent. Multivariable three-level logistic models with random intercepts were run separately by sex. Results: In multivariable analyses, higher overall age norms were associated with reduced likelihood of ESI among girls (AOR .60, 95% CI .45-.79); associations with ESI were stronger for parent cohort (ages 31-65 years) norms (AOR .37, 95% CI .23-.58) than for peer cohort (ages 15-20 years) norms (AOR .60, 95% CI .49-.74). For boys, overall norms were also significantly negatively associated with ESI (AOR .68, 95% CI .46-.99), as were parent cohort norms (AOR .66, 95% CI .45-.96). Peer cohort norms were not significantly related to boys' ESI. Conclusion: Macrolevel cultural norms may impact adolescents' sexual initiation timing. Research exploring the sexual health outcomes of early initiators in countries with contrasting age norms is warranted. (C) 2014 Society for Adolescent Health and Medicine. All rights reserved. C1 [Madkour, Aubrey Spriggs; Ma, Ping] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Global Community Hlth & Behav Sci, New Orleans, LA 70118 USA. [de Looze, Margaretha] Univ Utrecht, Fac Social & Behav Sci, Dept Child & Adolescent Studies, Utrecht, Netherlands. [Halpern, Carolyn Tucker] Gillings Sch Global Publ Hlth, Dept Maternal & Child Hlth, Chapel Hill, NC USA. [Farhat, Tilda] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Bethesda, MD USA. [ter Bogt, Tom F. M.] Univ Utrecht, Dept Interdisciplinary Social Sci, Utrecht, Netherlands. [Ehlinger, Virginie; Godeau, Emmanuelle] Univ Toulouse 3, Res Unit Perinatal Epidemiol & Childhood Disabil, F-31062 Toulouse, France. [Gabhainn, Saoirse Nic] Natl Univ Ireland, Dept Hlth Promot, Aras Moyola, Galway, Ireland. [Currie, Candace] Sch Med, Child & Adolescent Hlth Res Unit, St Andrews, Fife, Scotland. [Godeau, Emmanuelle] Serv Med Rectorat Toulouse, Toulouse, France. RP Madkour, AS (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Global Community Hlth & Behav Sci, New Orleans, LA 70118 USA. EM aspriggs@tulane.edu FU Maternal and Child Health Bureau of the Health Resources and Services Administration [T76MC04927]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN2672008000009 C]; Maternal and Child Health Bureau of the Health Resources and Services Administration FX This research was supported in part by grant T76MC04927 from the Maternal and Child Health Bureau of the Health Resources and Services Administration and by grant HHSN2672008000009 C from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Maternal and Child Health Bureau of the Health Resources and Services Administration. NR 38 TC 3 Z9 4 U1 5 U2 23 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JUL PY 2014 VL 55 IS 1 BP 114 EP 121 DI 10.1016/j.jadohealth.2013.12.008 PG 8 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA AK2RI UT WOS:000338266700017 PM 24508092 ER PT J AU Tong, SQ Zhang, H Shen, MM Ito, Y Yan, JZ AF Tong, Shengqiang Zhang, Hu Shen, Mangmang Ito, Yoichiro Yan, Jizhong TI Enantioseparation of mandelic acid derivatives by high performance liquid chromatography with substituted beta-cyclodextrin as chiral mobile phase additive and evaluation of inclusion complex formation SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Mandelic acid derivatives; Chiral separation; Hydroxypropyl-beta-cyclodextrin; Sulfobutyl ether-beta-cyclodextrin; High performance liquid chromatography ID COUNTER-CURRENT CHROMATOGRAPHY; ALPHA-CYCLOHEXYLMANDELIC ACID; ENANTIOMERIC SEPARATION; HPLC; RECOGNITION; SELECTOR; EXTRACTION; RESOLUTION; DRUGS AB The enantioseparation of ten mandelic acid derivatives was performed by reverse phase high performance liquid chromatography with hydroxypropy1-beta-cyclodextrin (HP-beta-CD) or sulfobutyl ether-beta-cyclodextrin (SBE-beta-CD) as chiral mobile phase additives, in which inclusion complex formations between cyclodextrins and enantiomers were evaluated. The effects of various factors such as the composition of mobile phase, concentration of cyclodextrins and column temperature on retention and enantioselectivity were studied. The peak resolutions and retention time of the enantiomers were strongly affected by the pH, the organic modifier and the type of beta-cyclodextrin in the mobile phase, while the concentration of buffer solution and temperature had a relatively low effect on resolutions. Enantioseparations were successfully achieved on a Shimpack CLC-ODS column (150 x 4.6 mm i.d., 5 mu m). The mobile phase was a mixture of acetonitrile and 0.10 mol L-1 of phosphate buffer at pH 2.68 containing 20 mmol L-1 of HP-beta-CD or SBE-beta-CD. Semi-preparative enantioseparation of about 10 mg of alpha-cyclohexylmandelic acid and alpha-cyclopentylmandelic acid were established individually. Cyclodextrin-enantiomer complex stoichiometries as well as binding constants were investigated. Results showed that stoichiometries for all the inclusion complex of cyclodextrin-enantiomers were 1:1. (C) 2014 Elsevier B.V. All rights reserved. C1 [Tong, Shengqiang; Zhang, Hu; Shen, Mangmang; Yan, Jizhong] Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou 310032, Zhejiang, Peoples R China. [Tong, Shengqiang; Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Yan, JZ (reprint author), Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou 310032, Zhejiang, Peoples R China. EM zyx@zjut.edu.cn FU National Natural Science Foundation of China [21105090]; Department of Education of Zhejiang Province of China [pd2013031] FX The authors are greatly indebted to National Natural Science Foundation of China (No. 21105090) and Department of Education of Zhejiang Province of China (pd2013031). S.Q. Tong also thanks Personnel Department of Zhejiang University of Technology for providing the visiting scholar program (2011). NR 28 TC 16 Z9 20 U1 3 U2 44 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 EI 1873-376X J9 J CHROMATOGR B JI J. Chromatogr. B PD JUL 1 PY 2014 VL 962 BP 44 EP 51 DI 10.1016/j.jchromb.2014.05.026 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AK4PO UT WOS:000338406800007 PM 24893270 ER PT J AU Foster, BL Ramnitz, MS Gafni, RI Burke, AB Boyce, AM Lee, JS Wright, JT Akintoye, SO Somerman, MJ Collins, MT AF Foster, B. L. Ramnitz, M. S. Gafni, R. I. Burke, A. B. Boyce, A. M. Lee, J. S. Wright, J. T. Akintoye, S. O. Somerman, M. J. Collins, M. T. TI Rare Bone Diseases and Their Dental, Oral, and Craniofacial Manifestations SO JOURNAL OF DENTAL RESEARCH LA English DT Review DE fibrous dysplasia of bone; osteogenesis imperfecta; familial hypophosphatemic rickets; hypophosphatasia; hyperphosphatemic familial tumoral calcinosis; Gorham-Stout disease ID FAMILIAL TUMORAL CALCINOSIS; MCCUNE-ALBRIGHT-SYNDROME; GORHAM-STOUT-DISEASE; LINKED HYPOPHOSPHATEMIC RICKETS; ENZYME-REPLACEMENT THERAPY; OSTEOGENESIS IMPERFECTA; FIBROUS DYSPLASIA; MASSIVE OSTEOLYSIS; MISSENSE MUTATION; DISAPPEARING BONE AB Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease. C1 [Foster, B. L.; Somerman, M. J.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Ramnitz, M. S.] NICHHD, NIH, Bethesda, MD 20892 USA. [Gafni, R. I.; Burke, A. B.; Boyce, A. M.; Collins, M. T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Boyce, A. M.] Childrens Natl Med Ctr, Bone Hlth Program, Div Orthoped & Sports Med, Washington, DC 20010 USA. [Boyce, A. M.] Childrens Natl Med Ctr, Div Endocrinol & Diabet, Washington, DC 20010 USA. [Lee, J. S.] Natl Inst Dent & Craniofacial Res, Off Clin Director, NIH, Bethesda, MD USA. [Wright, J. T.] Univ N Carolina, Dept Pediat Dent, Sch Dent, Chapel Hill, NC 27599 USA. [Akintoye, S. O.] Univ Penn, Sch Dent Med, Dept Oral Med, Philadelphia, PA 19104 USA. [Somerman, M. J.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Foster, BL (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. EM brian.foster@nih.gov RI Foster, Brian/H-8375-2015 OI Foster, Brian/0000-0003-3444-0576 FU National Institute of Dental and Craniofacial Research (NIDCR); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); NIDCR/ National Institutes of Health (NIH) [1R56DE022932] FX This research was supported by the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Intramural Research Programs, and by NIDCR/ National Institutes of Health (NIH) grant 1R56DE022932 (SOA). We thank Alan Hoofring (NIH) for Fig. 1 illustration. We recognize the International Association for Dental Research (IADR) and its Executive Director, Dr. Christopher Fox, for calling for this timely review, acknowledge the important support of patient advocacy groups, and thank affected individuals who have participated in studies and provided consent to be included in publications. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 63 TC 13 Z9 14 U1 4 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD JUL PY 2014 VL 93 IS 7 SU 1 BP 7 EP 19 DI 10.1177/0022034514529150 PG 13 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AK5XP UT WOS:000338500700002 PM 24700690 ER PT J AU Jena, AB Sun, EC Prasad, V AF Jena, Anupam B. Sun, Eric C. Prasad, Vinay TI Does the Declining Lethality of Gunshot Injuries Mask a Rising Epidemic of Gun Violence in the United States? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID TRAUMA SYSTEM-DEVELOPMENT; FIREARM; DECADE; RATES AB Recent mass shootings in the U.S. have reignited the important public health debate concerning measures to decrease the epidemic of gun violence. Editorialists and gun lobbyists have criticized the recent focus on gun violence, arguing that gun-related homicide rates have been stable in the last decade. While true, data from the U.S. Centers for Disease Control and Prevention also demonstrate that although gun-related homicide rates were stable between 2002 and 2011, rates of violent gunshot injuries increased. These seemingly paradoxical trends may reflect the declining lethality of gunshot injuries brought about by surgical advances in the care of the patient with penetrating trauma. Focusing on gun-related homicide rates as a summary statistic of gun violence, rather than total violent gunshot injuries, can therefore misrepresent the rising epidemic of gun violence in the U.S. C1 [Jena, Anupam B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Dept Med, Cambridge, MA USA. [Jena, Anupam B.] NBER, Cambridge, MA 02138 USA. [Sun, Eric C.] Stanford Univ Hosp, Dept Anesthesia, Stanford, CA 94305 USA. [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu; esun1@stanford.edu; vinayak.prasad@nih.gov FU Office of the Director, National Institutes of Health [1DP5OD017897-01] FX Dr. Jena had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Support was provided by the Office of the Director, National Institutes of Health (1DP5OD017897-01, Dr. Jena). NR 23 TC 9 Z9 9 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2014 VL 29 IS 7 BP 1065 EP 1069 DI 10.1007/s11606-014-2779-z PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK1VW UT WOS:000338207100023 PM 24452421 ER PT J AU Onda, M Ghoreschi, K Steward-Tharp, S Thomas, C O'Shea, JJ Pastan, IH FitzGerald, DJ AF Onda, Masanori Ghoreschi, Kamran Steward-Tharp, Scott Thomas, Craig O'Shea, John J. Pastan, Ira H. FitzGerald, David J. TI Tofacitinib Suppresses Antibody Responses to Protein Therapeutics in Murine Hosts SO JOURNAL OF IMMUNOLOGY LA English DT Article ID B-CELL EPITOPES; IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; RECEPTOR-DEFICIENT MICE; PHASE-I TRIAL; RECOMBINANT IMMUNOTOXIN; ANTITUMOR-ACTIVITY; HEMATOLOGIC MALIGNANCIES; RHEUMATOID-ARTHRITIS; LYMPHOID DEVELOPMENT; ANIMAL TOXICITY AB Immunogenicity remains the "Achilles' heel" of protein-based therapeutics. Anti-drug Abs produced in response to protein therapeutics can severely limit both the safety and efficacy of this expanding class of agent. In this article, we report that monotherapy of mice with tofacitinib (the JAK inhibitor) quells Ab responses to an immunotoxin derived from the bacterial protein Pseudomonas exotoxin A, as well as to the model Ag keyhole limpet hemocyanin. Thousand-fold reductions in IgG1 titers to both Ags were observed 21 d post immunization. In fact, suppression was evident for all IgG isotypes and IgM. A reduction in IgG3 production was also noted with a thymus-independent type II Ag. Mechanistic investigations revealed that tofacitinib treatment led to reduced numbers of CD127(+) pro-B cells. Furthermore, we observed fewer germinal center B cells and the impaired formation of germinal centers of mice treated with tofacitinib. Because normal Ig levels were still present during tofacitinib treatment, this agent specifically reduced anti-drug Abs, thus preserving the potential efficacy of biological therapeutics, including those used as cancer therapeutics. C1 [Onda, Masanori; Pastan, Ira H.; FitzGerald, David J.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ghoreschi, Kamran; Steward-Tharp, Scott; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Thomas, Craig] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Onda, M (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5110, Bethesda, MD 20892 USA. EM ondam@mail.nih.gov; fitzgerd@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Institute of Arthritis and Musculoskeletal and Skin Disease FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the National Institute of Arthritis and Musculoskeletal and Skin Disease. NR 44 TC 12 Z9 12 U1 0 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2014 VL 193 IS 1 BP 48 EP 55 DI 10.4049/jimmunol.1400063 PG 8 WC Immunology SC Immunology GA AK5BN UT WOS:000338438900009 PM 24890727 ER PT J AU Crites, TJ Padhan, K Muller, J Krogsgaard, M Gudla, PR Lockett, SJ Varma, R AF Crites, Travis J. Padhan, Kartika Muller, James Krogsgaard, Michelle Gudla, Prabhakar R. Lockett, Stephen J. Varma, Rajat TI TCR Microclusters Pre-Exist and Contain Molecules Necessary for TCR Signal Transduction SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-ACTIVATION; IMMUNOLOGICAL SYNAPSE; NANOSCALE ORGANIZATION; RECEPTOR MICROCLUSTERS; PEPTIDE; ANTIGEN; LAT; SENSITIVITY; COMPLEX; PROTEIN AB TCR-dependent signaling events have been observed to occur in TCR microclusters. We found that some TCR microclusters are present in unstimulated murine T cells, indicating that the mechanisms leading to microcluster formation do not require ligand binding. These pre-existing microclusters increase in absolute number following engagement by low-potency ligands. This increase is accompanied by an increase in cell spreading, with the result that the density of TCR microclusters on the surface of the T cell is not a strong function of ligand potency. In characterizing their composition, we observed a constant number of TCRs in a microcluster, constitutive exclusion of the phosphatase CD45, and preassociation with the signaling adapters linker for activation of T cells and growth factor receptor-bound protein 2. The existence of TCR microclusters prior to ligand binding in a state that is conducive for the initiation of downstream signaling could explain, in part, the rapid kinetics with which TCR signal transduction occurs. C1 [Crites, Travis J.; Padhan, Kartika; Muller, James; Varma, Rajat] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Muller, James] NYU, Sch Med, Skirball Inst Biomol Med, Mol Pathogenesis Program, New York, NY 10016 USA. [Muller, James; Krogsgaard, Michelle] NYU, Sch Med, Dept Pathol, New York, NY 10026 USA. [Krogsgaard, Michelle] NYU, Sch Med, Inst Canc, New York, NY 10026 USA. [Gudla, Prabhakar R.; Lockett, Stephen J.] Frederick Natl Lab Canc Res, Opt Microscopy & Anal Lab, Frederick, MD 21702 USA. RP Varma, R (reprint author), NIAID, NIH, 9000 Rockville Pike,Bldg 4,Room 431, Bethesda, MD 20892 USA. EM rajat.varma@nih.gov FU Intramural Research Program of the 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 Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health and in part by federal funds from the National Cancer Institute, National Institutes of Health under Contract HHSN261200800001E. NR 40 TC 13 Z9 13 U1 0 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2014 VL 193 IS 1 BP 56 EP 67 DI 10.4049/jimmunol.1400315 PG 12 WC Immunology SC Immunology GA AK5BN UT WOS:000338438900010 PM 24860189 ER PT J AU Sadhukhan, S Sarkar, K Taylor, M Candotti, F Vyas, YM AF Sadhukhan, Sanjoy Sarkar, Koustav Taylor, Matthew Candotti, Fabio Vyas, Yatin M. TI Nuclear Role of WASp in Gene Transcription Is Uncoupled from Its ARP2/3-Dependent Cytoplasmic Role in Actin Polymerization SO JOURNAL OF IMMUNOLOGY LA English DT Article ID WISKOTT-ALDRICH-SYNDROME; REGULATORY T-CELLS; SYNDROME PROTEIN; ARP2/3 COMPLEX; IMMUNOLOGICAL SYNAPSE; ACTIVATION; HOMEOSTASIS; MUTATIONS; THROMBOCYTOPENIA; DEFICIENT AB Defects in Wiskott-Aldrich Syndrome protein (WASp) underlie development of WAS, an X-linked immunodeficiency and auto-immunity disorder of childhood. Nucleation-promoting factors (NPFs) of the WASp family generate F-actin in the cytosol via the VCA (verprolin-homology, cofilin-homology, and acidic) domain and support RNA polymerase II-dependent transcription in the nucleus. Whether nuclear-WASp requires the integration of its actin-related protein (ARP) 2/3-dependent cytoplasmic function to reprogram gene transcription, however, remains unresolved. Using the model of human T-H cell differentiation, we find that WASp has a functional nuclear localizing and nuclear exit sequences, and accordingly, its effects on transcription are controlled mainly at the level of its nuclear entry and exit via the nuclear pore. Human WASp does not use its VCA-dependent, ARP2/3-driven, cytoplasmic effector mechanisms to support histone H3K4 methyltransferase activity in the nucleus of T(H)1-skewed cells. Accordingly, an isolated deficiency of nuclear-WASp is sufficient to impair the transcriptional reprogramming of TBX21 and IFNG promoters in T(H)1-skewed cells, whereas an isolated deficiency of cytosolic-WASp does not impair this process. In contrast, nuclear presence of WASp in T(H)2-skewed cells is small, and its loss does not impair transcriptional reprogramming of GATA3 and IL4 promoters. Our study unveils an ARP2/3: VCA-independent function of nuclear-WASp in T(H)1 gene activation that is uncoupled from its cytoplasmic role in actin polymerization. C1 [Sadhukhan, Sanjoy; Sarkar, Koustav; Taylor, Matthew; Vyas, Yatin M.] Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Div Pediat Hematol Oncol, Pittsburgh, PA 15213 USA. [Sarkar, Koustav; Vyas, Yatin M.] Univ Iowa, Childrens Hosp, Div Pediat Hematol Oncol, Iowa City, IA 52242 USA. [Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Vyas, YM (reprint author), Univ Iowa, Childrens Hosp, Div Pediat Hematol Oncol, Iowa City, IA 52242 USA. EM yatin-vyas@uiowa.edu FU National Institutes of Health [R01AI073561, R01AI084957]; National Genome Research Institute/National Institutes of Health intramural funds FX This work was supported by National Institutes of Health Grants R01AI073561 and R01AI084957 (to Y.M.V.) and National Genome Research Institute/National Institutes of Health intramural funds (to F.C.). NR 51 TC 12 Z9 12 U1 1 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2014 VL 193 IS 1 BP 150 EP 160 DI 10.4049/jimmunol.1302923 PG 11 WC Immunology SC Immunology GA AK5BN UT WOS:000338438900020 PM 24872192 ER PT J AU Li, SX Barrett, BS Heilman, KJ Messer, RJ Liberatore, RA Bieniasz, PD Kassiotis, G Hasenkrug, KJ Santiago, ML AF Li, Sam X. Barrett, Bradley S. Heilman, Karl J. Messer, Ronald J. Liberatore, Rachel A. Bieniasz, Paul D. Kassiotis, George Hasenkrug, Kim J. Santiago, Mario L. TI Tetherin Promotes the Innate and Adaptive Cell-Mediated Immune Response against Retrovirus Infection In Vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; FRIEND-VIRUS INFECTION; MHC CLASS-I; FELINE IMMUNODEFICIENCY VIRUS; DEHYDROGENASE-ELEVATING VIRUS; NATURAL-KILLER-CELLS; INDUCED LEUKEMIA; LYMPHOCYTE-ACTIVATION; FUNCTIONAL IMPAIRMENT; ANTIGEN PRESENTATION AB Tetherin/BST-2 is a host restriction factor that could directly inhibit retroviral particle release by tethering nascent virions to the plasma membrane. However, the immunological impact of Tetherin during retrovirus infection remains unknown. We now show that Tetherin influences antiretroviral cell-mediated immune responses. In contrast to the direct antiviral effects of Tetherin, which are dependent on cell surface expression, the immunomodulatory effects are linked to the endocytosis of the molecule. Mice encoding endocytosis-competent C57BL/6 Tetherin exhibited lower viremia and pathology at 7 d postinfection with Friend retrovirus (FV) compared with mice encoding endocytosis-defective NZW/LacJ Tetherin. Notably, antiretroviral protection correlated with stronger NK cell responses. In addition, Friend retrovirus infection levels were significantly lower in wild-type C57BL/6 mice than in Tetherin knockout mice at 2 wk postinfection, and antiretroviral protection correlated with stronger NK cell and virus-specific CD8(+) T cell responses. The results demonstrate that Tetherin acts as a modulator of the cell-mediated immune response against retrovirus infection in vivo. C1 [Li, Sam X.; Barrett, Bradley S.; Heilman, Karl J.; Santiago, Mario L.] Univ Colorado, Dept Med, Aurora, CO 80045 USA. [Li, Sam X.; Santiago, Mario L.] Univ Colorado, Dept Microbiol, Aurora, CO 80045 USA. [Messer, Ronald J.; Hasenkrug, Kim J.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Liberatore, Rachel A.; Bieniasz, Paul D.] Rockefeller Univ, Howard Hughes Med Inst, Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. [Kassiotis, George] Natl Inst Med Res, MRC, Div Immunoregulat, London NW7 1AA, England. [Santiago, Mario L.] Univ Colorado, Dept Immunol, Aurora, CO 80045 USA. RP Santiago, ML (reprint author), Univ Colorado, Div Infect Dis, Mail Stop B168,12700 19th Ave,Bldg RC2,Room 11013, Aurora, CO 80045 USA. EM mario.santiago@ucdenver.edu FU National Institutes of Health [R01 AI090795]; Colorado Clinical and Translational Sciences Institute [TL1 TR000155]; Molecular Pathogenesis of Infectious Disease [T32 AI052066]; Howard Hughes Medical Institute; National Institutes of Health Division of Intramural Research; University of Colorado, Denver, Department of Medicine Early Career Scholar Program FX This work was supported by National Institutes of Health Grant R01 AI090795 (to M.L.S.), Colorado Clinical and Translational Sciences Institute Grant TL1 TR000155 (to S.X.L.), Molecular Pathogenesis of Infectious Disease Grant T32 AI052066 (to S.X.L.), the Howard Hughes Medical Institute (to P.D.B.), the National Institutes of Health Division of Intramural Research (to K.J. Hasenkrug), and the University of Colorado, Denver, Department of Medicine Early Career Scholar Program (to M.L.S.). NR 68 TC 19 Z9 20 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2014 VL 193 IS 1 BP 306 EP 316 DI 10.4049/jimmunol.1400490 PG 11 WC Immunology SC Immunology GA AK5BN UT WOS:000338438900036 PM 24872193 ER PT J AU Tarrio, ML Lee, SH Fragoso, MF Sun, HW Kanno, Y O'Shea, JJ Biron, CA AF Tarrio, Margarite L. Lee, Seung-Hwan Fragoso, Maria F. Sun, Hong-Wei Kanno, Yuka O'Shea, John J. Biron, Christine A. TI Proliferation Conditions Promote Intrinsic Changes in NK Cells for an IL-10 Response SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; CD4(+) T-CELLS; MURINE CYTOMEGALOVIRUS-INFECTION; IFN-ALPHA-BETA; GENE-EXPRESSION; IMMUNE-RESPONSES; VIRAL-INFECTIONS; VIRUS-INFECTION; CUTTING EDGE; IN-VIVO AB Constitutively found at high frequencies, the role for NK cell proliferation remains unclear. In this study, a shift in NK cell function from predominantly producing IFN-gamma, a cytokine with proinflammatory and antimicrobial functions, to producing the immunoregulatory cytokine IL-10 was defined during extended murine CMV infection. The response occurred at times subsequent to IL-12 production, but the NK cells elicited acquired responsiveness to IL-12 and IL-21 for IL-10 production. Because neither IL-12 nor IL-21 was required in vivo, however, additional pathways appeared to be available to promote NK cell IL-10 expression. In vitro studies with IL-2 to support proliferation and in vivo adoptive transfers into murine CMV-infected mice demonstrated that NK cell proliferation and further division enhanced the change. In contrast to the sustained open profile of the IFN-gamma gene, NK cells responding to infection acquired histone modifications in the IL-10 gene indicative of changing from a closed to an open state. The IL-10 response to IL-12 was proliferation dependent ex vivo if the NK cells had not yet expanded in vivo but independent if they had. Thus, a novel role for proliferation in supporting changing innate cell function is reported. C1 [Tarrio, Margarite L.; Lee, Seung-Hwan; Fragoso, Maria F.; Biron, Christine A.] Brown Univ, Div Biol & Med, Dept Mol Microbiol & Immunol, Providence, RI 02912 USA. [Sun, Hong-Wei] NIAMSD, Biodata Min & Discovery Sect, NIH, Bethesda, MD 20892 USA. [Kanno, Yuka; O'Shea, John J.] NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Biron, CA (reprint author), Brown Univ, Dept Mol Microbiol & Immunol, Box G-B, Providence, RI 02912 USA. EM Christine_Biron@brown.edu OI Kanno, Yuka/0000-0001-5668-9319 FU National Institutes of Health; Graduate Assistance in Area of National Need award from the U.S. Department of Education FX The work was supported by the National Institutes of Health and by a Graduate Assistance in Area of National Need award from the U.S. Department of Education. NR 54 TC 6 Z9 6 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2014 VL 193 IS 1 BP 354 EP 363 DI 10.4049/jimmunol.1302999 PG 10 WC Immunology SC Immunology GA AK5BN UT WOS:000338438900041 PM 24907347 ER PT J AU Resnik, DB Parasidis, E AF Resnik, David B. Parasidis, Efthimios TI Waiving legal rights in research SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID INFORMED-CONSENT; PATERNALISM AB The US federal research regulations prohibit informed consent, whether written or oral, from including provisions in which human subjects waive or appear to waive legal rights. We argue that policies that prevent human subjects from waiving legal rights in research can be ethically justified under the rationale of group, soft paternalism. These policies protect competent adults from making adverse decisions about health and legal matters that they may not understand fully. However, this rationale is less defensible if there is a comprehensive compensation for injury programme available in which subjects are asked to waive some legal rights in order to participate in the programme. In this situation, subjects should be allowed to waive some legal rights to obtain the benefits of the programme. C1 [Resnik, David B.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Parasidis, Efthimios] Ohio State Univ, Moritz Coll Law, Columbus, OH 43210 USA. [Parasidis, Efthimios] Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA. RP Resnik, DB (reprint author), NIEHS, NIH, BOX 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov NR 27 TC 0 Z9 0 U1 1 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD JUL PY 2014 VL 40 IS 7 BP 475 EP 478 DI 10.1136/medethics-2013-101547 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA AK1QI UT WOS:000338189900010 PM 23893867 ER PT J AU Vande Voort, JL He, JP Jameson, ND Merikangas, KR AF Vande Voort, Jennifer L. He, Jian-Ping Jameson, Nicole D. Merikangas, Kathleen R. TI Impact of the DSM-5 Attention-Deficit/Hyperactivity Disorder Age-of-Onset Criterion in the US Adolescent Population SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE ADHD; age of onset; prevalence; epidemiology; NHANES ID DEFICIT HYPERACTIVITY DISORDER; COMORBIDITY SURVEY REPLICATION; IV FIELD TRIALS; BIRTH COHORT; FAMILY INCOME; CHILDREN; ADHD; PREVALENCE; SYMPTOMS; CHILDHOOD AB Objective: The present study aims to compare the prevalence and clinical correlates of DSM-IV versus DSM-5-defined attention-deficit/hyperactivity disorder (ADHD) and subtypes in a nationally representative sample of US youth based on the age-of-onset criterion. Method: The sample includes 1,894 participants 12 to 15 years of age from cross-sectional National Health and Nutrition Examination Survey (NHANES) surveys conducted from 2001 to 2004. Data on DSM-IV and DSM-5 criteria for ADHD were derived from administration of the parental ADHD module of the National Institute of Mental Health (NIMH) Diagnostic Interview Schedule for Children, Version W (DISC-IV). Results: Extension of the age-of-onset criterion from 7 to 12 years led to an increase in the prevalence rate of ADHD from 7.38% (DSM-IV) to 10.84% (DSM-5). Youth with later age of onset did not differ from those with earlier age of onset in terms of severity and patterns of comorbidity. However, the group. with later age of onset was more likely to be from lower income and ethnic minority families. Conclusion: The comparability of the clinical significance of the early and later age-of-onset groups supports the DSM-5 extension of the age-of-onset criterion in ADHD. C1 [Vande Voort, Jennifer L.; He, Jian-Ping; Jameson, Nicole D.; Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Bldg 35,Room 1-A201,35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM merikank@mail.nih.gov FU Intramural Research Program of NIMH [Z01 MH002804] FX Funding for this study was supported by the Intramural Research Program of NIMH (Z01 MH002804). NR 39 TC 18 Z9 18 U1 5 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2014 VL 53 IS 7 BP 736 EP 744 DI 10.1016/j.jaac.2014.03.005 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AK2SI UT WOS:000338269400007 PM 24954823 ER PT J AU Shaw, P De Rossi, P Watson, B Wharton, A Greenstein, D Raznahan, A Sharp, W Lerch, JP Chakravarty, MM AF Shaw, Philip De Rossi, Pietro Watson, Bethany Wharton, Amy Greenstein, Deanna Raznahan, Armin Sharp, Wendy Lerch, Jason P. Chakravarty, M. Mallar TI Mapping the Development of the Basal Ganglia in Children With Attention-Deficit/Hyperactivity Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE attention-deficit/hyperactivity disorder; basal ganglia; ventral striatum; development; neuroimaging ID DEFICIT-HYPERACTIVITY-DISORDER; BEHAVIORAL-INHIBITION; PREFRONTAL CORTEX; BRAIN-DEVELOPMENT; ADHD; METAANALYSIS; ADOLESCENTS; DOPAMINE; STRIATUM; MOTOR AB Objective: The basal ganglia are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), but little is known of their development in the disorder. Here, we mapped basal ganglia development from childhood into late adolescence using methods that define surface morphology with an exquisite level of spatial resolution. Method: Surface morphology of the basal ganglia was defined from neuroanatomic magnetic resonance images acquired in 270 youth with DSM-117 defined ADHD and 270 age- and sex-matched typically developing controls; 220 individuals were scanned at least twice. Using linear mixed model regression, we mapped developmental trajectories from age 4 through 19 years at approximately 7,500 surface vertices in the striatum and globus pallidus. Results: In the ventral striatal surfaces, there was a diagnostic difference in developmental trajectories (t = 5.6, p < .0001). Here, the typically developing group showed surface area expansion with age (estimated rate of increase of 0.54 mm(2) per year, standard error [SE] 0.29 mm(2) per year), whereas the ADHD group showed progressive contraction (decrease of 1.75 mm(2) per year, SE 0.28 mm(2) per year). The ADHD group also showed significant, fixed surface area reductions in dorsal striatal regions, which were detected in childhood at study entry and persisted into adolescence. There was no significant association between history of psychostimulant treatment and developmental trajectories. Conclusions: Progressive, atypical contraction of the ventral striatal surfaces characterizes ADHD, localizing to regions pivotal in reward processing. This contrasts with fixed, nonprogressive contraction of dorsal striatal surfaces in regions that support executive function and motor planning. C1 [Shaw, Philip; Watson, Bethany; Wharton, Amy; Sharp, Wendy] NHGRI, Behav Res Branch, Bethesda, MD 20892 USA. [De Rossi, Pietro] Univ Roma La Sapienza, Sch Med & Psychol, St Andrea Hosp, I-00185 Rome, Italy. [Lerch, Jason P.] Hosp Sick Children, Program Neurosci & Mental Hlth, Toronto, ON M5G 1X8, Canada. [Chakravarty, M. Mallar] Ctr Addict & Mental Hlth, Res Imaging Ctr, Toronto, ON, Canada. RP Shaw, P (reprint author), NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bldg 31,B1 B37, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov FU NIMH; NHGRI FX The research was funded by the Intramural Programs of NIMH and NHGRI. NR 59 TC 22 Z9 22 U1 2 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2014 VL 53 IS 7 BP 780 EP 789 DI 10.1016/j.jaac.2014.05.003 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AK2SI UT WOS:000338269400011 PM 24954827 ER PT J AU Greenbaum, AB O'Neill, WW Paone, G Guerrero, ME Wyman, JF Cooper, RL Lederman, RJ AF Greenbaum, Adam B. O'Neill, William W. Paone, Gaetano Guerrero, Mayra E. Wyman, Janet F. Cooper, R. Lebron Lederman, Robert J. TI Caval-Aortic Access to Allow Transcatheter Aortic Valve Replacement in Otherwise Ineligible Patients SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID VASCULAR COMPLICATIONS; IMPLANTATION; PRESSURE; STENOSIS AB Objectives This study describes the first use of caval- aortic access and closure to enable transcatheter aortic valve replacement (TAVR) in patients who lacked other access options. Caval- aortic access refers to percutaneous entry into the abdominal aorta from the femoral vein through the adjoining inferior vena cava. Background TAVR is attractive in high- risk or inoperable patients with severe aortic stenosis. Available transcatheter valves require large introducer sheaths, which are a risk for major vascular complications or preclude TAVR altogether. Caval- aortic access has been successful in animals. Methods We performed a single- center retrospective review of procedural and 30- day outcomes of prohibitive- risk patients who underwent TAVR via caval- aortic access. Results Between July 2013 and January 2014, 19 patients underwent TAVR via caval- aortic access; 79% were women. Caval- aortic access and tract closure were successful in all 19 patients; TAVR was successful in 17 patients. Six patients experienced modified VARC- 2 major vascular complications, 2 (11%) of whom required intervention. Most (79%) required blood transfusion. There were no deaths attributable to caval- aortic access. Throughout the 111 (range 39 to 229) days of follow up, there were no post- discharge complications related to tract creation or closure. All patients had persistent aorto- caval flow immediately post- procedure. Of the 16 patients who underwent repeat imaging after the first week, 15 (94%) had complete closure of the residual aorto- caval tract. Conclusions Percutaneous transcaval venous access to the aorta allows TAVR in otherwise ineligible patients, and may offer a new access strategy for other applications requiring large transcatheter implants. (C) 2014 by the American College of Cardiology Foundation C1 [Greenbaum, Adam B.; O'Neill, William W.; Guerrero, Mayra E.; Wyman, Janet F.] Henry Ford Hlth Syst, Inst Struct Heart Dis, Div Cardiol, Detroit, MI USA. [Paone, Gaetano] Henry Ford Hlth Syst, Div Cardiac Surg, Detroit, MI USA. [Cooper, R. Lebron] Henry Ford Hlth Syst, Dept Anesthesiol, Detroit, MI USA. [Lederman, Robert J.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, Bethesda, MD 20892 USA. RP Greenbaum, AB (reprint author), Henry Ford Hosp, Cardiac Catheterizat Lab K2, 2799 W Grand Blvd, Detroit, MI 48202 USA. EM agreenb1@hfhs.org OI lederman, robert/0000-0003-1202-6673 FU Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health [Z01-HL006040]; Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland FX From the * Institute for Structural Heart Disease, Division of Cardiology, Henry Ford Health System, Detroit, Michigan; yDivision of Cardiac Surgery, Henry Ford Health System, Detroit, Michigan; zDepartment of Anesthesiology, Henry Ford Health System, Detroit, Michigan; and the xCardiovascular and Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland. Drs. Greenbaum, O'Neil, Paone, Guerrero, Wyman, and Cooper were supported by the Institute for Structural Heart Disease, Division of Cardiology, Henry Ford Health System. Dr. Lederman was supported by the Division of Intramural Research (Z01-HL006040), National Heart, Lung, and Blood Institute, National Institutes of Health. Drs. Greenbaum and Lederman are inventors on patent applications for devices for caval- aortic access; these patent applications have been assigned to their employers, Henry Ford Hospital and the National Institutes of Health, respectively. Drs. Greenbaum and O'Neil were funded intramurally by the Center for Structural Heart Disease, Henry Ford Hospital, Detroit, Michigan. Dr. Lederman was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Dr. Greenbaum has been a proctor for SentreHeart. Dr. O'Neill has been a consultant for Medtronic and Edwards Lifesciences; he owns equity in Syntheon Cardiology and Aegis Cardiology; and he is also the owner of Accumed Systems. Dr. Cooper has received a grant from PharMEDium LLC; is a co-owner, co-founder, board member, and stockholder of Board Stiff Inc., and has received profits from Board Stiff Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 14 TC 36 Z9 36 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 1 PY 2014 VL 63 IS 25 BP 2795 EP 2804 DI 10.1016/j.jacc.2014.04.015 PN A PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AK4ZY UT WOS:000338434600006 PM 24814495 ER PT J AU Rinschen, MM Wu, XW Konig, T Pisitkun, T Hagmann, H Pahmeyer, C Lamkemeyer, T Kohli, P Schnell, N Schermer, B Dryer, S Brooks, BR Beltrao, P Krueger, M Brinkkoetter, PT Benzing, T AF Rinschen, Markus M. Wu, Xiongwu Koenig, Tim Pisitkun, Trairak Hagmann, Henning Pahmeyer, Caroline Lamkemeyer, Tobias Kohli, Priyanka Schnell, Nicole Schermer, Bernhard Dryer, Stuart Brooks, Bernard R. Beltrao, Pedro Krueger, Marcus Brinkkoetter, Paul T. Benzing, Thomas TI Phosphoproteomic Analysis Reveals Regulatory Mechanisms at the Kidney Filtration Barrier SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; RESISTANT NEPHROTIC SYNDROME; PODOCYTE TRPC6 CHANNELS; COLLECTING DUCT CELLS; SLIT-DIAPHRAGM; POSTTRANSLATIONAL MODIFICATIONS; QUANTITATIVE PHOSPHOPROTEOMICS; PHOSPHORYLATION SITES; PROTEIN INTERACTIONS; ACTIN CYTOSKELETON AB Diseases of the kidney filtration barrier are a leading cause of ESRD. Most disorders affect the podocytes, polarized cells with a limited capacity for self-renewal that require tightly controlled signaling to maintain their integrity, viability, and function. Here, we provide an atlas of in vivo phosphorylated, glomerulus-expressed proteins, including podocyte-specific gene products, identified in an unbiased tandem mass spectrometry-based approach. We discovered 2449 phosphorylated proteins corresponding to 4079 identified high-confidence phosphorylated residues and performed a systematic bioinformatics analysis of this dataset. We discovered 146 phosphorylation sites on proteins abundantly expressed in podocytes. The prohibitin homology domain of the slit diaphragm protein podocin contained one such site, threonine 234 (T234), located within a phosphorylation motif that is mutated in human genetic forms of proteinuria. The T234 site resides at the interface of podocin dimers. Free energy calculation through molecular dynamic simulations revealed a role for T234 in regulating podocin dimerization. We show that phosphorylation critically regulates formation of high molecular weight complexes and that this may represent a general principle for the assembly of proteins containing prohibitin homology domains. C1 [Rinschen, Markus M.; Hagmann, Henning; Pahmeyer, Caroline; Kohli, Priyanka; Schermer, Bernhard; Brinkkoetter, Paul T.; Benzing, Thomas] Univ Cologne, Dept Internal Med 2, Ctr Mol Med, D-50937 Cologne, Germany. [Rinschen, Markus M.; Koenig, Tim; Lamkemeyer, Tobias; Kohli, Priyanka; Schnell, Nicole; Schermer, Bernhard; Benzing, Thomas] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50937 Cologne, Germany. [Rinschen, Markus M.; Schermer, Bernhard; Benzing, Thomas] Univ Cologne, Syst Biol Ageing Cologne, D-50937 Cologne, Germany. [Koenig, Tim] Univ Cologne, Inst Genet, D-50937 Cologne, Germany. [Wu, Xiongwu; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Pisitkun, Trairak] Chulalongkorn Univ, Fac Med, Bangkok 10330, Thailand. [Dryer, Stuart] Univ Houston, Dept Biol & Biochem, Houston, TX USA. [Dryer, Stuart] Baylor Coll Med, Div Nephrol, Houston, TX 77030 USA. [Beltrao, Pedro] European Bioinformat Inst, European Mol Biol Lab, Cambridge, England. [Krueger, Marcus] Max Planck Inst Heart & Lung Res, Bad Nauheim, Germany. RP Brinkkoetter, PT (reprint author), Univ Cologne, Dept Internal Med 2, Kerpener Str 62, D-50937 Cologne, Germany. EM paul.brinkkoetter@uk-koeln.de; thomas.benzing@uk-koeln.de RI Schermer, Bernhard/E-9972-2014; OI Schermer, Bernhard/0000-0002-5194-9000; Beltrao, Pedro/0000-0002-2724-7703 FU German Research Foundation [Sonderforschungsbereich 635, BR2955]; German Federal Ministry of Education and Research; Koln-Fortune grant from the University of Cologne; Fritz-Scheler stipendium by the German Kidney Foundation; KfH Foundation for Preventative Medicine FX This work was supported by the German Research Foundation (Sonderforschungsbereich 635 to T.B. and BR2955 to P.T.B.]) and the German Federal Ministry of Education and Research (GerontoSys2 program Sybacol to T.B.). M.M.R. was supported by a Koln-Fortune grant from the University of Cologne as well as a Fritz-Scheler stipendium by the German Kidney Foundation and KfH Foundation for Preventative Medicine. NR 66 TC 10 Z9 10 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2014 VL 25 IS 7 BP 1509 EP 1522 DI 10.1681/ASN.2013070760 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA AK1LL UT WOS:000338176500017 PM 24511133 ER PT J AU Pani, A Bragg-Gresham, J Masala, M Piras, D Atzeni, A Pilia, MG Ferreli, L Balaci, L Curreli, N Delitala, A Loi, F Abecasis, GR Schlessinger, D Cucca, F AF Pani, Antonello Bragg-Gresham, Jennifer Masala, Marco Piras, Doloretta Atzeni, Alice Pilia, Maria G. Ferreli, Liana Balaci, Lenuta Curreli, Nicolo Delitala, Alessandro Loi, Francesco Abecasis, Goncalo R. Schlessinger, David Cucca, Francesco TI Prevalence of CKD and Its Relationship to eGFR-Related Genetic Loci and Clinical Risk Factors in the SardiNIA Study Cohort SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; IMPROVING GLOBAL OUTCOMES; RENAL-FUNCTION; POSITION STATEMENT; POPULATION; HEALTH; EPIDEMIOLOGY; CHALLENGE; EQUATIONS AB The prevalence of CKD and of renal failure vary worldwide, yet parallel increases in leading risk factors explain only part of the differential prevalence. We measured CKD prevalence and eGFR, and their relationship with traditional and additional risk factors, in a Sardinian founder population cohort. The eGFR was calculated using equations from the CKD Epidemiology Collaboration and Modification of Diet in Renal Disease studies. With use of the Kidney Disease Improving Global Outcomes guidelines, a cross-sectional analysis of 4842 individuals showed that CKD prevalence was 15.1%, including 3.6% of patients in the high-risk and 0.46% in the very-high-risk categories. Longitudinal analyses performed on 4074 of these individuals who completed three visits with an average follow-up of 7 years revealed that, consistent with other populations, average eGFR slope was -0.79 ml/min per 1.73 m(2) per year, but 11.4% of the participants had an eGFR decline >2.3 ml/min per 1.73 m(2) per year (fast decline). A genetic score was generated from 13 reported eGFR- and CKD-related loci, and univariable and multivariable analyses were applied to assess the relationship between clinical, ultrasonographic, and genetic variables with three outcomes: CKD, change in eGFR, and fast eGFR decline. Genetic risk score, older age, and female sex independently correlated with each outcome. Diabetes was associated with CKD prevalence, whereas hypertension and hyperuricemia correlated more strongly with fast eGFR decline. Diabetes, hypertension, hyperuricemia, and high baseline eGFR were associated with a decline of eGFR. Along with differential health practices, population variations in this spectrum of risk factors probably contributes to the variable CKD prevalence worldwide. C1 [Pani, Antonello; Piras, Doloretta; Atzeni, Alice] Azienda Osped G Brotzu, I-09134 Cagliari, Italy. [Bragg-Gresham, Jennifer; Abecasis, Goncalo R.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Masala, Marco] CNR, IRGB, Monserrato, Italy. [Pilia, Maria G.; Ferreli, Liana; Balaci, Lenuta; Curreli, Nicolo; Delitala, Alessandro; Loi, Francesco] CNR, IRGB, Ctr ProgeNIA, Lanusei, Italy. [Schlessinger, David] NIA, Dept Genet, Baltimore, MD 21224 USA. [Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. RP Pani, A (reprint author), Azienda Osped G Brotzu, Piazzale Alessandro Ricchi 1, I-09134 Cagliari, Italy. EM antonellopani@aob.it RI Delitala, Alessandro/L-3194-2016 OI Delitala, Alessandro/0000-0003-1729-8969 FU Intramural Research Program of the National Institutes of Health's National Institute on Aging FX We thank Ms. Laura Lecca and Dr. Valery Perricone for secretarial assistance and proofreading, and Dr. Marcello Angius for the laboratory calibration study. None of the individuals listed herein received any compensation. This research was supported in part by the Intramural Research Program of the National Institutes of Health's National Institute on Aging. NR 34 TC 12 Z9 12 U1 0 U2 4 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2014 VL 25 IS 7 BP 1533 EP 1544 DI 10.1681/ASN.2013060591 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA AK1LL UT WOS:000338176500019 PM 24511125 ER PT J AU Sarnak, MJ Katz, R Newman, A Harris, T Peralta, CA Devarajan, P Bennett, MR Fried, L Ix, JH Satterfield, S Simonsick, EM Parikh, CR Shlipak, MG AF Sarnak, Mark J. Katz, Ronit Newman, Anne Harris, Tamara Peralta, Carmen A. Devarajan, Prasad Bennett, Michael R. Fried, Linda Ix, Joachim H. Satterfield, Suzanne Simonsick, Eleanor M. Parikh, Chirag R. Shlipak, Michael G. CA Hlth ABC Study TI Association of Urinary Injury Biomarkers with Mortality and Cardiovascular Events SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GELATINASE-ASSOCIATED LIPOCALIN; ACUTE KIDNEY INJURY; GLOMERULAR-FILTRATION-RATE; PROXIMAL TUBULAR CELLS; MOLECULE-1 KIM-1; FUNCTION DECLINE; CARDIAC-SURGERY; RISK; NGAL; INTERLEUKIN-18 AB Kidney damage is a common sequela of several chronic pathologic conditions. Whether biomarkers of kidney damage are prognostic for more severe outcomes is unknown. We measured three urinary bionnarkers (kidney injury molecule-1 [KIM-1], IL-18, and albumin) in 3010 individuals enrolled in the Health, Aging and Body Composition (Health ABC) study and used Cox proportional hazards models to investigate the associations of urinary KIM-1/creatinine (cr), IL-18/cr, and albumin/cr (ACR) with all-cause mortality and cardiovascular disease (CVD). Multivariable models adjusted for demographics, traditional CVD risk factors, and eGFR. Mean age of participants was 74 years, 49% of participants were men, and 41% of participants were black. During the median 12.4 years of follow-up, 1450 deaths and 797 CVD outcomes occurred. Compared with the lowest quartile, successive quartiles had the following adjusted hazard ratios (HRs; 95% confidence intervals [95% as]) for mortality: KIM-1/cr: (1.21; 1.03 to 1.41), (1.13; 0.96 to 1.34), and (1.28; 1.08 to 1.52); IL-18/cr: (1.02; 0.88 to 1.19), (1.16; 0.99 to 1.35), and (1.06; 0.90 to 1.25); ACR: (1.08; 0.91 to 1.27), (1.24; 1.06 to 1.46), and (1.63; 1.39 to 1.91). In similar analyses, only ACR quartiles associated with CVD: (1.19; 0.95 to 1.48), (1.35; 1.08 to 1.67), and (1.54; 1.24 to 1.91). Urinary KIM-1 had a modest association with all-cause mortality but did not associate with CVD, and urinary IL-18 did not associate with either outcome. In contrast, albuminuria strongly associated with all-cause mortality and CVD. Future studies should evaluate reasons for these differences in the prognostic importance of individual kidney injury markers. C1 [Sarnak, Mark J.] Tufts Med Ctr, Div Nephrol, Boston, MA 02111 USA. [Katz, Ronit] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Newman, Anne] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Harris, Tamara] NIA, Geriatr Epidemiol Sect, NIH, Bethesda, MD 20892 USA. [Peralta, Carmen A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Peralta, Carmen A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Devarajan, Prasad; Bennett, Michael R.] Cincinnati Childrens Hosp Med Ctr, Div Nephrol & Hypertens, Cincinnati, OH 45229 USA. [Fried, Linda] Univ Pittsburgh, Sch Med, Renal Electrolyte Div, Pittsburgh, PA USA. [Fried, Linda] Univ Pittsburgh, Sch Med, Renal Sect, Pittsburgh, PA USA. [Fried, Linda] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Prevent Med, San Diego, CA 92103 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Parikh, Chirag R.] Yale Univ, Dept Med, Sect Nephrol, New Haven, CT 06520 USA. [Parikh, Chirag R.] Yale Univ, Program Appl Translat Res, New Haven, CT USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol, Div Gen Internal Med, San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Biostat, Div Gen Internal Med, San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. RP Sarnak, MJ (reprint author), Tufts Med Ctr, Div Nephrol, Box 391,800 Washington St, Boston, MA 02111 USA. EM msarnak@tuftsmedicalcenter.org RI Bennett, Maxwell/J-8504-2015; Newman, Anne B./C-6408-2013 OI Newman, Anne B./0000-0002-0106-1150 FU National Institute on Aging [R01-AG027002, R01-AG028050, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute of Nursing Research [R01-NR012459]; Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported by National Institute on Aging Grants R01-AG027002 and R01-AG028050; National Institute on Aging Contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; and National Institute of Nursing Research Grant R01-NR012459. This study was also supported, in part, by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 38 TC 12 Z9 12 U1 0 U2 4 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2014 VL 25 IS 7 BP 1545 EP 1553 DI 10.1681/ASN.2013070713 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AK1LL UT WOS:000338176500020 PM 24511130 ER PT J AU Carpenter, MA John, A Weir, MR Smith, SR Hunsicker, L Kasiske, BL Kusek, JW Bostom, A Ivanova, A Levey, AS Solomon, S Pesavento, T Weiner, DE AF Carpenter, Myra A. John, Alin Weir, Matthew R. Smith, Stephen R. Hunsicker, Lawrence Kasiske, Bertram L. Kusek, John W. Bostom, Andrew Ivanova, Anastasia Levey, Andrew S. Solomon, Scott Pesavento, Todd Weiner, Daniel E. TI BP, Cardiovascular Disease, and Death in the Folic Acid for Vascular Outcome Reduction in Transplantation Trial SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; BLOOD-PRESSURE CONTROL; DIABETIC-NEPHROPATHY TRIAL; CONGESTIVE-HEART-FAILURE; RENAL-TRANSPLANTATION; FAVORIT TRIAL; RISK; RECIPIENTS; MORTALITY; MELLITUS AB The optimal BP level in kidney transplant recipients remains uncertain. This post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial cohort assessed associations of BP with a pooled cardiovascular disease (CVD) outcome and with all-cause mortality. In 3474 prevalent kidney transplant patients, mean age was 52+/-9 years, 63% were men, 76% were white, 20% had a history of CVD, 40% had a history of diabetes mellitus, and the median time since transplant was 4.1 years (25th to 75th percentiles, 1.7-7.4); mean systolic BP was 136+/-20 mmHg and mean diastolic BP was 79+/-12 mmHg. There were 497 CVD events and 406 deaths. After adjustment for demographic and transplant characteristics and CVD risk factors, each 20-mmHg increase in baseline systolic BP associated with a 32% increase in subsequent CVD risk (hazard ratio [H IR], 1.32; 95% confidence interval [95% CI], 1.19 to 1.46) and a 13% increase in mortality risk (HR, 1.13; 95% CI, 1.01 to 1.27). Similarly, after adjustment, at diastolic BP levels<70 mmHg, each 10-mmHg decrease in diastolic BP level associated with a 31% increase in CVD risk (HR, 1.31; 95% CI, 1.06 to 1.62) and a 31% increase in mortality risk (HR, 1.31; 95% Cl, 1.03 to 1.66). However, at diastolic BP levels>70 mmHg, there was no significant relationship between diastolic BP and outcomes. Higher systolic BP strongly and independently associated with increased risk of CVD and all-cause mortality, without evidence of a J shape, whereas only lower levels of diastolic BP associated with increased risk of CVD and death in this trial. C1 [Carpenter, Myra A.; Ivanova, Anastasia] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [John, Alin; Levey, Andrew S.; Weiner, Daniel E.] Tufts Med Ctr, Div Nephrol, Boston, MA USA. [Weir, Matthew R.] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21201 USA. [Smith, Stephen R.] Duke Univ, Div Nephrol, Durham, NC USA. [Hunsicker, Lawrence] Univ Iowa, Coll Med, Iowa City, IA USA. [Kasiske, Bertram L.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Kasiske, Bertram L.] Univ Minnesota, Minneapolis, MN USA. [Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. [Bostom, Andrew] Brown Univ, Mem Hosp Rhode Isl, Pawtucket, RI 02860 USA. [Solomon, Scott] Brigham & Womens Hosp, Boston, MA 02115 USA. [Solomon, Scott] Harvard Univ, Sch Med, Boston, MA USA. [Pesavento, Todd] Ohio State Univ, Wexner Med Ctr, Div Nephrol, Columbus, OH 43210 USA. RP Carpenter, MA (reprint author), Univ N Carolina, Dept Biostat, CSCC, 137 E Franklin St,Suite 203,Campus Box 8030, Chapel Hill, NC 27599 USA. EM Myra_Carpenter@unc.edu FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01-DK61700]; National Institutes of Health Office of Dietary Supplements FX The FAVORIT trial is supported by cooperative agreement U01-DK61700 from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). J.W.K., an employee of the NIDDK, was involved in the study design, interpretation, and writing of the report. Support also provided by the National Institutes of Health Office of Dietary Supplements. PamLab, LLC of Covington, Louisiana, provided the high- and low-dose multivitamins. NR 40 TC 12 Z9 13 U1 0 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2014 VL 25 IS 7 BP 1554 EP 1562 DI 10.1681/ASN.2013040435 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AK1LL UT WOS:000338176500021 PM 24627349 ER PT J AU Mell, MW Pettinger, M Proulx-Burns, L Heckbert, SR Allison, MA Criqui, MH Hlatky, MA Burwen, DR AF Mell, Matthew W. Pettinger, Mary Proulx-Burns, Lori Heckbert, Susan R. Allison, Matthew A. Criqui, Michael H. Hlatky, Mark A. Burwen, Dale R. CA WHI PVD Writing Workgrp TI Evaluation of Medicare claims data to ascertain peripheral vascular events in the Women's Health Initiative SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 37th Annual Meeting of the Midwestern-Vascular-Surgical-Society CY SEP 06-08, 2013 CL Chicago, IL SP Midwestern Vasc Surg Soc ID ABDOMINAL AORTIC-ANEURYSMS; ARTERIAL-DISEASE; RISK; MORTALITY; REPAIR; BENEFICIARIES; VALIDATION; SAFETY; TRENDS; CODES AB Objective: Capturing long-term outcomes from large clinical databases by use of claims data is a potential strategy for improving efficiency while reducing study costs. We sought to compare the use of Medicare data with data from the Women's Health Initiative (WHI) to determine peripheral vascular events, as defined by the WHI study design. Methods: We studied participants from the WHI with both adjudicated outcomes and links to Medicare enrollment and utilization data through 2007. Outcomes of interest included hospitalizations for treatment of abdominal aortic aneurysm (AAA), lower extremity peripheral artery disease (LE PAD), and carotid artery stenosis (CAS). Events determined by WHI adjudication were compared with events defined by coding algorithms using diagnosis and procedure codes from Medicare data with a pilot data set and then validated with a test data set. We assessed agreement by a kappa statistic and evaluated reasons for disagreement. Results: In the pilot set, records from 50,511 participants were analyzed. Agreement between the Centers for Medicare and Medicaid Services and WHI for admissions with a diagnosis but no treatment procedures for vascular conditions was poor (kappa, 0.02-0.18). On the basis of WHI outcome data collection, vascular treatment procedures occurred in 29 participants for AAA, 204 for LE PAD events, and 281 for CAS. Medicare hospital claims recorded 41 treatments for AAA, 255 for LE PAD, and 317 for CAS. For participants with a Centers for Medicare and Medicaid Services-captured vascular procedure and a record adjudicated by WHI, kappa values for treatment procedures were 0.81 for AAA, 0.77 for PAD, and 0.93 for CAS. For vascular procedures identified by WHI but not by Medicare hospital data (n = 82), 55% were captured by Medicare physician claims. Conversely, for treatments identified by Medicare hospital data but not captured by WHI adjudication (n = 57), 74% had physician claims consistent with the procedure. Fifteen participants with AAA or LE PAD procedures in hospital claims had medical records available for review, and nine of these had definitive documentation of procedures that were not captured by the WHI adjudication process. Estimated positive predictive value of Medicare data was 91% to 94% for AAA, 92% to 95% for LE PAD, and 94% to 99% for CAS. Available test set data (n = 50,253) yielded generally similar results with kappa of 0.77 for AAA, 0.79 for LE PAD, and 0.94 for CAS. Conclusions: Medicare data appear useful for identifying vascular treatment procedures for WHI participants. Medicare hospital claims identify more procedures than WHI does, with high positive predictive value, but also may not capture some procedures identified in WHI. C1 [Mell, Matthew W.; Hlatky, Mark A.] Stanford Univ, Stanford, CA 94305 USA. [Pettinger, Mary; Proulx-Burns, Lori] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Heckbert, Susan R.] Univ Washington, Seattle, WA 98195 USA. [Allison, Matthew A.; Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Burwen, Dale R.] NHLBI, Bethesda, MD 20892 USA. RP Mell, MW (reprint author), 300 Pasteur Dr,Ste H3600, Stanford, CA 94305 USA. EM mwmell@stanford.edu OI Allison, Matthew/0000-0003-0777-8272 FU PHS HHS [HHSN268201100004C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100046C, HHSN271201100004C] NR 22 TC 6 Z9 6 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUL PY 2014 VL 60 IS 1 BP 98 EP 105 DI 10.1016/j.jvs.2014.01.056 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA AK5FG UT WOS:000338449500015 PM 24636641 ER PT J AU Shalhub, S Black, JH Cecchi, AC Xu, Z Griswold, BF Safi, HJ Milewicz, DM McDonnell, NB AF Shalhub, Sherene Black, James H., III Cecchi, Alana C. Xu, Zhi Griswold, Ben F. Safi, Hazim J. Milewicz, Dianna M. McDonnell, Nazli B. TI Molecular diagnosis in vascular Ehlers-Danlos syndrome predicts pattern of arterial involvement and outcomes SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT Vascular Annual Meeting of the Society-for-Vascular-Surgery (SVS) CY MAY 29-JUN 01, 2013 CL San Francisco, CA SP Soc Vasc Surg ID SYNDROME TYPE-IV; COL3A1 GENE; MUTATIONS; MANAGEMENT; CELIPROLOL AB Objective: The management of arterial pathology in individuals with vascular Ehlers-Danlos syndrome (vEDS) remains a challenge. Here we describe the correlation between COL3A1 gene mutation type and the clinical phenotype in individuals with vEDS. Methods: Individuals with confirmed molecular diagnoses of vEDS were enrolled in a multi-institutional natural history study. Data collected included demographics, clinical and family histories, arterial pathology (aneurysm, dissection, and rupture), operative details, and autopsy reports. Individuals were classified into two cohorts by the type of COL3A1 mutations and their effect on the amount of normal collagen produced: those with mutations that lead to minimal (MIN) production (10%-15%) of normal type III collagen and those with haploinsufficiency (HI) mutations that lead to production of 50% of the normal type III collagen. Results: A cohort of 68 individuals (72%) from 56 families had arterial pathology (44% male) with 13% HI. The HI group was older at the time of their first vascular event (mean, 42 [range, 26-58] years vs 33 [range, 8-62] years; P = .016) and had a higher incidence of aortic pathology than the MIN group (56% vs 21%; P = .025). Visceral arterial pathology was seen in 43 arteries in 23 individuals in the MIN group vs only one artery in five individuals in the HI group. Emergency surgical procedures were more likely to be undertaken when vEDS diagnosis was not known (81% vs 41%; P = .005), and 81% of these procedures were open surgical repair compared with 19% endovascular repairs (P = .019). Open and endovascular repairs were equally used in the elective setting. Postoperative complications were highest when the diagnosis of vEDS was not known (62% vs 14%; P < .001) and when procedures were undertaken in an emergency setting (5% vs 55% P < .001). Mortality due to arterial complications was 0% in the HI cohort and 21% in the MIN cohort (P = .132). Conclusions: Arterial pathology in vEDS individuals is related to the underlying COL3A1 mutation type. The arterial pathology in individuals with HI mutations occurs at later ages with a higher incidence of aortic disease compared with other COL3A1 mutation types. Molecular diagnosis is recommended because diagnosis confirmation, appropriate surveillance, and prophylactic interventions in an elective setting improve surgical outcomes. C1 [Shalhub, Sherene] Univ Washington, Dept Gen Surg, Div Vasc Surg, Seattle, WA 98195 USA. [Black, James H., III] Johns Hopkins Univ Hosp, Dept Surg, Div Vasc Surg & Endovasc Therapy, Baltimore, MD 21287 USA. [Cecchi, Alana C.; Milewicz, Dianna M.] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Med Genet, Houston, TX 77030 USA. [Xu, Zhi; Griswold, Ben F.; McDonnell, Nazli B.] NIA, Baltimore, MD 21224 USA. [Safi, Hazim J.] Univ Texas Med Sch Houston, Dept Cardiothorac & Vasc Surg, Houston, TX USA. RP Shalhub, S (reprint author), Univ Washington, Dept Gen Surg, Div Vasc Surg, 1959 NE Pacific St,Box 356410, Seattle, WA 98195 USA. EM shalhub@uw.edu FU NCRR NIH HHS [UL1 RR024148, UL1-RR-024148]; NHLBI NIH HHS [R01-HL-109942-01A1, R01 HL109942] NR 14 TC 9 Z9 9 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUL PY 2014 VL 60 IS 1 BP 160 EP 169 DI 10.1016/j.jvs.2014.01.070 PG 10 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA AK5FG UT WOS:000338449500027 PM 24650746 ER PT J AU Lee, JS Bevins, SN Serieys, LEK Vickers, W Logan, KA Aldredge, M Boydston, EE Lyren, LM McBride, R Roelke-Parker, M Pecon-Slattery, J Troyer, JL Riley, SP Boyce, WM Crooks, KR VandeWoude, S AF Lee, Justin S. Bevins, Sarah N. Serieys, Laurel E. K. Vickers, Winston Logan, Ken A. Aldredge, Mat Boydston, Erin E. Lyren, Lisa M. McBride, Roy Roelke-Parker, Melody Pecon-Slattery, Jill Troyer, Jennifer L. Riley, Seth P. Boyce, Walter M. Crooks, Kevin R. VandeWoude, Sue TI Evolution of Puma Lentivirus in Bobcats (Lynx rufus) and Mountain Lions (Puma concolor) in North America SO JOURNAL OF VIROLOGY LA English DT Article ID FELINE IMMUNODEFICIENCY VIRUS; FRAGMENTED URBAN LANDSCAPE; NATURALLY INFECTED COUGARS; GENE FLOW; SELECTION; SEQUENCE; TRANSMISSION; PROTEINS; WILD; RECOMBINATION AB Mountain lions (Puma concolor) throughout North and South America are infected with puma lentivirus clade B (PLVB). A second, highly divergent lentiviral clade, PLVA, infects mountain lions in southern California and Florida. Bobcats (Lynx rufus) in these two geographic regions are also infected with PLVA, and to date, this is the only strain of lentivirus identified in bobcats. We sequenced full-length PLV genomes in order to characterize the molecular evolution of PLV in bobcats and mountain lions. Low sequence homology (88% average pairwise identity) and frequent recombination (1 recombination breakpoint per 3 isolates analyzed) were observed in both clades. Viral proteins have markedly different patterns of evolution; sequence homology and negative selection were highest in Gag and Pol and lowest in Vif and Env. A total of 1.7% of sites across the PLV genome evolve under positive selection, indicating that host-imposed selection pressure is an important force shaping PLV evolution. PLVA strains are highly spatially structured, reflecting the population dynamics of their primary host, the bobcat. In contrast, the phylogeography of PLVB reflects the highly mobile mountain lion, with diverse PLVB isolates cocirculating in some areas and genetically related viruses being present in populations separated by thousands of kilometers. We conclude that PLVA and PLVB are two different viral species with distinct feline hosts and evolutionary histories. IMPORTANCE An understanding of viral evolution in natural host populations is a fundamental goal of virology, molecular biology, and disease ecology. Here we provide a detailed analysis of puma lentivirus (PLV) evolution in two natural carnivore hosts, the bobcat and mountain lion. Our results illustrate that PLV evolution is a dynamic process that results from high rates of viral mutation/recombination and host-imposed selection pressure. C1 [Lee, Justin S.; VandeWoude, Sue] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Bevins, Sarah N.] USDA, Natl Wildlife Res Ctr, Ft Collins, CO USA. [Serieys, Laurel E. K.; Riley, Seth P.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA. [Vickers, Winston; Boyce, Walter M.] Univ Calif Davis, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. [Logan, Ken A.] Colorado Pk & Wildlife, Montrose, CO USA. [Aldredge, Mat] Colorado Pk & Wildlife, Ft Collins, CO USA. [Boydston, Erin E.; Lyren, Lisa M.] USGS Western Ecol Res Ctr, Thousand Oaks, CA USA. [McBride, Roy] Ranchers Supply Inc, Ochopee, FL USA. [Roelke-Parker, Melody; Pecon-Slattery, Jill; Troyer, Jennifer L.] NCI, Lab Genet Div, Frederick, MD 21701 USA. [Crooks, Kevin R.] Colorado State Univ, Dept Fish Wildlife & Conservat Biol, Ft Collins, CO 80523 USA. RP Lee, JS (reprint author), Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. EM justinlee337@gmail.com FU Ecology of Infectious Disease grant from the National Science Foundation; Wildlife Fellowship grant from the Morris Animal Foundation FX This work was supported by an Ecology of Infectious Disease grant from the National Science Foundation and a Wildlife Fellowship grant from the Morris Animal Foundation. NR 52 TC 6 Z9 6 U1 6 U2 52 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2014 VL 88 IS 14 BP 7727 EP 7737 DI 10.1128/JVI.00473-14 PG 11 WC Virology SC Virology GA AK5CT UT WOS:000338442600006 PM 24741092 ER PT J AU Ying, TL Du, LY Ju, TW Prabakaran, P Lau, CCY Lu, L Liu, Q Wang, LL Feng, Y Wang, YP Zheng, BJ Yuen, KY Jiang, SB Dimitrov, DS AF Ying, Tianlei Du, Lanying Ju, Tina W. Prabakaran, Ponraj Lau, Candy C. Y. Lu, Lu Liu, Qi Wang, Lili Feng, Yang Wang, Yanping Zheng, Bo-Jian Yuen, Kwok-Yung Jiang, Shibo Dimitrov, Dimiter S. TI Exceptionally Potent Neutralization of Middle East Respiratory Syndrome Coronavirus by Human Monoclonal Antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID RECEPTOR-BINDING DOMAIN; MERS-COV; SAUDI-ARABIA; THERAPEUTICS; VIRUSES; IDENTIFICATION; PROTEIN; HENDRA; NIPAH; HIV-1 AB The recently discovered Middle East respiratory syndrome coronavirus (MERS-CoV) continues to infect humans, with high mortality. Specific, highly effective therapeutics and vaccines against the MERS-CoV are urgently needed to save human lives and address the pandemic concerns. We identified three human monoclonal antibodies (MAbs), m336, m337, and m338, targeting the receptor (CD26/DPP4) binding domain (RBD) of the MERS-CoV spike glycoprotein from a very large naive-antibody library (containing similar to 10(11) antibodies). They bound with high affinity: equilibrium dissociation constants for the three MAbs were equal to 4.2, 9.3, and 15 nM, respectively, as measured by Biacore for Fabs binding to RBD. The avidity for IgG1 m336, m337, and m338 was even higher: 99, 820, and 560 pM, respectively. The antibodies bound to overlapping epitopes that overlap the receptor binding site on the RBD as suggested by competition experiments and further supported by site-directed mutagenesis of the RBD and a docking model of the m336-RBD complex. The highest-affinity MAb, m336, neutralized both pseudotyped and live MERS-CoV with exceptional potency, 50% neutralization at 0.005 and 0.07 mu g/ml, respectively, likely by competing with DPP4 for binding to the S glycoprotein. The exceptionally high neutralization activity of these antibodies and especially m336 suggests that they have great potential for prophylaxis and therapy of MERS-CoV infection in humans and as a tool for development of vaccine immunogens. The rapid identification (within several weeks) of potent MAbs suggests a possibility to use the new large antibody library and related methodology for a quick response to the public threat resulting from emerging coronaviruses. IMPORTANCE A novel human coronavirus, the Middle East respiratory syndrome coronavirus (MERS-CoV), was found to infect humans with a high mortality rate in 2012, just 1 decade after the appearance of the first highly pathogenic coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV). There are no effective therapeutics available. It is highly desirable to find an approach for rapidly developing potent therapeutics against MERS-CoV, which not only can be implemented for MERS treatment but also can help to develop a platform strategy to combat future emerging coronaviruses. We report here the identification of human monoclonal antibodies (MAbs) from a large nonimmune antibody library that target MERS-CoV. One of the antibodies, m336, neutralized the virus with exceptional potency. It therefore may have great potential as a candidate therapeutic and as a reagent to facilitate the development of vaccines against MERS-CoV. C1 [Ying, Tianlei; Ju, Tina W.; Prabakaran, Ponraj; Feng, Yang; Wang, Yanping; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Expt Immunol Lab, Canc & Inflammat Program,Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Du, Lanying; Wang, Lili; Jiang, Shibo] New York Blood Ctr, Lindsley Kimball Res Inst, New York, NY 10021 USA. [Prabakaran, Ponraj; Zheng, Bo-Jian; Yuen, Kwok-Yung] Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab, Frederick, MD USA. [Lau, Candy C. Y.] Univ Hong Kong, Dept Microbiol, Pokfulam, Hong Kong, Peoples R China. [Lu, Lu; Liu, Qi; Jiang, Shibo] Fudan Univ, Key Lab Med Mol Virol, Minist Educ, Shanghai Med Coll, Shanghai 200433, Peoples R China. [Lu, Lu; Liu, Qi; Jiang, Shibo] Fudan Univ, Key Lab Med Mol Virol, Minist Hlth, Shanghai Med Coll, Shanghai 200433, Peoples R China. [Lu, Lu; Liu, Qi; Jiang, Shibo] Fudan Univ, Inst Med Microbiol, Shanghai 200433, Peoples R China. RP Ying, TL (reprint author), NCI, Prot Interact Grp, Expt Immunol Lab, Canc & Inflammat Program,Ctr Canc Res,NIH, Frederick, MD 21701 USA. EM yingt@mail.nih.gov; dimiter.dimitrov@nih.gov RI Jiang, Shibo/L-4500-2014; Lu, Lu/K-7070-2014; OI Lu, Lu/0000-0002-2255-0391 FU NIH, National Cancer Institute, Center for Cancer Research; NIH, National Cancer Institute [N01-CO-12400, HHSN261200800001E] FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by Federal funds from the NIH, National Cancer Institute, under contract no. N01-CO-12400 and HHSN261200800001E. NR 32 TC 46 Z9 50 U1 1 U2 23 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2014 VL 88 IS 14 BP 7796 EP 7805 DI 10.1128/JVI.00912-14 PG 10 WC Virology SC Virology GA AK5CT UT WOS:000338442600012 PM 24789777 ER PT J AU Del Prete, GQ Park, H Fennessey, CM Reid, C Lipkey, L Newman, L Oswald, K Kahl, C Piatak, M Quinones, OA Alvord, WG Smedley, J Estes, JD Lifson, JD Picker, LJ Keele, BF AF Del Prete, Gregory Q. Park, Haesun Fennessey, Christine M. Reid, Carolyn Lipkey, Leslie Newman, Laura Oswald, Kelli Kahl, Christoph Piatak, Michael, Jr. Quinones, Octavio A. Alvord, W. Gregory Smedley, Jeremy Estes, Jacob D. Lifson, Jeffrey D. Picker, Louis J. Keele, Brandon F. TI Molecularly Tagged Simian Immunodeficiency Virus SIVmac239 Synthetic Swarm for Tracking Independent Infection Events SO JOURNAL OF VIROLOGY LA English DT Article ID RHESUS MACAQUES; GAG/POL/NEF VACCINE; CHALLENGE EXPOSURE; HIV-1 INFECTION; SIV CHALLENGE; REPLICATION; PROTECTION; VARIANTS; IDENTIFICATION; TRANSMISSION AB Following mucosal human immunodeficiency virus type 1 transmission, systemic infection is established by one or only a few viral variants. Modeling single-variant, mucosal transmission in nonhuman primates using limiting-dose inoculations with a diverse simian immunodeficiency virus isolate stock may increase variability between animals since individual variants within the stock may have substantial functional differences. To decrease variability between animals while retaining the ability to enumerate transmitted/founder variants by sequence analysis, we modified the SIVmac239 clone to generate 10 unique clones that differ by two or three synonymous mutations (molecular tags). Transfection-and infection-derived virus stocks containing all 10 variants showed limited phenotypic differences in 9 of the 10 clones. Twenty-nine rhesus macaques were challenged intrarectally or intravenously with either a single dose or repeated, limiting doses of either stock. The proportion of each variant within each inoculum and in plasma from infected animals was determined by using a novel real-time single-genome amplification assay. Each animal was infected with one to five variants, the number correlating with the dose. Longitudinal sequence analysis revealed that the molecular tags are highly stable with no reversion to the parental sequence detected in > 2 years of follow-up. Overall, the viral stocks are functional and mucosally transmissible and the number of variants is conveniently discernible by sequence analysis of a small amplicon. This approach should be useful for tracking individual infection events in preclinical vaccine evaluations, long-term viral reservoir establishment/clearance research, and transmission/early-event studies. IMPORTANCE Human immunodeficiency virus type 1 transmission is established by one or only a few viral variants. Modeling of limited variant transmission in nonhuman primates with a diverse simian immunodeficiency virus isolate stock may increase the variability between animals because of functional differences in the individual variants within the stock. To decrease such variability while retaining the ability to distinguish and enumerate transmitted/founder variants by sequence analysis, we generated a viral stock with 10 sequence-identifiable but otherwise genetically identical variants. This virus was characterized in vitro and in vivo and shown to allow discrimination of distinct transmission events. This approach provides a novel nonhuman primate challenge system for the study of viral transmission, evaluation of vaccines and other prevention approaches, and characterization of viral reservoirs and strategies to target them. C1 [Del Prete, Gregory Q.; Fennessey, Christine M.; Reid, Carolyn; Lipkey, Leslie; Newman, Laura; Oswald, Kelli; Piatak, Michael, Jr.; Estes, Jacob D.; Lifson, Jeffrey D.; Keele, Brandon F.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Leidos Biomed Res Inc, Frederick, MD 21702 USA. [Quinones, Octavio A.; Alvord, W. Gregory] Frederick Natl Lab Canc Res, Data Management Serv, Leidos Biomed Res Inc, Frederick, MD USA. [Smedley, Jeremy] Frederick Natl Lab Canc Res, Lab Anim Sci Program, Leidos Biomed Res Inc, Frederick, MD USA. [Park, Haesun; Picker, Louis J.] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR USA. [Park, Haesun; Kahl, Christoph; Picker, Louis J.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR USA. RP Keele, BF (reprint author), Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Leidos Biomed Res Inc, Frederick, MD 21702 USA. EM keelebf@mail.nih.gov OI Smedley, Jeremy/0000-0003-3369-4662 FU National Cancer Institute; National Institutes of Health [HHSN261200800001E]; NIAID grant [AI054292] FX This work was supported in part with federal funds from the National Cancer Institute; National Institutes of Health, under contract HHSN261200800001E and NIAID grant AI054292. NR 36 TC 7 Z9 7 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2014 VL 88 IS 14 BP 8077 EP 8090 DI 10.1128/JVI.01026-14 PG 14 WC Virology SC Virology GA AK5CT UT WOS:000338442600036 PM 24807714 ER PT J AU Matsuoka, Y Suguitan, A Orandle, M Paskel, M Boonnak, K Gardner, DJ Feldmann, F Feldmann, H Marino, M Jin, H Kemble, G Subbarao, K AF Matsuoka, Yumiko Suguitan, Amorsolo, Jr. Orandle, Marlene Paskel, Myeisha Boonnak, Kobporn Gardner, Donald J. Feldmann, Friederike Feldmann, Heinz Marino, Michael Jin, Hong Kemble, George Subbarao, Kanta TI African Green Monkeys Recapitulate the Clinical Experience with Replication of Live Attenuated Pandemic Influenza Virus Vaccine Candidates SO JOURNAL OF VIROLOGY LA English DT Article ID A H5N1 VACCINE; LOWER RESPIRATORY-TRACT; HEALTHY-ADULTS; PHASE-I; RECEPTOR SPECIFICITY; HUMAN INFECTION; PRIMATE MODEL; IMMUNOGENICITY; FERRETS; SAFETY AB Live attenuated cold-adapted (ca) H5N1, H7N3, H6N1, and H9N2 influenza vaccine viruses replicated in the respiratory tract of mice and ferrets, and 2 doses of vaccines were immunogenic and protected these animals from challenge infection with homologous and heterologous wild-type (wt) viruses of the corresponding subtypes. However, when these vaccine candidates were evaluated in phase I clinical trials, there were inconsistencies between the observations in animal models and in humans. The vaccine viruses did not replicate well and immune responses were variable in humans, even though the study subjects were seronegative with respect to the vaccine viruses before vaccination. Therefore, we sought a model that would better reflect the findings in humans and evaluated African green monkeys (AGMs) as a nonhuman primate model. The distribution of sialic acid (SA) receptors in the respiratory tract of AGMs was similar to that in humans. We evaluated the replication of wt and ca viruses of avian influenza (AI) virus subtypes H5N1, H6N1, H7N3, and H9N2 in the respiratory tract of AGMs. All of the wt viruses replicated efficiently, while replication of the ca vaccine viruses was restricted to the upper respiratory tract. Interestingly, the patterns and sites of virus replication differed among the different subtypes. We also evaluated the immunogenicity and protective efficacy of H5N1, H6N1, H7N3, and H9N2 ca vaccines. Protection from wt virus challenge correlated well with the level of serum neutralizing antibodies. Immune responses were slightly better when vaccine was delivered by both intranasal and intratracheal delivery than when it was delivered intranasally by sprayer. We conclude that live attenuated pandemic influenza virus vaccines replicate similarly in AGMs and human subjects and that AGMs may be a useful model to evaluate the replication of ca vaccine candidates. IMPORTANCE Ferrets and mice are commonly used for preclinical evaluation of influenza vaccines. However, we observed significant inconsistencies between observations in humans and in these animal models. We used African green monkeys (AGMs) as a nonhuman primate (NHP) model for a comprehensive and comparative evaluation of pairs of wild-type and pandemic live attenuated influenza virus vaccines (pLAIV) representing four subtypes of avian influenza viruses and found that pLAIVs replicate similarly in AGMs and humans and that AGMs can be useful for evaluation of the protective efficacy of pLAIV. C1 [Matsuoka, Yumiko; Suguitan, Amorsolo, Jr.; Paskel, Myeisha; Boonnak, Kobporn; Marino, Michael; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Orandle, Marlene] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. [Gardner, Donald J.; Feldmann, Friederike] NIAID, Rocky Mt Vet Branch, Rocky Mt Labs, NIH, Hamilton, MO USA. [Feldmann, Friederike] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MO USA. [Jin, Hong; Kemble, George] MedImmune LLC, Mountain View, CA USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU NIH; NIAID FX This research was performed as part of a Cooperative Research and Development Agreement (CRADA) between the Laboratory of Infectious Diseases, NIAID, and MedImmune and was supported in part by the Intramural Research Program of the NIH, NIAID. NR 63 TC 7 Z9 8 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2014 VL 88 IS 14 BP 8139 EP 8152 DI 10.1128/JVI.00425-14 PG 14 WC Virology SC Virology GA AK5CT UT WOS:000338442600041 PM 24807726 ER PT J AU Zaits, MN Rennert, OM AF Zaits, M. N. Rennert, O. M. TI Identification of differentially expressed microRNAs across the developing human brain SO MOLECULAR PSYCHIATRY LA English DT Article DE brain development; gene expression; microRNA; sex differences ID SEX-DIFFERENCES; TRANSCRIPTION FACTORS; GENE-REGULATION; DISEASE; NEUROSCIENCE; ANNOTATION; EVOLUTION; ROLES; RNA AB We present a spatio-temporal assessment of microRNA (miRNA) expression throughout early human brain development. We assessed the prefrontal cortex, hippocampus and cerebellum of 18 normal human donor brains spanning infancy through adolescence by RNA-seq. We discovered differentially expressed miRNAs and broad miRNA patterns across both temporal and spatial dimensions, and between male and female prefrontal cortex. Putative target genes of the differentially expressed miRNAs were identified, which demonstrated functional enrichment for transcription regulation, synaptogenesis and other basic intracellular processes. Sex-biased miRNAs also targeted genes related to Wnt and transforming growth factor-beta pathways. The differentially expressed miRNA targets were highly enriched for gene sets related to autism, schizophrenia, bipolar disorder and depression, but not neurodegenerative diseases, epilepsy or other adult-onset psychiatric diseases. Our results suggest critical roles for the identified miRNAs in transcriptional networks of the developing human brain and neurodevelopmental disorders. C1 [Zaits, M. N.; Rennert, O. M.] NICHHD, NIH, Bethesda, MD 20814 USA. [Zaits, M. N.] Univ Cambridge, NIH, Biomed Scholars Program, Cambridge, England. [Zaits, M. N.] Baylor Coll Med MSTP, Houston, TX USA. RP Zaits, MN (reprint author), NICHHD, NIH, 49 Convent Dr,Bldg 49,Room 2C08, Bethesda, MD 20814 USA. EM ziatsm@mail.nih.gov; rennerto@mail.nih.gov FU National Institute of Child Health and Human Development, NIH; Baylor College of Medicine Medical Scientist Training Program (MSTP); NIH-Oxford/Cambridge Biomedical Scholars Program FX We thank the Allen Institute for Brain Science. This work was supported by the Intramural Research Program (IRP) of the National Institute of Child Health and Human Development, NIH. MNZ was also supported by the Baylor College of Medicine Medical Scientist Training Program (MSTP) and the NIH-Oxford/Cambridge Biomedical Scholars Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 12 Z9 13 U1 4 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 2014 VL 19 IS 7 BP 848 EP 852 DI 10.1038/mp.2013.93 PG 5 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA AK1OV UT WOS:000338185300014 ER PT J AU Kiem, HP Baum, C Bushman, FD Byrne, BJ Carter, BJ Cavagnaro, J Malech, HL Mendell, JR Naldini, LM Sorrentino, BP Williams, DA Flotte, TR AF Kiem, Hans-Peter Baum, Christopher Bushman, Frederic D. Byrne, Barry J. Carter, Barrie J. Cavagnaro, Joy Malech, Harry L. Mendell, Jerry R. Naldini, Luigi M. Sorrentino, Brian P. Williams, David A. Flotte, Terence R. TI Charting a Clear Path: The ASGCT Standardized Pathways Conference SO MOLECULAR THERAPY LA English DT News Item ID SEVERE COMBINED IMMUNODEFICIENCY; RETROVIRAL VECTOR DESIGN; GENE-THERAPY; BIODISTRIBUTION; ACTIVATION; DISEASE C1 [Kiem, Hans-Peter] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98104 USA. [Kiem, Hans-Peter] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Baum, Christopher] Hannover Med Sch, Dept Expt Hematol, Hannover, Germany. [Bushman, Frederic D.] Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Byrne, Barry J.] Univ Florida, Coll Med, Dept Pediat, Div Cellular & Mol Therapy, Gainesville, FL USA. [Byrne, Barry J.] Univ Florida, Coll Med, Dept Pediat, Div Pediat, Gainesville, FL USA. [Byrne, Barry J.] Univ Florida, Powell Gene Therapy Ctr, Gainesville, FL USA. [Carter, Barrie J.] BioMarin Pharmaceut, San Rafael, CA USA. [Cavagnaro, Joy] Access BIO, Boyce, VA USA. [Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Mendell, Jerry R.] Nationwide Childrens Hosp, Paul D Wellstone Ctr, Columbus, OH USA. [Naldini, Luigi M.] San Raffaele Telethon Inst Gene Therapy TIGET, San Raffaele Sci Inst, Div Regenerat Med Stem Cells & Gene Therapy, Milan, Italy. [Sorrentino, Brian P.] St Jude Childrens Res Hosp, Dept Hematol, Div Expt Hematol, Memphis, TN 38105 USA. [Williams, David A.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Hematol Oncol, Boston, MA USA. [Williams, David A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA USA. [Flotte, Terence R.] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA 01605 USA. RP Kiem, HP (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave North,Mail Stop D1-100, Seattle, WA 98109 USA. EM hkiem@fhcrc.org OI Malech, Harry/0000-0001-5874-5775 FU NIDDK NIH HHS [R01 DK098252] NR 16 TC 4 Z9 4 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JUL PY 2014 VL 22 IS 7 BP 1235 EP 1238 DI 10.1038/mt.2014.95 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AK1QH UT WOS:000338189800002 PM 24981438 ER PT J AU Ito, S Bollard, CM Carlsten, M Melenhorst, JJ Biancotto, A Wang, EN Chen, JG Kotliarov, Y Cheung, F Xie, Z Marincola, F Tanimoto, K Battiwalla, M Olnes, MJ Perl, S Schum, P Hughes, TE Keyvanfar, K Hensel, N Muranski, P Young, NS Barrett, AJ AF Ito, Sawa Bollard, Catherine M. Carlsten, Mattias Melenhorst, Jan Joseph Biancotto, Angelique Wang, Ena Chen, Jinguo Kotliarov, Yuri Cheung, Foo Xie, Zhi Marincola, Francesco Tanimoto, Kazushi Battiwalla, Minoo Olnes, Matthew J. Perl, Shira Schum, Paula Hughes, Thomas E. Keyvanfar, Keyvan Hensel, Nancy Muranski, Pawel Young, Neal S. Barrett, A. John TI Ultra-low Dose Interleukin-2 Promotes Immune-m(o)dulating Function of Regulatory T Cells and Natural Killer Cells in Healthy Volunteers SO MOLECULAR THERAPY LA English DT Article ID VERSUS-HOST-DISEASE; METASTATIC MELANOMA; IL-2 THERAPY; NK CELLS; RECOMBINANT INTERLEUKIN-2; DENDRITIC CELLS; LYMPH-NODES; SUBSET; HELIOS(-); EXPRESSION AB Low-dose interleukin-2 (IL-2) expands regulatory T cells (T-regs) and natural killer (NK) cells after stem cell transplantation (SCT) and may reduce graft-versus-host disease (GVHD). We hypothesized that ultra-low dose (ULD) IL-2 could serve as an immune-modulating agent for stem cell donors to prevent GVHD following SCT. However, the safety, dose level, and immune signatures of ULD IL-2 in immune-competent healthy subjects remain unknown. Here, we have characterized the phenotype and function of T-regs and NK cells as well as the gene expression and cytokine profiles of 21 healthy volunteers receiving 50,000 to 200,000 units/m(2)/day IL-2 for 5 days. ULD IL-2 was well tolerated and induced a significant increase in the frequency of T-regs with increased suppressive function. There was a marked expansion of CD56(bright) NK cells with enhanced interferon-gamma (IFN-gamma) production. Serum cytokine profiling demonstrated increase of IFN-gamma induced protein 10 (IP-10). Gene expression analysis revealed significant changes in a highly restricted set of genes, including FOXP3, IL-2RA, and CISH. This is the first study to evaluate global immune-modulating function of ULD IL-2 in healthy subjects and to support the future studies administrating ULD IL-2 to stem cell donors. C1 [Ito, Sawa; Carlsten, Mattias; Melenhorst, Jan Joseph; Tanimoto, Kazushi; Battiwalla, Minoo; Olnes, Matthew J.; Keyvanfar, Keyvan; Hensel, Nancy; Muranski, Pawel; Young, Neal S.; Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Bollard, Catherine M.] Childrens Natl Hlth Syst, Washington, DC USA. [Bollard, Catherine M.] George Washington Univ, Washington, DC USA. [Biancotto, Angelique; Wang, Ena; Chen, Jinguo; Kotliarov, Yuri; Cheung, Foo; Xie, Zhi; Marincola, Francesco; Olnes, Matthew J.; Perl, Shira; Schum, Paula; Young, Neal S.] Trans NIH, Ctr Human Immunol Autoimmun & Inflammat, NIH, Bethesda, MD USA. [Wang, Ena] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD USA. [Hughes, Thomas E.] NIH, Dept Pharm, Ctr Clin, Bethesda, MD USA. RP Ito, S (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM S.I.itos2@mail.nih.gov RI Kotliarov, Yuri/B-6938-2017; OI Carlsten, Mattias/0000-0001-9815-0012 FU National Institutes of Health, National Heart, Lung, and Blood Institute FX We thank H Zhou, R Shi (Center for Human Immunology, NIH, USA) and S Miner, M Franco Colon, and F Chinian (Hematology Branch, NHLBI, NIH, USA) for their technical support. We thank L Bojanowski, V Williams, and A Byrnes (NHLBI, NIH, USA) for their protocol support. We also thank all volunteers who participated in this study. This research was supported by the Intramural Research Program of the National Institutes of Health, at the National Heart, Lung, and Blood Institute. Study concept and design were performed by S. I., C. B., O.J.M., T. H., P. M., and A.J.B. In vitro experiment and data collection were done by S. I., J.J.M., A. B., J.C., F. M., K. T., K. K., and N.H. Analysis and interpretation of data were done by S. I., M. C., E. W., S. P., N.H., P. M., and A.J.B. Drafting of the manuscript was done by S. I., B. C., M. C., P. M., N.S.Y., and A.J.B. Statistical analysis was performed by S. I., Y.K., F. C., and Z.X. Subject enrollment and clinical data collection were performed by S. I., M. B., P. S., T. H., and A.J.B. N.S.Y. and A.J.B. obtained funding and study supervision. All authors declare no conflict of interest. NR 48 TC 25 Z9 25 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD JUL PY 2014 VL 22 IS 7 BP 1388 EP 1395 DI 10.1038/mt.2014.50 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AK1QH UT WOS:000338189800018 PM 24686272 ER PT J AU Kawagishi, H Finkel, T AF Kawagishi, Hiroyuki Finkel, Toren TI ROS and disease: finding the right balance SO NATURE MEDICINE LA English DT Editorial Material ID OXIDATIVE STRESS; REACTIVE OXYGEN; AUTOPHAGY C1 [Kawagishi, Hiroyuki; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Kawagishi, H (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM finkelt@nih.gov NR 16 TC 27 Z9 29 U1 7 U2 26 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JUL PY 2014 VL 20 IS 7 BP 711 EP 713 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AK8PF UT WOS:000338689500012 PM 24999942 ER PT J AU Whiteaker, JR Halusa, GN Hoofnagle, AN Sharma, V MacLean, B Yan, P Wrobel, JA Kennedy, J Mani, DR Zimmerman, LJ Meyer, MR Mesri, M Rodriguez, H Paulovich, AG AF Whiteaker, Jeffrey R. Halusa, Goran N. Hoofnagle, Andrew N. Sharma, Vagisha MacLean, Brendan Yan, Ping Wrobel, John A. Kennedy, Jacob Mani, D. R. Zimmerman, Lisa J. Meyer, Matthew R. Mesri, Mehdi Rodriguez, Henry Paulovich, Amanda G. CA CPTAC TI CPTAC Assay Portal: a repository of targeted proteomic assays SO NATURE METHODS LA English DT Letter ID MASS-SPECTROMETRY; PEPTIDES; DATABASE; LIBRARY; CANCER C1 [Whiteaker, Jeffrey R.; Yan, Ping; Kennedy, Jacob; Paulovich, Amanda G.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Halusa, Goran N.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Hoofnagle, Andrew N.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Sharma, Vagisha; MacLean, Brendan] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Wrobel, John A.] Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Mani, D. R.] Broad Inst, Cambridge, MA USA. [Zimmerman, Lisa J.] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37235 USA. [Zimmerman, Lisa J.] Vanderbilt Univ, Sch Med, Jim Ayers Inst Precanc Detect & Diag, Nashville, TN 37235 USA. [Meyer, Matthew R.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Mesri, Mehdi; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, Bethesda, MD USA. RP Whiteaker, JR (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. EM apaulovi@fhcrc.org OI Liebler, Daniel/0000-0002-7873-3031; Fenyo, David/0000-0001-5049-3825; Ruggles, Kelly/0000-0002-0152-0863 FU NCI NIH HHS [U01 CA164186, U01CA164186, U24 CA159988, U24 CA160019, U24 CA160034, U24 CA160035, U24 CA160036, U24CA159988, U24CA160019, U24CA160034, U24CA160035, U24CA160036]; NIGMS NIH HHS [R01 GM103551, R01GM103551] NR 13 TC 27 Z9 27 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD JUL PY 2014 VL 11 IS 7 BP 703 EP 704 DI 10.1038/nmeth.3002 PG 2 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AK3KE UT WOS:000338321400004 PM 24972168 ER PT J AU Fornoni, A Merscher, S Kopp, JB AF Fornoni, Alessia Merscher, Sandra Kopp, Jeffrey B. TI Lipid biology of the podocyte-new perspectives offer new opportunities SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; LECITHIN-CHOLESTEROL ACYLTRANSFERASE; LOW-DENSITY-LIPOPROTEIN; DEPENDENT DIABETES-MELLITUS; URINARY ALBUMIN EXCRETION; GLOMERULAR SLIT DIAPHRAGM; APOL1 GENETIC-VARIANTS; CHRONIC KIDNEY-DISEASE; AUTOPHAGIC CELL-DEATH; TNF RECEPTORS 1 AB In the past 15 years, major advances have been made in understanding the role of lipids in podocyte biology. First, susceptibility to focal segmental glomerulosclerosis (FSGS) and glomerular disease is associated with an APOL1 sequence variant, is expressed in podocytes and encodes apolipoprotein L1, an important component of HDL. Second, acid sphingomyelinase-like phosphodiesterase 3b encoded by SMPDL3b has a role in the conversion of sphingomyelin to ceramide and its levels are reduced in renal biopsy samples from patients with recurrent FSGS. Furthermore, decreased SMPDL3b expression is associated with increased susceptibility of podocytes to injury after exposure to sera from these patients. Third, in many individuals with membranous nephropathy, autoantibodies against the phospholipase A(2) (PLA(2)) receptor, which is expressed in podocytes, have been identified. Whether these autoantibodies affect the activity of PLA(2), which liberates arachidonic acid from glycerophospholipids and modulates podocyte function, is unknown. Fourth, clinical and experimental evidence support a role for ATP-binding cassette sub-family A member 1-dependent cholesterol efflux, free fatty acids and glycerophospolipids in the pathogenesis of diabetic kidney disease. An improved understanding of lipid biology in podocytes might provide insights to develop therapeutic targets for primary and secondary glomerulopathies. C1 [Fornoni, Alessia; Merscher, Sandra] Univ Miami, Miller Sch Med, Peggy & Harold Katz Family Drug Discovery Ctr, Div Nephrol & Hypertens, Miami, FL 33136 USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. RP Fornoni, A (reprint author), Univ Miami, Miller Sch Med, Peggy & Harold Katz Family Drug Discovery Ctr, Div Nephrol & Hypertens, 1580 North West 10th Ave, Miami, FL 33136 USA. EM afornoni@med.miami.edu OI Kopp, Jeffrey/0000-0001-9052-186X FU NIH; NIDDK [DK090316, 5U24DX076169]; National Center for Advancing Translational Sciences [1UL1TR000460]; Diabetes Research Institute Foundation; Nephcure Foundation; Peggy and Harold Katz Family Foundation; Stanley J. Glaser Foundation; NIDDK Intramural Research Program FX A.F. and S.M. are supported by the NIH and NIDDK (grant numbers DK090316 and 5U24DX076169), the National Center for Advancing Translational Sciences (grant number 1UL1TR000460), the Diabetes Research Institute Foundation, the Nephcure Foundation and the Peggy and Harold Katz Family Foundation. S.M. is supported by the Stanley J. Glaser Foundation Research Award. J.B.K. is supported by the NIDDK Intramural Research Program. NR 141 TC 18 Z9 21 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD JUL PY 2014 VL 10 IS 7 BP 379 EP 388 DI 10.1038/nrneph.2014.87 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA AK5PY UT WOS:000338479500005 PM 24861084 ER PT J AU Uchida, M Ito, T Nakamura, T Hijioka, M Igarashi, H Oono, T Kato, M Nakamura, K Suzuki, K Takayanagi, R Jensen, RT AF Uchida, Masahiko Ito, Tetsuhide Nakamura, Taichi Hijioka, Masayuki Igarashi, Hisato Oono, Takamasa Kato, Masaki Nakamura, Kazuhiko Suzuki, Koichi Takayanagi, Ryoichi Jensen, Robert T. TI Pancreatic Stellate Cells and CX3CR1 Occurrence in Normal Pancreas and Acute and Chronic Pancreatitis and Effect of Their Activation by a CX3CR1 Agonist SO PANCREAS LA English DT Article DE fractalkine; fractalkine receptor; chemokine; pancreatic stellate cells; pancreatitis; signal transduction pathways ID INDUCED NEUTROPHIL CHEMOATTRACTANT; CERULEIN-INDUCED PANCREATITIS; CHEMOKINE RECEPTOR CCR5; ANGIOTENSIN-II; BRONCHOALVEOLAR MACROPHAGES; RHEUMATOID-ARTHRITIS; COLLAGEN PRODUCTION; GENE-EXPRESSION; LUNG INJURY; GLIAL-CELLS AB Objectives: Numerous studies suggest important roles of the chemokine, fractalkine (CX3CL1), in acute/chronic pancreatitis; however, the possible mechanisms of the effects are unclear. Pancreatic stellate cells (PSCs) can play important roles in pancreatitis, secreting inflammatory cytokines/chemokines, as well as proliferation. Therefore, we investigated CX3CL1 receptor (CX3CR1) occurrence in normal pancreas and pancreatitis (acute/chronic) tissues and the effects of CX3CL1 on activated PSCs. Methods: CX3CR1 expression/localization in normal pancreas and pancreatitis (acute/chronic) tissues was evaluated with immunohistochemical analysis. CX3CR1 expression and effects of CX3CL1 on activated PSCs were examined with real-time polymerase chain reaction, BrdU (5-bromo-2-deoxyuridine) assays, and Western blotting. Results: In normal pancreas, acinar cells expressed CX3CR1 within granule-like formations in the cytoplasm, whereas in acute/chronic pancreatitis, acinar, ductal, and activated PSCs expressed CX3CR1 on cell membranes. With activation of normal PSCs, CX3CR1 is increased. CX3CL1 activated multiple signaling cascades in PSCs. CX3CL1 did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Conclusions: CX3CR1s are expressed in normal pancreas. Expression is increased in acute/chronic pancreatitis, and the CX3CR1s are activated. CX3CL1 induces proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest that CX3CR1 activation of PSCs could be important in their effects in pancreatitis, especially to PSC proliferation in pancreatitis where CX3CL1 levels are elevated. C1 [Uchida, Masahiko; Ito, Tetsuhide; Nakamura, Taichi; Hijioka, Masayuki; Igarashi, Hisato; Oono, Takamasa; Kato, Masaki; Nakamura, Kazuhiko; Takayanagi, Ryoichi] Kyushu Univ, Dept Med & Bioregulatory Sci, Fukuoka 8128582, Japan. [Nakamura, Taichi; Jensen, Robert T.] NIDDK, Dept Cell Biol Sect, NIH, Bethesda, MD USA. [Suzuki, Koichi] Natl Inst Infect Dis, Dept Leprosy Res Ctr, Tokyo, Japan. RP Ito, T (reprint author), Kyushu Univ, Dept Med & Bioregulatory Sci, Grad Sch Med Sci, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan. EM itopapa@intmed3.med.kyushu-u.ac.jp RI U-ID, Kyushu/C-5291-2016 FU Ministry of Education, Culture, Sports, Science, and Technology, Japan [20590808]; Research Committee provided by the Ministry of Health, Labour, and Welfare Japan [50253448]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This work was supported by a grant from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (20590808, to T. I.), and the Research Committee provided by the Ministry of Health, Labour, and Welfare Japan (50253448, to T. I.). This work was also partially supported by intramural research funds of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 94 TC 3 Z9 3 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD JUL PY 2014 VL 43 IS 5 BP 708 EP 719 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AK0UY UT WOS:000338132700007 PM 24681877 ER PT J AU Joyce, AP Wang, MM Lawrence-Henderson, R Filliettaz, C Leung, SS Xu, X O'Hara, DM AF Joyce, Alison P. Wang, Mengmeng Lawrence-Henderson, Rosemary Filliettaz, Cynthia Leung, Sheldon S. Xu, Xin O'Hara, Denise M. TI One Mouse, One Pharmacokinetic Profile: Quantitative Whole Blood Serial Sampling for Biotherapeutics SO PHARMACEUTICAL RESEARCH LA English DT Article DE gyrolab; ligand-binding assay (LBA); mouse serial sampling; pharmacokinetics (PK) ID MICE; PLATFORM; ASSAYS AB The purpose of this study was to validate the approach of serial sampling from one mouse through ligand binding assay (LBA) quantification of dosed biotherapeutic in diluted whole blood to derive a pharmacokinetic (PK) profile. This investigation compared PK parameters obtained using serial and composite sampling methods following administration of human IgG monoclonal antibody. The serial sampling technique was established by collecting 10 mu L of blood via tail vein at each time point following drug administration. Blood was immediately diluted into buffer followed by analyte quantitation using Gyrolab to derive plasma concentrations. Additional studies were conducted to understand matrix and sampling site effects on drug concentrations. The drug concentration profiles, irrespective of biological matrix, and PK parameters using both sampling methods were not significantly different. There were no sampling site effects on drug concentration measurements except that concentrations were slightly lower in sodium citrated plasma than other matrices. We recommend the application of mouse serial sampling, particularly with limiting drug supply or specialized animal models. Overall the efficiencies gained by serial sampling were 40-80% savings in study cost, animal usage, study length and drug conservation while inter-subject variability across PK parameters was less than 30%. C1 [Joyce, Alison P.; Wang, Mengmeng; Lawrence-Henderson, Rosemary; Leung, Sheldon S.; O'Hara, Denise M.] Pfizer Inc, Dept Pharmacokinet Dynam & Metab, Andover, MA 01810 USA. [Filliettaz, Cynthia] Comparat Med Pfizer Inc, Andover, MA 01810 USA. [Xu, Xin] NIH, Therapeut Rare & Neglected Dis Program, Natl Ctr Translat Therapeut, Rockville, MD 20850 USA. RP Wang, MM (reprint author), Pfizer Inc, Dept Pharmacokinet Dynam & Metab, One Burtt Rd, Andover, MA 01810 USA. EM mengmeng.wang@pfizer.com NR 14 TC 10 Z9 10 U1 2 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 EI 1573-904X J9 PHARM RES-DORDR JI Pharm. Res. PD JUL PY 2014 VL 31 IS 7 BP 1823 EP 1833 DI 10.1007/s11095-013-1286-y PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA AK2UN UT WOS:000338275100018 PM 24464271 ER PT J AU Kolobe, THA Christy, JB Gannotti, ME Heathcock, JC Damiano, DL Taub, E Majsak, MJ Gordon, AM Fuchs, RK O'Neil, ME Caiozzo, VJ AF Kolobe, Thubi H. A. Christy, Jennifer Braswell Gannotti, Mary E. Heathcock, Jill C. Damiano, Diane L. Taub, Edward Majsak, Michael J. Gordon, Andrew M. Fuchs, Robyn K. O'Neil, Margaret E. Caiozzo, Vincent J. TI Research Summit III Proceedings on Dosing in Children With an Injured Brain or Cerebral Palsy: Executive Summary SO PHYSICAL THERAPY LA English DT Editorial Material ID INDUCED MOVEMENT THERAPY; CONSTRAINT-INDUCED THERAPY; CONGENITAL HEMIPLEGIA; MOTOR FUNCTION; NIH TOOLBOX; TRIAL; EXERCISE; BONE; COORDINATION; PLASTICITY C1 [Kolobe, Thubi H. A.] Univ Oklahoma, Hlth Sci Ctr, Dept Rehabil Sci, Oklahoma City, OK 73104 USA. [Christy, Jennifer Braswell] Univ Alabama Birmingham, Dept Phys Therapy, Birmingham, AL USA. [Gannotti, Mary E.] Univ Hartford, Dept Rehabil Sci, Hartford, CT 06117 USA. [Heathcock, Jill C.] Ohio State Univ, Med Ctr, Div Phys Therapy, Columbus, OH 43210 USA. [Damiano, Diane L.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Taub, Edward] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35294 USA. [Majsak, Michael J.] New York Med Coll, Sch Publ Hlth, Program Phys Therapy, Valhalla, NY 10595 USA. [Gordon, Andrew M.] Columbia Univ, Dept Biobehav Sci, New York, NY USA. [Fuchs, Robyn K.] Indiana Univ, Sch Hlth & Rehabil Sci, Dept Phys Therapy, Indianapolis, IN 46204 USA. [O'Neil, Margaret E.] Drexel Univ, Dept Phys Therapy & Rehabil Sci, Philadelphia, PA 19104 USA. [Caiozzo, Vincent J.] Univ Calif Irvine, Sch Med, Dept Orthopedics & Physiol & Biophys, Irvine, CA 92717 USA. RP Kolobe, THA (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Rehabil Sci, 801 NE 13th St, Oklahoma City, OK 73104 USA. EM hkolobe@ouhsc.edu RI Heathcock, Jill/E-3226-2011; Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU NICHD NIH HHS [R13 HD070615, R13HD070615] NR 54 TC 14 Z9 14 U1 0 U2 6 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 EI 1538-6724 J9 PHYS THER JI Phys. Ther. PD JUL PY 2014 VL 94 IS 7 BP 907 EP 920 DI 10.2522/ptj.20130024 PG 14 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA AK1IZ UT WOS:000338170100002 PM 24525862 ER PT J AU Maraia, RJ Iben, JR AF Maraia, Richard J. Iben, James R. TI Different types of secondary information in the genetic code SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Review DE anticodon; codons; silent mutation; tRNA modification ID TRANSFER-RNA GENES; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; SYNONYMOUS MUTATIONS; POLYMERASE III; USAGE BIAS; SCHIZOSACCHAROMYCES-POMBE; TRANSLATIONAL SELECTION; MOLECULAR-GENETICS; PROTEIN EVOLUTION AB Whole-genome and functional analyses suggest a wealth of secondary or auxiliary genetic information (AGI) within the redundancy component of the genetic code. Although there are multiple aspects of biased codon use, we focus on two types of auxiliary information: codon-specific translational pauses that can be used by particular proteins toward their unique folding and biased codon patterns shared by groups of functionally related mRNAs with coordinate regulation. AGI is important to genetics in general and to human disease; here, we consider influences of its three major components, biased codon use itself, variations in the tRNAome, and anticodon modifications that distinguish synonymous decoding. AGI is plastic and can be used by different species to different extents, with tissue-specificity and in stress responses. Because AGI is species-specific, it is important to consider codon-sensitive experiments when using heterologous systems; for this we focus on the tRNA anticodon loop modification enzyme, CDKAL1, and its link to type 2 diabetes. Newly uncovered tRNAome variability among humans suggests roles in penetrance and as a genetic modifier and disease modifier. Development of experimental and bioinformatics methods are needed to uncover additional means of auxiliary genetic information. C1 [Maraia, Richard J.; Iben, James R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program Genom Differentiat, NIH, Bethesda, MD 20892 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 Intramural Research Program on Genomics of Differentiation in the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank Robert Crouch, Dolph Hatfield, Mark Mortin, and Harold Burgess for critical reading of this work at various stages of its development; T. Begley, N. Blewett, R. Crouch, and the PGD Seminar Series members for discussion; R. Crouch, T. Pederson, and P. Schimmel for encouragement; and anonymous reviewers for insightful and helpful comments. This work was supported by the Intramural Research Program on Genomics of Differentiation in the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 105 TC 5 Z9 5 U1 1 U2 24 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 EI 1469-9001 J9 RNA JI RNA-Publ. RNA Soc. PD JUL PY 2014 VL 20 IS 7 BP 977 EP 984 DI 10.1261/rna.044115.113 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AK2TA UT WOS:000338271200002 PM 24935971 ER PT J AU Ford, JM Morris, SE Hoffman, RE Sommer, I Waters, F McCarthy-Jones, S Thoma, RJ Turner, JA Keedy, SK Badcock, JC Cuthbert, BN AF Ford, Judith M. Morris, Sarah E. Hoffman, Ralph E. Sommer, Iris Waters, Flavie McCarthy-Jones, Simon Thoma, Robert J. Turner, Jessica A. Keedy, Sarah K. Badcock, Johanna C. Cuthbert, Bruce N. TI Studying Hallucinations Within the NIMH RDoC Framework SO SCHIZOPHRENIA BULLETIN LA English DT Article DE Hallucinations; Research Domain Criteria; RDoC ID AUDITORY VERBAL HALLUCINATIONS; INNER SPEECH; COGNITIVE NEUROPSYCHIATRY; COROLLARY DISCHARGE; SCHIZOPHRENIA; THOUGHT; PSYCHOPATHOLOGY; DIRECTIONS; DISORDERS; VOICES AB We explore how hallucinations might be studied within the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) framework, which asks investigators to step back from diagnoses based on symptoms and focus on basic dimensions of functioning. We start with a description of the objectives of the RDoC project and its domains and constructs. Because the RDoC initiative asks investigators to study phenomena across the wellness spectrum and different diagnoses, we address whether hallucinations experienced in nonclinical populations are the same as those experienced by people with psychotic diagnoses, and whether hallucinations studied in one clinical group can inform our understanding of the same phenomenon in another. We then discuss the phenomenology of hallucinations and how different RDoC domains might be relevant to their study. We end with a discussion of various challenges and potential next steps to advance the application of the RDoC approach to this area of research. C1 [Ford, Judith M.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Ford, Judith M.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Morris, Sarah E.; Cuthbert, Bruce N.] NIMH, Div Adult Translat Res, Bethesda, MD 20892 USA. [Hoffman, Ralph E.] Yale New Haven Psychiat Hosp, Dept Psychiat, New Haven, CT USA. [Sommer, Iris] Univ Med Ctr, Dept Psychiat, Utrecht, Netherlands. [Waters, Flavie] Univ Western Australia, Ctr Clin Res Neuropsychiat, Sch Psychiat & Clin Neurosci, Perth, WA 6009, Australia. [Waters, Flavie] North Metro Hlth Serv Mental Hlth, Graylands Hosp, Perth, WA, Australia. [McCarthy-Jones, Simon] Macquarie Univ, ARC Ctr Excellence Cognit & Its Disorders, Dept Cognit Sci, Sydney, NSW 2109, Australia. [McCarthy-Jones, Simon] Univ Durham, Dept Psychol, Durham DH1 3LE, England. [Thoma, Robert J.] Univ New Mexico, Dept Psychiat, Albuquerque, NM 87131 USA. [Turner, Jessica A.] Georgia State Univ, Dept Psychol, Atlanta, GA 30303 USA. [Turner, Jessica A.] Georgia State Univ, Inst Neurosci, Atlanta, GA 30303 USA. [Keedy, Sarah K.] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Badcock, Johanna C.] Univ Western Australia, Sch Psychol, Crawley, WA, Australia. [Badcock, Johanna C.] North Metropolitan Hlth Serv Mental Hlth, Clin Res Ctr, Mt Claremont, WA, Australia. RP Ford, JM (reprint author), San Francisco VA Med Ctr, Psychiat Serv 116D, 4150 Clement St, San Francisco, CA 94121 USA. EM judith.ford@ucsf.edu RI Keedy, Sarah/H-6557-2014; Badcock, Johanna/C-3682-2013; Turner, Jessica/H-7282-2015 OI Keedy, Sarah/0000-0002-2139-9271; Badcock, Johanna/0000-0003-4629-2929; Turner, Jessica/0000-0003-0076-8434 FU National Institute of Mental Health [MH058262, MH067073, MH073673]; Veterans Administration; VIDI from the Netherlands Organization for Scientific Research; National Institutes of Health [2P20GM103472-06]; Wellcome Trust [WT098455]; Macquarie University; [K23MH092702]; [P20RR021938 Phase 1NCRR COBRE] FX National Institute of Mental Health (MH058262 [J.M.F.], MH067073 [R. E. H.], MH073673 [R. E. H.]); Veterans Administration (J.M.F.); VIDI grant from the Netherlands Organization for Scientific Research (I. E. C. S.); K23MH092702 (S. K. K.); National Institutes of Health 2P20GM103472-06 (R.J.T.; J.A.T.); P20RR021938 Phase 1NCRR COBRE (R.J.T.); Wellcome Trust Grant (WT098455 to S.M.-J.); Macquarie University Research Fellowship (S.M.-J.). NR 61 TC 35 Z9 35 U1 5 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JUL PY 2014 VL 40 SU 4 BP S295 EP S304 DI 10.1093/schbul/sbu011 PG 10 WC Psychiatry SC Psychiatry GA AK0US UT WOS:000338132100012 PM 24847862 ER PT J AU Jardri, R Bartels-Velthuis, AA Debbane, M Jenner, JA Kelleher, I Dauvilliers, Y Plazzi, G Demeulemeester, M David, CN Rapoport, J Dobbelaere, D Escher, S Fernyhough, C AF Jardri, Renaud Bartels-Velthuis, Agna A. Debbane, Martin Jenner, Jack A. Kelleher, Ian Dauvilliers, Yves Plazzi, Giuseppe Demeulemeester, Morgane David, Christopher N. Rapoport, Judith Dobbelaere, Dries Escher, Sandra Fernyhough, Charles TI From Phenomenology to Neurophysiological Understanding of Hallucinations in Children and Adolescents SO SCHIZOPHRENIA BULLETIN LA English DT Article DE hallucinations; childhood; review; adolescence ID PSYCHOTIC-LIKE EXPERIENCES; AUDITORY VERBAL HALLUCINATIONS; TRANSCRANIAL MAGNETIC STIMULATION; CHILDHOOD-ONSET SCHIZOPHRENIA; FOCUSED INTEGRATIVE TREATMENT; RANDOMIZED CONTROLLED-TRIAL; COMMUNITY SAMPLE; BIRTH-COHORT; GENERAL-POPULATION; DEVELOPMENTAL EXPRESSION AB Typically reported as vivid, multisensory experiences which may spontaneously resolve, hallucinations are present at high rates during childhood. The risk of associated psychopathology is a major cause of concern. On the one hand, the risk of developing further delusional ideation has been shown to be reduced by better theory of mind skills. On the other hand, ideas of reference, passivity phenomena, and misidentification syndrome have been shown to increase the risk of self-injury or heteroaggressive behaviors. Cognitive psychology and brain-imaging studies have advanced our knowledge of the mechanisms underlying these early-onset hallucinations. Notably, specific functional impairments have been associated with certain phenomenological characteristics of hallucinations in youths, including intrusiveness and the sense of reality. In this review, we provide an update of associated epidemiological and phenomenological factors ( including sociocultural context, social adversity, and genetics, considered in relation to the psychosis continuum hypothesis), cognitive models, and neurophysiological findings concerning hallucinations in children and adolescents. Key issues that have interfered with progress are considered and recommendations for future studies are provided. C1 [Jardri, Renaud] Univ Med Ctr Lille, Child & Adolescent Psychiat Dept, Lille, France. [Jardri, Renaud; Demeulemeester, Morgane] Lille Nord France Univ, UDSL, Funct Neurosci & Disorders Lab, Lille, France. [Bartels-Velthuis, Agna A.] Univ Groningen, Univ Med Ctr Groningen, Univ Ctr Psychiat, Groningen, Netherlands. [Debbane, Martin] Univ Geneva, Adolescence Clin Psychol Res Unit, Fac Psychol & Educ Sci, Geneva, Switzerland. [Debbane, Martin] UCL, Res Dept Clin Educ & Hlth Psychol, London, England. [Jenner, Jack A.] Jenner Consult Haren & Audito Practice Child & Ad, Ten Boer, Netherlands. [Kelleher, Ian] Karolinska Inst, Natl Ctr Suicide Res & Prevent Mental Ill Hlth, Stockholm, Sweden. [Dauvilliers, Yves] CHU Montpellier, Sleep Unit, Dept Neurol, Hop Gui de Chauliac, Montpellier, France. [Dauvilliers, Yves] INSERM, U1061, Natl Reference Network Narcolepsy, Montpellier, France. [Plazzi, Giuseppe] Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy. [Plazzi, Giuseppe] IRCCS, Inst Neurol Sci, Bologna, Italy. [Demeulemeester, Morgane] ORPEACLINEA Grp, Lautreamont Clin, Loos, France. [David, Christopher N.; Rapoport, Judith] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [David, Christopher N.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Dobbelaere, Dries] Univ Childrens Hosp Jeanne Flandre, Natl Reference Ctr Inherited Metab Dis Child & Ad, Lille, France. [Escher, Sandra] City Univ Birmingham, Birmingham, W Midlands, England. [Fernyhough, Charles] Univ Durham, Dept Psychol, Durham DH1 3LE, England. RP Jardri, R (reprint author), CHRU Lille, Unite CURE, Hop Fontan, CS 70001, F-59037 Lille, France. EM renaud.jardri@chru-lille.fr RI Jardri, Renaud/J-9202-2012; Fernyhough, Charles/A-1057-2010; OI Jardri, Renaud/0000-0003-4596-1502; Fernyhough, Charles/0000-0002-3822-710X; Plazzi, Giuseppe/0000-0002-1051-0472; Kelleher, Ian/0000-0003-1484-651X FU Wellcome Trust [WT098455] FX Wellcome Trust grant (WT098455 to C.F.). NR 102 TC 18 Z9 18 U1 12 U2 23 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JUL PY 2014 VL 40 SU 4 BP S221 EP S232 DI 10.1093/schbul/sbu029 PG 12 WC Psychiatry SC Psychiatry GA AK0US UT WOS:000338132100005 PM 24936083 ER PT J AU Cheon, S Liang, FM Chen, YG Yu, K AF Cheon, Sooyoung Liang, Faming Chen, Yuguo Yu, Kai TI Stochastic approximation Monte Carlo importance sampling for approximating exact conditional probabilities SO STATISTICS AND COMPUTING LA English DT Article DE Contingency table; Exact inference; Importance sampling; MCMC; Stochastic approximation; Monte Carlo ID BINARY CONTINGENCY-TABLES; WANG-LANDAU ALGORITHM; MARKOV BASES; EFFICIENT; COMPUTATION; MODELS; OPTIMIZATION; CONVERGENCE; INFERENCE; VALUES AB Importance sampling and Markov chain Monte Carlo methods have been used in exact inference for contingency tables for a long time, however, their performances are not always very satisfactory. In this paper, we propose a stochastic approximation Monte Carlo importance sampling (SAMCIS) method for tackling this problem. SAMCIS is a combination of adaptive Markov chain Monte Carlo and importance sampling, which employs the stochastic approximation Monte Carlo algorithm (Liang et al., J. Am. Stat. Assoc., 102(477):305-320, 2007) to draw samples from an enlarged reference set with a known Markov basis. Compared to the existing importance sampling and Markov chain Monte Carlo methods, SAMCIS has a few advantages, such as fast convergence, ergodicity, and the ability to achieve a desired proportion of valid tables. The numerical results indicate that SAMCIS can outperform the existing importance sampling and Markov chain Monte Carlo methods: It can produce much more accurate estimates in much shorter CPU time than the existing methods, especially for the tables with high degrees of freedom. C1 [Cheon, Sooyoung] Korea Univ, Dept Informat Stat, Jochiwon 339700, South Korea. [Liang, Faming] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Chen, Yuguo] Univ Illinois, Dept Stat, Champaign, IL 61820 USA. [Yu, Kai] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Liang, FM (reprint author), Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. EM scheon@korea.ac.kr; fliang@stat.tamu.edu; yuguo@illinois.edu; yuka@mail.nih.gov FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2011-0015000]; National Science Foundation [DMS-1007457, DMS-1106494, DMS-1106796]; King Abdullah University of Science and Technology (KAUST) [KUS-C1-016-04] FX The authors thank the editor, associate editor and two referees for their constructive comments which have led to significant improvement of this paper. Cheon's research was partially supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0015000). Liang's research was partially supported by grants from the National Science Foundation (DMS-1007457 and DMS-1106494) and the award (KUS-C1-016-04) made by King Abdullah University of Science and Technology (KAUST). Chen's research was partly supported by the National Science Foundation grant DMS-1106796. NR 54 TC 0 Z9 0 U1 3 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0960-3174 EI 1573-1375 J9 STAT COMPUT JI Stat. Comput. PD JUL PY 2014 VL 24 IS 4 BP 505 EP 520 DI 10.1007/s11222-013-9384-6 PG 16 WC Computer Science, Theory & Methods; Statistics & Probability SC Computer Science; Mathematics GA AK2UP UT WOS:000338275300002 ER PT J AU Bielejec, F Lemey, P Baele, G Rambaut, A Suchard, MA AF Bielejec, Filip Lemey, Philippe Baele, Guy Rambaut, Andrew Suchard, Marc A. TI Inferring Heterogeneous Evolutionary Processes Through Time: from Sequence Substitution to Phylogeography SO SYSTEMATIC BIOLOGY LA English DT Article ID NUCLEOTIDE SUBSTITUTION; STATISTICAL PHYLOGENETICS; POPULATION-DYNAMICS; LIKELIHOOD APPROACH; MOLECULAR CLOCK; DNA-SEQUENCES; BAYES FACTORS; MODEL; VIRUS; LIFE AB Molecular phylogenetic and phylogeographic reconstructions generally assume time-homogeneous substitution processes. Motivated by computational convenience, this assumption sacrifices biological realism and offers little opportunity to uncover the temporal dynamics in evolutionary histories. Here, we propose an evolutionary approach that explicitly relaxes the time-homogeneity assumption by allowing the specification of different infinitesimal substitution rate matrices across different time intervals, called epochs, along the evolutionary history. We focus on an epoch model implementation in a Bayesian inference framework that offers great modeling flexibility in drawing inference about any discrete data type characterized as a continuous-time Markov chain, including phylogeographic traits. To alleviate the computational burden that the additional temporal heterogeneity imposes, we adopt a massively parallel approach that achieves both fine- and coarse-grain parallelization of the computations across branches that accommodate epoch transitions, making extensive use of graphics processing units. Through synthetic examples, we assess model performance in recovering evolutionary parameters from data generated according to different evolutionary scenarios that comprise different numbers of epochs for both nucleotide and codon substitution processes. We illustrate the usefulness of our inference framework in two different applications to empirical data sets: the selection dynamics on within-host HIV populations throughout infection and the seasonality of global influenza circulation. In both cases, our epoch model captures key features of temporal heterogeneity that remained difficult to test using ad hoc procedures. [Bayesian inference; BEAGLE; BEAST; Epoch Model; phylogeography; Phylogenetics.]. C1 [Bielejec, Filip; Lemey, Philippe; Baele, Guy] Katholieke Univ Leuven, Rega Inst, Dept Microbiol & Immunol, Leuven, Belgium. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Suchard, Marc A.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA. RP Bielejec, F (reprint author), Katholieke Univ Leuven, Rega Inst, Dept Microbiol & Immunol, Leuven, Belgium. EM filip.bielejec@rega.kuleuven.be OI Rambaut, Andrew/0000-0003-4337-3707 FU European Research Council under the European Community [278433-PREDEMICS]; ERC [260864]; Wellcome Trust [092807]; National Science Foundation [DMS 1264153]; National Institutes of Health [R01 HG006139] FX The research leading to these results has received funding from the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013) under Grant Agreement no. 278433-PREDEMICS and ERC Grant agreement no. 260864, the Wellcome Trust (grant no. 092807), the National Science Foundation (DMS 1264153), and the National Institutes of Health (R01 HG006139). The National Evolutionary Synthesis Center (NESCent) catalyzed this collaboration through a working group (NSF EF-0423641). NR 48 TC 9 Z9 9 U1 3 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1063-5157 EI 1076-836X J9 SYST BIOL JI Syst. Biol. PD JUL PY 2014 VL 63 IS 4 BP 493 EP 504 DI 10.1093/sysbio/syu015 PG 12 WC Evolutionary Biology SC Evolutionary Biology GA AK0VE UT WOS:000338133300003 PM 24627184 ER PT J AU Guertin, KA Moore, SC Sampson, JN Huang, WY Xiao, Q Stolzenberg-Solomon, RZ Sinha, R Cross, AJ AF Guertin, Kristin A. Moore, Steven C. Sampson, Joshua N. Huang, Wen-Yi Xiao, Qian Stolzenberg-Solomon, Rachael Z. Sinha, Rashmi Cross, Amanda J. TI Metabolomics in nutritional epidemiology: identifying metabolites associated with diet and quantifying their potential to uncover diet-disease relations in populations SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID PROLINE BETAINE; ADDITIONAL MEASUREMENTS; BIOCHEMICAL MARKERS; GLYCINE BETAINE; GUT MICROBIOME; URINE SAMPLES; CITRUS-FRUIT; DISCOVERY; CANCER; BIOMARKERS AB Background: Metabolomics is an emerging field with the potential to advance nutritional epidemiology; however, it has not yet been applied to large cohort studies. Objectives: Our first aim was to identify metabolites that are biomarkers of usual dietary intake. Second, among serum metabolites correlated with diet, we evaluated metabolite reproducibility and required sample sizes to determine the potential for metabolomics in epidemiologic studies. Design: Baseline serum from 502 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was analyzed by using ultra-high-performance liquid-phase chromatography with tandem mass spectrometry and gas chromatography-mass spectrometry. Usual intakes of 36 dietary groups were estimated by using a food-frequency questionnaire. Dietary biomarkers were identified by using partial Pearson's correlations with Bonferroni correction for multiple comparisons. Intraclass correlation coefficients (ICCs) between samples collected l y apart in a subset of 30 individuals were calculated to evaluate intraindividual metabolite variability. Results: We detected 412 known metabolites. Citrus, green vegetables, red meat, shellfish, fish, peanuts, rice, butter, coffee, beer, liquor, total alcohol, and multivitamins were each correlated with at least one metabolite (P < 1.093 x 10(-6); r = -0.312 to 0.398); in total, 39 dietary biomarkers were identified. Some correlations (citrus intake with stachydrine) replicated previous studies; others, such as peanuts and tryptophan betaine, were novel findings. Other strong associations included coffee (with trigonelline-N-methylnicotinate and quinate) and alcohol (with ethyl glucuronide). Intraindividual variability in metabolite levels (1-y ICCs) ranged from 0.27 to 0.89. Large, but attainable, sample sizes are required to detect associations between metabolites and disease in epidemiologic studies, further emphasizing the usefulness of metabolomics in nutritional epidemiology. Conclusions: We identified dietary biomarkers by using metabolomics in an epidemiologic data set. Given the strength of the associations observed, we expect that some of these metabolites will be validated in future studies and later used as biomarkers in large cohorts to study diet-disease associations. C1 [Guertin, Kristin A.; Moore, Steven C.; Xiao, Qian; Stolzenberg-Solomon, Rachael Z.; Sinha, Rashmi; Cross, Amanda J.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv,Nutr Epidemiol Branch, Bethesda, MD 20892 USA. [Sampson, Joshua N.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv,Biostat Branch, Bethesda, MD 20892 USA. [Huang, Wen-Yi] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv,Occupat & Environm Epidemi, Bethesda, MD 20892 USA. RP Guertin, KA (reprint author), NCI, NIH, 9609 Med Ctr Dr,Room 6E326,MSC 9760, Bethesda, MD 20892 USA. EM kristin.guertin@nih.gov RI Sinha, Rashmi/G-7446-2015; Moore, Steven/D-8760-2016; OI Sinha, Rashmi/0000-0002-2466-7462; Moore, Steven/0000-0002-8169-1661; Guertin, Kristin/0000-0003-0844-205X FU Intramural Research Program of the National Cancer Institute, NIH FX Supported by the Intramural Research Program of the National Cancer Institute, NIH. NR 41 TC 36 Z9 37 U1 7 U2 66 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2014 VL 100 IS 1 BP 208 EP 217 DI 10.3945/ajcn.113.078758 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AJ7FG UT WOS:000337862000024 PM 24740205 ER PT J AU Kirkpatrick, SI Subar, AF Douglass, D Zimmerman, TP Thompson, FE Kahle, LL George, SM Dodd, KW Potischtnan, N AF Kirkpatrick, Sharon I. Subar, Amy F. Douglass, Deirdre Zimmerman, Thea P. Thompson, Frances E. Kahle, Lisa L. George, Stephanie M. Dodd, Kevin W. Potischtnan, Nancy TI Performance of the Automated Self-Administered 24-hour Recall relative to a measure of true intakes and to an interviewer-administered 24-h recall SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID MULTIPLE-PASS METHOD; DIETARY MEASUREMENT ERROR; ENERGY-INTAKE; FOOD-INTAKE; VALIDATION; BIOMARKERS; ACCURACY; INTERVAL; RECORDS; GENDER AB Background: The Automated Self-Administered 24-hour Recall (ASA24), a freely available Web-based tool, was developed to enhance the feasibility of collecting high-quality dietary intake data from large samples. Objective: The purpose of this study was to assess the criterion validity of ASA24 through a feeding study in which the true intake for 3 meals was known. Design: True intake and plate waste from 3 meals were ascertained for 81 adults by inconspicuously weighing foods and beverages offered at a buffet before and after each participant served him-or herself. Participants were randomly assigned to complete an ASA24 or an interviewer-administered Automated Multiple-Pass Method (AMPM) recall the following day. With the use of linear and Poisson regression analysis, we examined the associations between recall mode and I) the proportions of items consumed for which a match was reported and that were excluded, 2) the number of intrusions (items reported but not consumed), and 3) differences between energy, nutrient, food group, and portion size estimates based on true and reported intakes. Results: Respondents completing ASA24 reported 80% of items truly consumed compared with 83% in AMPM (P = 0.07). For both ASA24 and AMPM, additions to or ingredients in multicomponent foods and drinks were more frequently omitted than were main foods or drinks. The number of intrusions was higher in ASA24 (P < 0.01). Little evidence of differences by recall mode was found in the gap between true and reported energy, nutrient, and food group intakes or portion sizes. Conclusions: Although the interviewer-administered AMPM performed somewhat better relative to true intakes for matches, exclusions, and intrusions, ASA24 performed well. Given the substantial cost savings that ASA24 offers, it has the potential to make important contributions to research aimed at describing the diets of populations, assessing the effect of interventions on diet, and elucidating diet and health relations. C1 [Kirkpatrick, Sharon I.; Subar, Amy F.; Thompson, Frances E.; George, Stephanie M.; Potischtnan, Nancy] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Douglass, Deirdre; Zimmerman, Thea P.] Westat Corp, Rockville, MD USA. [Kahle, Lisa L.] Information Management Serv Inc, Rockville, MD USA. [Dodd, Kevin W.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Kirkpatrick, SI (reprint author), Univ Waterloo, Sch Publ Hlth & Hlth Syst, 200 Univ Ave West,BMH 1036, Waterloo, ON N2L 3G1, Canada. EM sharon.kirkpatrick@uwaterloo.ca OI Kirkpatrick, Sharon/0000-0001-9896-5975 FU US government via a contract with Westat [NO2-PC-64406, HHSN261200644006C] FX The data for this study were collected by the US government via a contract with Westat (NO2-PC-64406, HHSN261200644006C). NR 19 TC 36 Z9 36 U1 2 U2 14 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2014 VL 100 IS 1 BP 233 EP 240 DI 10.3945/ajcn.114.083238 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AJ7FG UT WOS:000337862000026 PM 24787491 ER PT J AU Koo, E Neuringer, M SanGiovanni, JP AF Koo, Euna Neuringer, Martha SanGiovanni, John Paul TI Macular xanthophylls, lipoprotein-related genes, and age-related macular degeneration SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT 6th International Congress on Vegetarian Nutrition (ICVN) CY FEB 24-26, 2013 CL Loma Linda Univ, Loma Linda, CA SP Loma Linda Univ Hlth, Kelloggs, Calif Walnut Commiss, Silk, Lifestyle Med Inst Sanitarium Hlth & Wellbeing, LifeLong Hlth, Int Nut & Dried Fruit Council HO Loma Linda Univ ID PIGMENT OPTICAL-DENSITY; SERUM CAROTENOID CONCENTRATIONS; APOLIPOPROTEIN-E GENE; BEAVER DAM EYE; HUMAN RETINA; SPATIAL-DISTRIBUTION; SCAVENGER RECEPTOR; CLASS-B; SR-BI; LUTEIN SUPPLEMENTATION AB Plant-based macular xanthophylls (MXs; lutein and zeaxanthin) and the lutein metabolite meso-zeaxanthin are the major constituents of macular pigment, a compound concentrated in retinal areas that are responsible for fine-feature visual sensation. There is an unmet need to examine the genetics of factors influencing regulatory mechanisms and metabolic fates of these 3 MXs because they are linked to processes implicated in the pathogenesis of age-related macular degeneration (AMD). In this work we provide an overview of evidence supporting a molecular basis for AMD-MX associations as they may relate to DNA sequence variation in AMD- and lipoproteinrelated genes. We recognize a number of emerging research opportunities, barriers, knowledge gaps, and tools offering promise for meaningful investigation and inference in the field. Overviews on AMD- and high-density lipoprotein (wHDL)-related genes encoding receptors, transporters, and enzymes affecting or affected by MXs are followed with information on localization of products from these genes to retinal cell types manifesting AMD-related pathophysiology. Evidence on the relation of each gene or gene product with retinal MX response to nutrient intake is discussed.. This information is followed by a review of results from mechanistic studies testing gene-disease relations. We then present findings on relations of AMD with DNA sequence variants in MX-associated genes. Our conclusion is that AMD-associated DNA variants that influence the actions and metabolic fates of HDL system constituents should be examined further for concomitant influence on MX absorption, retinal tissue responses to MX intake, and the capacity to modify MX-associated factors and processes implicated in AMD pathogenesis. C1 [Koo, Euna] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA USA. [Neuringer, Martha] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Portland, OR USA. [Neuringer, Martha] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR USA. [SanGiovanni, John Paul] NEI, NIH, Bethesda, MD 20892 USA. RP SanGiovanni, JP (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM jpsangio@post.harvard.edu NR 176 TC 6 Z9 6 U1 4 U2 13 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2014 VL 100 IS 1 SU S BP 336S EP 346S DI 10.3945/ajcn.113.071563 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AJ7FI UT WOS:000337862200005 PM 24829491 ER PT J AU Abid, Z Cross, AJ Sinha, R AF Abid, Zaynah Cross, Amanda J. Sinha, Rashmi TI Meat, dairy, and cancer SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT 6th International Congress on Vegetarian Nutrition (ICVN) CY FEB 24-26, 2013 CL Loma Linda Univ, Loma Linda, CA SP Loma Linda Univ Hlth, Kelloggs, Calif Walnut Commiss, Silk, Lifestyle Med Inst Sanitarium Hlth & Wellbeing, LifeLong Hlth, Int Nut & Dried Fruit Council HO Loma Linda Univ ID NIH-AARP DIET; POSTMENOPAUSAL BREAST-CANCER; LARGE PROSPECTIVE COHORT; PROCESSED MEAT; OVARIAN-CANCER; COLORECTAL-CANCER; PANCREATIC-CANCER; PROSTATE-CANCER; SCREENING TRIAL; BLADDER-CANCER AB In 2007 the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) report judged that the evidence for an association between red and processed meat consumption and colorectal cancer was convincing. In addition, the effect of other animal products on cancer risk has been studied, and the WCRF/AICR report concluded that milk probably decreases the risk of colorectal cancer but diets high in calcium probably increase the risk of prostate cancer, whereas there was limited evidence for an association between milk and bladder cancer and insufficient evidence for other cancers. There are several potential mechanisms relating meat to cancer, including heterocyclic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, and heme iron. Although the evidence in favor of a link between red and processed meat and colorectal cancer is convincing, the relations with other cancers are unclear. In this review, we summarize cohort studies conducted by the National Cancer Institute on meat and dairy intake in relation to cancer since the 2007 WCRF/AICR report. We also report the findings of meta-analyses published since 2007. C1 [Abid, Zaynah; Cross, Amanda J.; Sinha, Rashmi] NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Sinha, R (reprint author), NCI, NIH, Dept Hlth & Human Serv, 9609 Med Ctr Dr,RM 6E336 MSC 9768, Bethesda, MD 20892 USA. EM sinhar@mail.nih.gov RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU Intramural NIH HHS NR 67 TC 29 Z9 29 U1 11 U2 54 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2014 VL 100 IS 1 SU S BP 386S EP 393S DI 10.3945/ajcn.113.071597 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AJ7FI UT WOS:000337862200012 PM 24847855 ER PT J AU Nussenblatt, RB Lee, RWJ Chew, E Wei, L Liu, BY Sen, HN Dick, AD Ferris, FL AF Nussenblatt, Robert B. Lee, Richard W. J. Chew, Emily Wei, Lai Liu, Baoying Sen, H. Nida Dick, Andrew D. Ferris, Frederick L. TI Immune Responses in Age-Related Macular Degeneration and a Possible Long-term Therapeutic Strategy for Prevention SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID COMPLEMENT FACTOR-H; T-CELL; ORAL TOLERANCE; UNITED-STATES; DOUBLE-BLIND; INFLAMMATION; DISEASE; UVEITIS; TRIAL; NEOVASCULARIZATION AB PURPOSE: To describe the immune alterations associated with age-related macular degeneration (AMD); and, based on these findings, to offer an approach to possibly prevent the expression of late disease. DESIGN: Perspective. METHODS: Review of the existing literature dealing with epidemiology, models, and immunologic findings in patients. RESULTS: Significant genetic associations have been identified and reported, but environmentally induced (including epigenetic) changes are also an important consideration. Immune alterations include a strong interleukin 17 family signature as well as marked expression of these molecules in the eye. Oxidative stress as well as other homeostatic altering mechanisms occur throughout life. With this immune dysregulation there is a rationale for considering immunotherapy. Indeed, immunotherapy has been shown to affect the late stages of AMD. CONCLUSION: Immune dysregulation appears to be an underlying alteration in AMD, as in other diseases thought to be degenerative and attributable to aging. Para-inflammation and immunosenescence may importantly contribute to the development of disease. The role of complement factor H still needs to be better defined, but in light of its association with ocular inflammatory conditions such as sarcoidosis, it does not appear to be unique to AMD but rather may be a marker for retinal pigment epithelium function. With the strong interleukin 17 family signature and the need to treat early on in the disease process, oral tolerance may be considered to prevent disease progression. Published by Elsevier Inc. C1 [Nussenblatt, Robert B.; Chew, Emily; Wei, Lai; Liu, Baoying; Sen, H. Nida; Ferris, Frederick L.] NEI, NIH, Bethesda, MD 20892 USA. [Lee, Richard W. J.; Dick, Andrew D.] Moorfields Eye Hosp Natl Hlth Serv Fdn Trust, NIH, Res Biomed Res Ctr, Bristol, Avon, England. [Lee, Richard W. J.; Dick, Andrew D.] Univ Coll London, Inst Ophthalmol, Univ Hosp Bristol, Natl Hlth Serv,Fdn Trust, Bristol, Avon, England. [Lee, Richard W. J.; Dick, Andrew D.] Univ Bristol, Bristol, Avon, England. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Lane, Bethesda, MD 20892 USA. EM DrBob@nei.nih.gov RI Lee, Richard/A-3116-2017 OI Lee, Richard/0000-0002-9480-6843 FU Novartis; Abbvie; Roche-Genentech; National Institute for Health Research Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology FX A.D.D. is a consultant for Novartis and received payment for lectures from Abbvie. R.W.J.L. is a consultant for Roche-Genentech. Patents for A.D.D. and R.W.J.L. are through the University of Bristol and National Institutes of Health (NIH). Patents for R.B.N. are through the University of Bristol and NIH. Support for all the NIH authors came from intramural funds. For A.D.D. and R.W.J.L., this work was partly supported by the National Institute for Health Research Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology. The views expressed are those of the author(s) (R.W.J.L., ADD.) and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health. Contributions of authors: conception and design (R.B.N., F.F., H.N.S.); analysis and interpretation (R.B.N., F.L.F., E.C.); writing the article (R.B.N., A.D.D., H.N.S., E.C., R.W.J.L., B.L., L.W.); critical revision of the article (R.B.N., R.W.J.L., F.L.F., E.C., H.N.S., A.D.D.); final approval of the article (R.B.N., A.D.D., H.N.S., E.C., R.W.J.L., B.L., L.W., F.L.F.); data collection (R.B.N., F.L.F., H.N.S.); provision of materials, etc (R.B.N., F.L.F.); statistical expertise (F.L.F.); obtaining funding (R.B.N., F.L.F.); literature search (R.B.N., R.W.J.L., F.L.F., H.N.S., A.D.D., L.W., B.L.); administrative support, etc (R.B.N., F.L.F.). NR 53 TC 17 Z9 18 U1 6 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUL PY 2014 VL 158 IS 1 BP 5 EP 11 DI 10.1016/j.ajo.2014.03.014 PG 7 WC Ophthalmology SC Ophthalmology GA AK0IY UT WOS:000338097300003 PM 24709810 ER PT J AU Uchiyama, A Yamada, K Ogino, S Yokoyama, Y Takeuchi, Y Udey, MC Ishikawa, O Motegi, S AF Uchiyama, Akihiko Yamada, Kazuya Ogino, Sachiko Yokoyama, Yoko Takeuchi, Yuko Udey, Mark C. Ishikawa, Osamu Motegi, Sei-ichiro TI MFG-E8 Regulates Angiogenesis in Cutaneous Wound Healing SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID DISCOIDIN-DOMAIN PROTEIN; APOPTOTIC CELLS; EGF REPEAT; LACTADHERIN; GROWTH; DISEASE; MYOFIBROBLASTS; BINDING; REPAIR; MILK AB Our research group recently demonstrated that pericytes are major sources of the secreted glycoprotein and integrin ligand Lactadherin (MFG-E8) in B16 melanoma tumors, and that MFG-E8 promotes angiogenesis via enhanced PDGF-PDGFR beta signaling mediated by integrin-growth factor receptor crosstalk. However, sources of MFG-E8 and its possible roles in skin physiology are not well characterized. The objective of this study was to characterize the involvement of MFG-E8 in skin wound healing. In the dermis of normal murine and human skin, accumulations of MFG-E8 were found around CD31(+) blood vessels, and MFG-E8 colocalized with PDGFR beta(+), alpha SMA(+), and NG2(+) pericytes. MFG-E8 protein and mRNA levels were elevated in the dermis during full-thickness wound healing in mice. MFG-E8 was diffusely present in granulation tissue and was localized around blood vessels. Wound healing was delayed in MFG-E8 knockout mice, compared with the wild type, and myofibroblast and vessel numbers in wound areas were significantly reduced in knockout mice. Inhibition of MFG-E8 production with siRNA attenuated the formation of capillary-like structures in vitro. Expression of MFG-E8 in fibrous human granulation tissue with scant blood vessels was less than that in granulation tissue with many blood vessels. These findings suggest that MFG-E8 promotes cutaneous wound healing by enhancing angiogenesis. C1 [Uchiyama, Akihiko; Yamada, Kazuya; Ogino, Sachiko; Yokoyama, Yoko; Takeuchi, Yuko; Ishikawa, Osamu; Motegi, Sei-ichiro] Gunma Univ, Dept Dermatol, Grad Sch Med, Maebashi, Gunma 3718511, Japan. [Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Motegi, S (reprint author), Gunma Univ, Dept Dermatol, Grad Sch Med, 3-39-22 Showa, Maebashi, Gunma 3718511, Japan. EM smotegi@gunma-u.ac.jp OI Ishikawa, Osamu/0000-0002-7655-0610 FU Adaptable and Seamless Technology Transfer Program of the Japan Science and Technology Agency; Uehara Memorial Foundation; Intramural Program of the NM; Center for Cancer Research, National Cancer Institute FX Supported in part by a grant from Adaptable and Seamless Technology Transfer Program of the Japan Science and Technology Agency, a grant from the Uehara Memorial Foundation (S.M.), and the Intramural Program of the NM, Center for Cancer Research, National Cancer Institute (M.C.U.). NR 38 TC 8 Z9 8 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2014 VL 184 IS 7 BP 1981 EP 1990 DI 10.1016/j.ajpath.2014.03.017 PG 10 WC Pathology SC Pathology GA AJ9CR UT WOS:000338004900007 PM 24838098 ER PT J AU Desrosiers, NA Milman, G Mendu, DR Lee, D Barnes, AJ Gorelick, DA Huestis, MA AF Desrosiers, Nathalie A. Milman, Garry Mendu, Damodara R. Lee, Dayong Barnes, Allan J. Gorelick, David A. Huestis, Marilyn A. TI Cannabinoids in oral fluid by on-site immunoassay and by GC-MS using two different oral fluid collection devices SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Cannabinoid; Oral fluid; On-site test; Draeger DrugTest 5000 ID DRUG-TESTING DEVICES; POINT; THC; MARIJUANA; DRIVERS; SMOKERS AB Oral fluid (OF) enables non-invasive sample collection for on-site drug testing, but performance of on-site tests with occasional and frequent smokers' OF to identify cannabinoid intake requires further evaluation. Furthermore, as far as we are aware, no studies have evaluated differences between cannabinoid disposition among OF collection devices with authentic OF samples after controlled cannabis administration. Fourteen frequent (a parts per thousand yen4 times per week) and 10 occasional (less than twice a week) adult cannabis smokers smoked one 6.8 % a dagger(9)-tetrahydrocannabinol (THC) cigarette ad libitum over 10 min. OF was collected with the StatSure Saliva Sampler, Oral-Eze, and Draeger DrugTest 5000 test cassette before and up to 30 h after cannabis smoking. Test cassettes were analyzed within 15 min and gas chromatography-mass spectrometry cannabinoid results were obtained within 24 h. Cannabinoid concentrations with the StatSure and Oral-Eze devices were compared and times of last cannabinoid detection (t (last)) and DrugTest 5000 test performance were assessed for different cannabinoid cutoffs. 11-nor-9-Carboxy-THC (THCCOOH) and cannabinol concentrations were significantly higher in Oral-Eze samples than in Stat-Sure samples. DrugTest 5000 t (last) for a positive cannabinoid test were median (range) 12 h (4-24 h) and 21 h (1-aEuro parts per thousand a parts per thousand yenaEuro parts per thousand 30 h) for occasional and frequent smokers, respectively. Detection windows in screening and confirmatory tests were usually shorter for occasional than for frequent smokers, especially when including THCCOOH a parts per thousand yen20 ng L-1 in confirmation criteria. No differences in t (last) were observed between collection devices, except for THC a parts per thousand yen2 mu g L-1. We thus report significantly different THCCOOH and cannabinol, but not THC, concentrations between OF collection devices, which may affect OF data interpretation. The DrugTest 5000 on-site device had high diagnostic sensitivity, specificity, and efficiency for cannabinoids. C1 [Desrosiers, Nathalie A.; Milman, Garry; Mendu, Damodara R.; Lee, Dayong; Barnes, Allan J.; Gorelick, David A.; Huestis, Marilyn A.] NIDA IRP, Chem & Drug Metab Sect, Baltimore, MD 21224 USA. [Desrosiers, Nathalie A.; Lee, Dayong] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA IRP, Chem & Drug Metab Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse, NIH FX We acknowledge the contributions of clinical staff of the National Institute on Drug Abuse, Intramural Research Program, and Behavioral Pharmacology Research Unit and Clinical Research Unit, Johns Hopkins Bayview Medical Center, and Dr Sebastien Anizan and Dr David M. Schwope for protocol assistance, the Graduate Partnership Program, NIH, and the "Fondation Baxter et Alma Ricard". The Draeger DrugTest 5000, Oral-Eze, and StatSure devices were provided by the manufacturers to NIH through Materials Transfer Agreements. This research was funded by the Intramural Research Program, National Institute on Drug Abuse, NIH. NR 27 TC 10 Z9 10 U1 7 U2 25 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JUL PY 2014 VL 406 IS 17 BP 4117 EP 4128 DI 10.1007/s00216-014-7813-9 PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA AJ6FZ UT WOS:000337787400009 PM 24828976 ER PT J AU Surampudi, P Page, ST Swerdloff, RS Nya-Ngatchou, JJ Liu, PY Amory, JK Leung, A Hull, L Blithe, DL Woo, J Bremner, WJ Wang, C AF Surampudi, P. Page, S. T. Swerdloff, R. S. Nya-Ngatchou, J. J. Liu, P. Y. Amory, J. K. Leung, A. Hull, L. Blithe, D. L. Woo, J. Bremner, W. J. Wang, C. TI Single, escalating dose pharmacokinetics, safety and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive SO ANDROLOGY LA English DT Article DE androgens; contraception; pharmacokinetics; progesterone; progestagens ID SELF-EMULSIFYING FORMULATION; TANDEM MASS-SPECTROMETRY; MALE-FERTILITY-CONTROL; TESTOSTERONE UNDECANOATE; HYPOGONADAL MEN; TRANSDERMAL TESTOSTERONE; SYNTHETIC ANDROGENS; SERUM TESTOSTERONE; CLINICAL-TRIAL; SUPPRESSION AB The novel androgen, dimethandrolone (DMA) has both androgenic and progestational activities, properties that may maximize gonadotropin suppression. We assessed the pharmacokinetics of dimethandrolone undecanoate (DMAU), an orally bioavailable, longer acting ester of DMA, for male contraceptive development. Our objective was to examine the safety and pharmacokinetics of single, escalating doses of DMAU (powder in capsule formulation) administered orally with or without food in healthy men. We conducted a randomized, double-blind Phase 1 study. For each dose of DMAU (25-800mg), 10 male volunteers received DMAU and two received placebo at two academic medical centres. DMAU was administered both fasting and after a high-fat meal (200-800mg doses). Serial serum samples were collected over 24h following each dose. DMAU was well tolerated without significant effects on vital signs, safety laboratory tests or electrocardiograms. When administered while fasting, serum DMA (active compound) was detectable in only 4/10 participants after the 800mg dose. When administered with a 50% fat meal, serum DMA was detectable in all participants given 200mg DMAU and showed a dose-incremental increase up to 800mg, with peak levels 4-8h after taking the dose. Serum gonadotropins and sex hormone concentrations were significantly suppressed 12h after DMAU administration with food at doses above 200mg. This first-in-man study demonstrated that a single, oral dose of DMAU up to 800mg is safe. A high-fat meal markedly improved DMAU/DMA pharmacokinetics. C1 [Surampudi, P.; Swerdloff, R. S.; Liu, P. Y.; Leung, A.; Hull, L.; Wang, C.] Harbor UCLA Med Ctr, Dept Med, Div Endocrinol, Torrance, CA 90509 USA. [Surampudi, P.; Swerdloff, R. S.; Liu, P. Y.; Leung, A.; Hull, L.; Wang, C.] Los Angeles Biomed Res Inst, Torrance, CA USA. [Page, S. T.; Nya-Ngatchou, J. J.; Amory, J. K.; Bremner, W. J.] Univ Washington, Dept Med, Div Endocrinol, Seattle, WA 98195 USA. [Blithe, D. L.; Woo, J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Wang, C (reprint author), Harbor UCLA Med Ctr, Clin & Translat Sci Inst, 1000 W Carson St, Torrance, CA 90509 USA. EM wang@labiomed.org FU NICHD [HHSN275201100033U, HHSN275201000080U]; Endocrinology, Metabolism and Nutrition training grant [T32 DK007571]; UCLA Clinical and Translational Science Institute at Harbor-UCLA/LA BioMed [UL1TR000124]; Eunice Kennedy Shriver National Institute of Child Health and Development [HHSN275200403370I, 5K12HD053984]; National Center For Advancing Translational Sciences of the National Institutes of Health [UL1TR000423]; Center for Research in Reproduction and Contraception [U54 HD 04245]; National Institute of Diabetes and Digestive and Kidney Diseases training grant [5T32 DK007247-35] FX The Los Angeles Center was supported by NICHD contracts HHSN275201100033U and HHSN275201000080U; the Endocrinology, Metabolism and Nutrition training grant (T32 DK007571) and the UCLA Clinical and Translational Science Institute (UL1TR000124) at Harbor-UCLA/LA BioMed. The Seattle center was supported by contract number HHSN275200403370I and 5K12HD053984 from the Eunice Kennedy Shriver National Institute of Child Health and Development, the National Center For Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000423, the Center for Research in Reproduction and Contraception U54 HD 04245 (NICHD), and the National Institute of Diabetes and Digestive and Kidney Diseases training grant 5T32 DK007247-35. We thank Peter Christenson, PhD, formerly at LA Biomed for his advice in study design and data analysis plans. We thank our research coordinators Elizabeth Ruiz, Jamie Custodian RN, Marilyn Busher RN, Kathryn Torrez-Duncan and Kathy Winter for their assistance with the study and the technical assistance of Feng Bai and Anne Taylor for DMA and DMAU assay development and validation and the staff of the Endocrine and Metabolic Research Laboratory at Harbor-UCLA/LA Biomed. NR 42 TC 11 Z9 11 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 EI 2047-2927 J9 ANDROLOGY-US JI Andrology PD JUL PY 2014 VL 2 IS 4 BP 579 EP 587 DI 10.1111/j.2047-2927.2014.00216.x PG 9 WC Andrology SC Endocrinology & Metabolism GA AJ9NM UT WOS:000338038400012 PM 24789057 ER PT J AU Randolph, DA Nolen, TL Ambalavanan, N Carlo, WA Peralta-Carcelen, M Das, A Bell, EF Davis, AS Laptook, AR Stoll, BJ Shankaran, S Higgins, RD AF Randolph, David A. Nolen, Tracy L. Ambalavanan, Namasivayam Carlo, Waldemar A. Peralta-Carcelen, Myriam Das, Abhik Bell, Edward F. Davis, Alexis S. Laptook, Abbot R. Stoll, Barbara J. Shankaran, Seetha Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst TI Outcomes of extremely low birthweight infants with acidosis at birth SO ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION LA English DT Article ID EXTREMELY PRETERM INFANTS; CLINICAL RISK INDEX; INTENSIVE-CARE; NEURODEVELOPMENTAL OUTCOMES; BABIES SCORE; BASE STATUS; PREDICTION; AGE; MORBIDITY; MORTALITY AB Objectives To test the hypothesis that acidosis at birth is associated with the combined primary outcome of death or neurodevelopmental impairment (NDI) in extremely low birthweight (ELBW) infants, and to develop a predictive model of death/NDI exploring perinatal acidosis as a predictor variable. Study design The study population consisted of ELBW infants born between 2002 and 2007 at National Institute of Child Health and Development (NICHD) Neonatal Research Network hospitals. Infants with cord blood gas data and documentation of either mortality prior to discharge or 18-22 month neurodevelopmental outcomes were included. Multiple logistic regression analysis was used to determine the contribution of perinatal acidosis, defined as a cord blood gas with a pH < 7 or base excess (BE) < -12, to death/NDI in ELBW infants. In addition, a multivariable model predicting death/NDI was developed. Results 3979 patients were identified of whom 249 had a cord gas pH < 7 or BE < -12 mEq/L. 2124 patients (53%) had the primary outcome of death/NDI. After adjustment for confounding variables, pH < 7 and BE < -12 mEq/L were each significantly associated with death/NDI (OR=2.5 (1.6, 4.2) and OR=1.5 (1.1, 2.0), respectively). However, inclusion of pH or BE did not improve the ability of the multivariable model to predict death/NDI. Conclusions Perinatal acidosis is significantly associated with death/NDI in ELBW infants. Perinatal acidosis is infrequent in ELBW infants, however, and other factors are more important in predicting death/NDI. C1 [Randolph, David A.; Ambalavanan, Namasivayam; Carlo, Waldemar A.; Peralta-Carcelen, Myriam] Univ Alabama Birmingham, Dept Pediat, Div Neonatol, Birmingham, AL USA. [Randolph, David A.] Rocky Mt Hosp Children, Dept Pediat, Denver, CO 80205 USA. [Nolen, Tracy L.; Das, Abhik] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Davis, Alexis S.] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA. [Laptook, Abbot R.] Brown Univ, Dept Pediat, Providence, RI 02912 USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Pregnancy & Perinatol Branch, Bethesda, MD USA. RP Randolph, DA (reprint author), Rocky Mt Hosp Children, 2055 High St,Suite 250, Denver, CO 80205 USA. EM drdrdrandolph@gmail.com OI Ambalavanan, Namasivayam/0000-0003-0731-9092 FU UAB Department of Paediatrics; Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD) [5U10HD034216] FX This work was supported by the UAB Department of Paediatrics and by the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD) grant 5U10HD034216. NR 30 TC 4 Z9 4 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1359-2998 EI 1468-2052 J9 ARCH DIS CHILD-FETAL JI Arch. Dis. Child.-Fetal Neonatal Ed. PD JUL PY 2014 VL 99 IS 4 BP F263 EP F268 DI 10.1136/archdischild-2013-304179 PG 6 WC Pediatrics SC Pediatrics GA AJ7XU UT WOS:000337915600004 PM 24554564 ER PT J AU Chuang, ML Gona, P Oyama-Manabe, N Manders, ES Salton, CJ Hoffmann, U Manning, WJ O'Donnell, CJ AF Chuang, Michael L. Gona, Philimon Oyama-Manabe, Noriko Manders, Emily S. Salton, Carol J. Hoffmann, Udo Manning, Warren J. O'Donnell, Christopher J. TI Risk Factor Differences in Calcified and Noncalcified Aortic Plaque The Framingham Heart Study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE atherosclerosis; epidemiology; magnetic resonance imaging; risk factors ID CORONARY-ARTERY CALCIUM; COMPUTED-TOMOGRAPHY; ABDOMINAL-AORTA; THORACIC AORTA; ATHEROSCLEROSIS; ASSOCIATION; CALCIFICATION; DEPOSITS; DISEASE; REPRODUCIBILITY AB Objective-The objective of this study was to determine the prevalence and risk factor (RF) correlates of aortic plaque (AP) detected by cardiovascular magnetic resonance (CMR), which mainly shows noncalcified plaques, and by noncontrast computed tomography (CT), which best depicts calcified plaques, in community-dwelling adults. Approach and Results-A total of 1016 Framingham Heart Study Offspring cohort members (64 +/- 9 years; 474 men) underwent CMR and CT of the aorta. Potential RFs for AP (age; sex; body mass index; blood pressure; low-density lipoprotein and high-density lipoprotein cholesterol; fasting glucose; C-reactive protein; prevalent hypertension, diabetes mellitus, smoking; use of antihypertensive, diabetes mellitus, or lipid-lowering drugs) were compared between participants, with zero versus nonzero AP by CMR and by CT. Candidate RFs attaining P<0.05 for difference with either imaging modality were entered into multivariable logistic regression models adjusting for age, sex, and other RFs. Odds ratios were calculated for modality-specific prevalence of AP. Associations between RFs and continuous measures of AP were assessed using Tobit regression. Prevalence of CMR and CT AP was 49% and 82%, respectively. AP burdens by CMR and CT were correlated, r=0.28, P<0.0001. Increasing age and smoking were associated with prevalent AP by both CMR and CT. Additionally, prevalent AP by CMR was associated with female sex and fasting glucose and prevalent AP by CT with hypertension treatment and adverse lipid profile. Conclusions-AP by CMR and CT are both associated with smoking and increasing age, but other RFs differ between calcified and noncalcified AP. The relative predictive value of AP detected by CMR versus by CT for incident cardiovascular events remains to be determined. C1 [Chuang, Michael L.; Gona, Philimon; Manders, Emily S.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Boston, MA USA. [Gona, Philimon] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Biostat & Hlth Serv Res, Worcester, MA USA. [Oyama-Manabe, Noriko; Salton, Carol J.; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Hoffmann, Udo; Manning, Warren J.; O'Donnell, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. RP O'Donnell, CJ (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM odonnellc@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, N01-HC-38038, R01 HL70279]; National Heart, Lung and Blood Institute Division of Intramural Research FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195 and N01-HC-38038 and by R01 HL70279). C.J. O'Donnell is supported by the National Heart, Lung and Blood Institute Division of Intramural Research. NR 23 TC 4 Z9 5 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2014 VL 34 IS 7 BP 1580 EP + DI 10.1161/ATVBAHA.114.303600 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AJ5OC UT WOS:000337732900035 PM 24833796 ER PT J AU Ringold, S Weiss, PF Colbert, RA DeWitt, EM Lee, T Onel, K Prahalad, S Schneider, R Shenoi, S Vehe, RK Kimura, Y AF Ringold, Sarah Weiss, Pamela F. Colbert, Robert A. DeWitt, Esi Morgan Lee, Tzielan Onel, Karen Prahalad, Sampath Schneider, Rayfel Shenoi, Susan Vehe, Richard K. Kimura, Yukiko CA Juvenile Idiopathic Arthrit Res Co Childhood Arthrit Rheumatology Res TI Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans for New-Onset Polyarticular Juvenile Idiopathic Arthritis SO ARTHRITIS CARE & RESEARCH LA English DT Article ID DOWN-SYNDROME; SELECT CATEGORIES; INACTIVE DISEASE; METHOTREXATE; TRIAL; CHILDREN; DERMATOMYOSITIS; ASSOCIATIONS; PREVALENCE; TOXICITY AB Objective. There is no standardized approach to the initial treatment of polyarticular juvenile idiopathic arthritis (JIA) among pediatric rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available will result in better health outcomes for polyarticular JIA. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) for use in clinical practice to facilitate such studies. Methods. A case-based survey was administered to CARRA members to identify the common treatment approaches for new-onset polyarticular JIA. Two face-to-face consensus conferences employed modified nominal group technique to identify treatment strategies, operational case definition, end points, and data elements to be collected. A core workgroup reviewed the relevant literature, refined plans, and developed medication dosing and monitoring recommendations. Results. The initial case-based survey identified significant variability among treatment approaches for new-onset polyarticular JIA. We developed 3 CTPs based on treatment strategies for the first 12 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The CTPs include a step-up plan (nonbiologic disease-modifying antirheumatic drug [DMARD] followed by a biologic DMARD), an early combination plan (nonbiologic and biologic DMARD combined within a month of treatment initiation), and a biologic only plan. This approach was approved by 96% of the CARRA JIA Research Committee members attending the 2013 CARRA face-to-face meeting. Conclusion. Three standardized CTPs were developed for new-onset polyarticular JIA. Coupled with data collection at defined intervals, use of these CTPs will enable the study of their comparative effectiveness in an observational setting to optimize initial management of polyarticular JIA. C1 [Ringold, Sarah; Shenoi, Susan] Seattle Childrens Hosp, Seattle, WA USA. [Weiss, Pamela F.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Colbert, Robert A.] NIAMSD, NIH, Bethesda, MD 20892 USA. [DeWitt, Esi Morgan] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Lee, Tzielan] Stanford Univ, Stanford, CA 94305 USA. [Onel, Karen] Univ Chicago, Chicago, IL 60637 USA. [Prahalad, Sampath] Emory Univ, Sch Med, Atlanta, GA USA. [Schneider, Rayfel] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Vehe, Richard K.] Univ Minnesota, Minneapolis, MN USA. [Kimura, Yukiko] Hackensack Univ, Med Ctr, Hackensack, NJ USA. RP Kimura, Y (reprint author), Hackensack Univ, Med Ctr, Sanzari Childrens Hosp, 30 Prospect Ave, Hackensack, NJ 07601 USA. EM ykimura@HackensackUMC.org FU Rheumatology Research Foundation Disease Targeted Initiative Research Pilot Grant; Childhood Arthritis and Rheumatology Research Alliance (CARRA); Arthritis Foundation; Wasie Foundation; Agency for Healthcare Research and Quality [K12HS019482]; NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases [K23-AR-059749]; Hoffman-LaRoche; Novartis; Innomar Strategies; Canadian Agency for Drugs and Technologies in Health FX Supported by a Rheumatology Research Foundation Disease Targeted Initiative Research Pilot Grant, the Childhood Arthritis and Rheumatology Research Alliance (CARRA), the Arthritis Foundation, the Wasie Foundation, and Friends of CARRA. Dr. Ringold's work was supported by the Agency for Healthcare Research and Quality for the duration of this project (grant K12HS019482). Dr. Weiss's work was supported by the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant K23-AR-059749).; Dr. Onel has received research support from Hoffman-LaRoche. Dr. Schneider has received consultant fees (less than $10,000 each) from Hoffman-La Roche, Novartis, Innomar Strategies, and the Canadian Agency for Drugs and Technologies in Health. Dr. Kimura has received consultant fees (less than $10,000) from Novartis. NR 27 TC 17 Z9 17 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD JUL PY 2014 VL 66 IS 7 BP 1063 EP 1072 DI 10.1002/acr.22259 PG 10 WC Rheumatology SC Rheumatology GA AJ8SD UT WOS:000337976700013 PM 24339215 ER PT J AU Elinoff, JM Bagci, U Moriyama, B Dreiling, JL Foster, B Gormley, NJ Salit, RB Cai, RM Sun, JF Beri, A Reda, DJ Fakhrejahani, F Battiwalla, M Baird, K Cuellar-Rodriguez, JM Kang, EM Pavletic, SZ Fowler, DH Barrett, AJ Lozier, JN Kleiner, DE Mollura, DJ Childs, RW Suffredini, AF AF Elinoff, Jason M. Bagci, Ulas Moriyama, Brad Dreiling, Jennifer L. Foster, Brent Gormley, Nicole J. Salit, Rachel B. Cai, Rongman Sun, Junfeng Beri, Andrea Reda, Debra J. Fakhrejahani, Farhad Battiwalla, Minoo Baird, Kristin Cuellar-Rodriguez, Jennifer M. Kang, Elizabeth M. Pavletic, Stephen Z. Fowler, Dan H. Barrett, A. John Lozier, Jay N. Kleiner, David E., Jr. Mollura, Daniel J. Childs, Richard W. Suffredini, Anthony F. TI Recombinant Human Factor VIIa for Alveolar Hemorrhage Following Allogeneic Stem Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Hematopoietic stem cell transplantation; Diffuse alveolar hemorrhage; Glucocorticoids; Recombinant human factor VIIa ID ACTIVATED FACTOR-VII; BONE-MARROW-TRANSPLANTATION; IDIOPATHIC PNEUMONIA SYNDROME; CORTICOSTEROID-THERAPY; PULMONARY HEMORRHAGE; ADJUNCTIVE THERAPY; CONTROLLED-TRIAL; CLINICAL-TRIALS; FACTOR-XA; RECIPIENTS AB The mortality rate of alveolar hemorrhage (AH) after allogeneic hematopoietic stem cell transplantation is greater than 60% with supportive care and high-dose steroid therapy. We performed a retrospective cohort analysis to assess the benefits and risks of recombinant human factor Vila (rFVIIa) as a therapeutic adjunct for AH. Between 2005 and 2012, 57 episodes of AH occurred in 37 patients. Fourteen episodes (in 14 patients) were treated with steroids alone, and 43 episodes (in 23 patients) were treated with steroids and rFVIIa. The median steroid dose was 1.9 mg/kg/d (interquartile range [IQR], 0.8 to 3.5 mg/kg/d; methylprednisolone equivalents) and did not differ statistically between the 2 groups. The median rFVIIa dose was 41 mu g/kg (IQR, 39 to 62 mu g/kg), and a median of 3 doses (IQR, 2 to 17) was administered per episode. Concurrent infection was diagnosed in 65% of the episodes. Patients had moderately severe hypoxia (median PaO2/FiO(2), 193 [IQR, 141 to 262]); 72% required mechanical ventilation, and 42% survived to extubation. The addition of rFVIIa did not alter time to resolution of AH (P = .50), duration of mechanical ventilation (P = .89), duration of oxygen supplementation (P = .55), or hospital mortality (P = .27). Four possible thrombotic events (9% of 43 episodes) occurred with rFVIIa. rFVIIa in combination with corticosteroids did not confer clear clinical advantages compared with corticosteroids alone. In patients with AH following hematopoietic stem cell transplantation, clinical factors (ie, worsening infection, multiple organ failure, or recrudescence of primary disease) may be more important than the benefit of enhanced hemostasis from rFVIIa. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Elinoff, Jason M.; Cai, Rongman; Sun, Junfeng; Reda, Debra J.; Fakhrejahani, Farhad; Suffredini, Anthony F.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Bagci, Ulas; Foster, Brent; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Moriyama, Brad] NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. [Dreiling, Jennifer L.; Kleiner, David E., Jr.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Gormley, Nicole J.; Battiwalla, Minoo; Barrett, A. John; Childs, Richard W.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Salit, Rachel B.; Pavletic, Stephen Z.; Fowler, Dan H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Beri, Andrea] NIH, Lab Informat Dev, Biomed Translat Res Informat Syst, Ctr Clin, Bethesda, MD 20892 USA. [Baird, Kristin] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Cuellar-Rodriguez, Jennifer M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Kang, Elizabeth M.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Lozier, Jay N.] NIH, Hematol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Elinoff, JM (reprint author), NIH, Dept Crit Care Med, Mark O Hatfield Clin Res Ctr, 9000 Rockville Pike,Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM elinoffj@cc.nih.gov RI Cai, Rongman/C-5998-2015; OI Cai, Rongman/0000-0003-2404-4852; Bagci, Ulas/0000-0001-7379-6829 FU National Institutes of Health (NIH) Intramural Research Program of the National Heart Lung and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Diseases; NIH Clinical Center FX This work was supported by the National Institutes of Health (NIH) Intramural Research Program of the National Heart Lung and Blood Institute, the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the NIH Clinical Center. 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 49 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2014 VL 20 IS 7 BP 969 EP 978 DI 10.1016/j.bbmt.2014.03.015 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AJ7AX UT WOS:000337850500010 PM 24657447 ER PT J AU Shah, NN Borowitz, MJ Robey, NC Gamper, CJ Symons, HJ Loeb, DM Wayne, AS Chen, AR AF Shah, Nirali N. Borowitz, Michael J. Robey, Nancy C. Gamper, Christopher J. Symons, Heather J. Loeb, David M. Wayne, Alan S. Chen, Allen R. TI Feasibility of Treating Post-Transplantation Minimal Residual Disease in Children with Acute Leukemia SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Relapse; Allogeneic hematopoietic cell transplantation; Pediatrics; Leukemia; Minimal residual disease ID STEM-CELL TRANSPLANTATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; INCREASING MIXED CHIMERISM; DONOR LYMPHOCYTE INFUSIONS; 1ST INTERNATIONAL WORKSHOP; CHRONIC MYELOID-LEUKEMIA; PREEMPTIVE IMMUNOTHERAPY; ALLOGENEIC TRANSPLANTATION; RISK-FACTORS; HEMATOLOGIC MALIGNANCIES AB Outcomes are poor for patients with hematologic malignancies who experience overt relapse after allogeneic hematopoietic stem cell transplantation (HCT). Data on outcomes of post-transplantation minimal residual disease (MRD) are limited. In this single-institution, retrospective cohort analysis of children with acute leukemia and myelodysplastic syndrome, we document the pattern of relapse with a primary focus on outcomes of post-transplantation MRD. Forty of 93 patients (43%) who underwent a first allogeneic HCT and had systematic pretransplantation and post-transplantation MRD evaluations at +30, +60, +90, +180 days and +1 and +2 years post-transplantation experienced relapse. The median time to relapse was 4.8 months post-transplantation, with a median survival of 4 months post-relapse. Despite frequent, systematic, routine post-HCT disease restaging evaluation, 31 patients (78%) presented with overt disease at the time of relapse. Seven patients with acute leukemia who had post-transplantation MRD presented at a median of 1 month post-transplantation. Owing to rapid disease progression or treatment-related mortality, there was no improvement in survival in those patients whose leukemia was detected in a state of MRD post-transplantation. Our results suggest that early intervention strategies targeting post-transplantation MRD for relapse prevention in acute leukemia may not be feasible. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Shah, Nirali N.; Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shah, Nirali N.; Robey, Nancy C.; Gamper, Christopher J.; Symons, Heather J.; Loeb, David M.; Chen, Allen R.] Johns Hopkins Univ, Baltimore, MD USA. [Borowitz, Michael J.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Wayne, Alan S.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Childrens Ctr Canc & Blood Dis, Los Angeles, CA 90033 USA. RP Shah, NN (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 1W-3750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Nirali.Shah@nih.gov OI Gamper, Christopher/0000-0003-0253-2177 FU National Institutes of Health [P30 CA006973] FX This work was supported in part by National Institutes of Health Grant P30 CA006973 (to A.R.C.). NR 44 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2014 VL 20 IS 7 BP 1000 EP 1007 DI 10.1016/j.bbmt.2014.03.021 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AJ7AX UT WOS:000337850500014 PM 24680975 ER PT J AU Shah, NN Borowitz, MJ Steinberg, SM Robey, NC Gamper, CJ Symons, HJ Loeb, DM Wayne, AS Chen, AR AF Shah, Nirali N. Borowitz, Michael J. Steinberg, Seth M. Robey, Nancy C. Gamper, Christopher J. Symons, Heather J. Loeb, David M. Wayne, Alan S. Chen, Allen R. TI Factors Predictive of Relapse of Acute Leukemia in Children after Allogeneic Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Post-transplantation relapse; Leukemia; Risk factors; Minimal residual disease ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MINIMAL RESIDUAL DISEASE; ACUTE MYELOID-LEUKEMIA; ONCOLOGY-GROUP; INTRATHECAL CHEMOPROPHYLAXIS; HEMATOLOGIC MALIGNANCIES; MARROW-TRANSPLANTATION; INTERNATIONAL WORKSHOP; HIGH-RISK; OUTCOMES AB The presence of minimal residual disease (MRD) before transplantation is the most important prognostic risk factor predictive of post-transplantation relapse in hematologic malignancies. However, MRD alone does not adequately predict relapse in all patients. To improve upon the ability to identify patients likely to relapse, we evaluated risk factors, in addition to MRD, that may be associated with development of post-transplantation relapse. In this single institution, retrospective cohort study of children with acute leukemia or myelodysplastic syndrome who had undergone a first allogeneic transplantation and had pretransplantation MRD evaluation, 40 of 93 patients (43%) experienced relapse. Univariate analysis demonstrated that African American race, high initial white blood cell count, central nervous system (CNS) disease at diagnosis, short first complete remission, nonmyeloablative (NMA) conditioning, lack of remission, and MRD before transplantation were associated with worse relapse-free survival (RFS). In a Cox multivariable analysis, CNS disease (P = .009), lack of remission (P = .01), and NMA conditioning (P = .04) were independently associated with inferior RFS. Among those in a morphologic complete remission who underwent a myeloablative transplantation, having both CNS disease at diagnosis (specifically in acute lymphoblastic leukemia) and MRD positivity was an independent risk factor predictive of relapse, which has not been previously reported. Results from our study support the existence of risk factors complimentary to pretransplantation MRD. Validation in a larger independent homogenous cohort is needed to develop a prognostic tool for clinical use to predict post-transplantation relapse. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Shah, Nirali N.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shah, Nirali N.; Robey, Nancy C.; Gamper, Christopher J.; Symons, Heather J.; Loeb, David M.; Chen, Allen R.] Johns Hopkins Univ, Baltimore, MD USA. [Borowitz, Michael J.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Wayne, Alan S.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Childrens Ctr Canc & Blood Dis, Los Angeles, CA 90033 USA. RP Shah, NN (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 1W-3750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shahnn@mail.nih.gov OI Gamper, Christopher/0000-0003-0253-2177 FU NCI NIH HHS [P30 CA006973] NR 41 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JUL PY 2014 VL 20 IS 7 BP 1033 EP 1039 DI 10.1016/j.bbmt.2014.03.028 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AJ7AX UT WOS:000337850500019 PM 24691222 ER PT J AU Troiano, RP McClain, JJ Brychta, RJ Chen, KY AF Troiano, Richard P. McClain, James J. Brychta, Robert J. Chen, Kong Y. TI Evolution of accelerometer methods for physical activity research SO BRITISH JOURNAL OF SPORTS MEDICINE LA English DT Review ID AMERICAN-HEART-ASSOCIATION; OF-SPORTS-MEDICINE; ENERGY-EXPENDITURE; PUBLIC-HEALTH; ACTIVITY GUIDELINES; ACTIVITY INTENSITY; ACTIVITY MONITORS; CALIBRATION; ADULTS; RECOMMENDATION AB The technology and application of current accelerometer-based devices in physical activity (PA) research allow the capture and storage or transmission of large volumes of raw acceleration signal data. These rich data not only provide opportunities to improve PA characterisation, but also bring logistical and analytic challenges. We discuss how researchers and developers from multiple disciplines are responding to the analytic challenges and how advances in data storage, transmission and big data computing will minimise logistical challenges. These new approaches also bring the need for several paradigm shifts for PA researchers, including a shift from count-based approaches and regression calibrations for PA energy expenditure (PAEE) estimation to activity characterisation and EE estimation based on features extracted from raw acceleration signals. Furthermore, a collaborative approach towards analytic methods is proposed to facilitate PA research, which requires a shift away from multiple independent calibration studies. Finally, we make the case for a distinction between PA represented by accelerometer-based devices and PA assessed by self-report. C1 [Troiano, Richard P.; McClain, James J.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Bethesda, MD 20892 USA. [Brychta, Robert J.; Chen, Kong Y.] NIDDK, Diabet Endocrinol & Obes Branch, Intramural Res Program, Bethesda, MD USA. RP Troiano, RP (reprint author), NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, NCI Shady Grove, 9609 Med Ctr Dr,MSC 9762, Bethesda, MD 20892 USA. EM troianor@mail.nih.gov OI Troiano, Richard/0000-0002-6807-989X; Chen, Kong/0000-0002-0306-1904 FU Intramural NIH HHS [Z99 CA999999] NR 32 TC 87 Z9 87 U1 18 U2 63 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-3674 EI 1473-0480 J9 BRIT J SPORT MED JI Br. J. Sports Med. PD JUL PY 2014 VL 48 IS 13 DI 10.1136/bjsports-2014-093546 PG 5 WC Sport Sciences SC Sport Sciences GA AJ7YK UT WOS:000337917600004 PM 24782483 ER PT J AU Rogers, T Lederman, RJ AF Rogers, Toby Lederman, Robert J. TI Right Heart Catheterization From the Arm: Back to First Principles SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material C1 [Rogers, Toby; Lederman, Robert J.] NHLBI, Div Intramural Res, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Lederman, RJ (reprint author), NHLBI, NIH, Bldg 10,Room 2c713, Bethesda, MD 20892 USA. EM lederman@nih.gov OI Rogers, Toby/0000-0002-6043-3137; lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [ZIA HL005062-11, ZID HL006061-04] NR 4 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD JUL 1 PY 2014 VL 84 IS 1 BP 75 EP 76 DI 10.1002/ccd.25531 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AJ8QA UT WOS:000337970100017 PM 24782342 ER PT J AU Martina, JA Diab, HI Li, HQ Puertollano, R AF Martina, Jose A. Diab, Heba I. Li, Huiqing Puertollano, Rosa TI Novel roles for the MiTF/TFE family of transcription factors in organelle biogenesis, nutrient sensing, and energy homeostasis SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE MITF; TFE3; TFEB; Autophagy; Lysosomes; Nutrients; Transcription; Disease ID RENAL-CELL CARCINOMA; LOOP-HELIX PROTEIN; LYSOSOMAL STORAGE DISORDERS; MASTER REGULATOR MITF; HUMAN-MELANOMA CELLS; SOFT PART SARCOMA; IN-VIVO; RAG GTPASES; FACTOR TFEB; CHROMOSOMAL TRANSLOCATIONS AB The MiTF/TFE family of basic helix-loop-helix leucine zipper transcription factors includes MITF, TFEB, TFE3, and TFEC. The involvement of some family members in the development and proliferation of specific cell types, such as mast cells, osteoclasts, and melanocytes, is well established. Notably, recent evidence suggests that the MiTF/TFE family plays a critical role in organelle biogenesis, nutrient sensing, and energy metabolism. The MiTF/TFE family is also implicated in human disease. Mutations or aberrant expression of most MiTF/TFE family members has been linked to different types of cancer. At the same time, they have recently emerged as novel and very promising targets for the treatment of neurological and lysosomal diseases. The characterization of this fascinating family of transcription factors is greatly expanding our understanding of how cells synchronize environmental signals, such as nutrient availability, with gene expression, energy production, and cellular homeostasis. C1 [Martina, Jose A.; Diab, Heba I.; Li, Huiqing; Puertollano, Rosa] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Puertollano, R (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, 9000 Rockville Pike,Bldg 50-3537, Bethesda, MD 20892 USA. EM puertolr@mail.nih.gov RI di Ronza, Alberto/H-7674-2016 OI di Ronza, Alberto/0000-0002-9813-5143 FU Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). NR 109 TC 29 Z9 29 U1 3 U2 25 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD JUL PY 2014 VL 71 IS 13 BP 2483 EP 2497 DI 10.1007/s00018-014-1565-8 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AJ8TD UT WOS:000337979600010 PM 24477476 ER PT J AU Lajoie, S Lewkowich, I Herman, NS Sproles, A Pesce, JT Wynn, TA Grusby, MJ Hamid, Q Wills-Karp, M AF Lajoie, S. Lewkowich, I. Herman, N. S. Sproles, A. Pesce, J. T. Wynn, T. A. Grusby, M. J. Hamid, Q. Wills-Karp, M. TI IL-21 receptor signalling partially mediates Th2-mediated allergic airway responses SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE airway hyperresponsiveness; asthma; IL-21; IL-21R; Tregs ID T-CELL-ACTIVATION; INTERLEUKIN-21 RECEPTOR; B-CELLS; CYTOKINE; DIFFERENTIATION; PROLIFERATION; SUPPRESSION; GENERATION; IGE; HYPERRESPONSIVENESS AB Background Interleukin-21 (IL-21) has been implicated in the development of Th2-mediated immune responses; however, the exact role it plays in allergic diseases is not well understood. Objective To elucidate the contribution of IL-21 receptor signalling to Th2-dependent immune responses in the lung. Methods We compared allergic airway responses in wild-type BALB/c and Il21r-deficient mice exposed to local airway challenge with house dust mite (HDM). Results We demonstrate that IL-21R-deficiency reduces HDM-driven airway hyperresponsiveness (AHR) with only partial effects on airway inflammation. Concomitant with the reduction in AHR in Il21r-deficient mice, significant suppression was observed in protein levels of the Th2 cytokines IL-4, and IL-13. In contrast, IL-21R-deficiency was associated with an increase in PBS- and allergen-driven IgE levels, while IgG1 and IgG2a levels were decreased. Moreover, our results suggest that IL-21 may contribute to AHR through its ability to both directly induce Th2 cell survival and to impair regulatory T-cell suppression of Th2 cytokine production. Importantly, we show that IL-21-positive cells are increased in the bronchial mucosa of asthmatics compared with non-asthmatics. Conclusion These results suggest that IL-21 plays an important role in the allergic diathesis by enhancing Th2 cytokine production through multiple mechanisms including the suppression of Treg inhibitory effects on Th2 cell cytokine production. C1 [Lajoie, S.; Wills-Karp, M.] Johns Hopkins Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. [Lewkowich, I.; Herman, N. S.; Sproles, A.] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA. [Pesce, J. T.; Wynn, T. A.] NIAID, NIH, Bethesda, MD 20892 USA. [Grusby, M. J.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Hamid, Q.] McGill Univ, Meakins Christie Labs, Montreal, PQ, Canada. RP Wills-Karp, M (reprint author), Johns Hopkins Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. EM mwkarp@jhsph.edu FU NHLBI [HL67736, HL076383]; Parker B. Francis fellowship FX This work was supported by NHLBI grants HL67736 and HL076383 to MWK. SL is supported by a Parker B. Francis fellowship. We want to thank Tricia Nilles and Hanhvy Bui at the Becton Dickinson Immune Function Laboratory (JHSPH), for their expert flow sorting assistance. NR 35 TC 8 Z9 8 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0954-7894 EI 1365-2222 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD JUL PY 2014 VL 44 IS 7 BP 976 EP 985 DI 10.1111/cea.12341 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA AJ9LZ UT WOS:000338034000009 PM 24807637 ER PT J AU Jialal, I Remaley, AT AF Jialal, I. Remaley, A. T. TI Measurement of Low-Density Lipoprotein Cholesterol in Assessment and Management of Cardiovascular Disease Risk SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB The deposition of cholesterol in the arterial wall by the infiltration of low-density lipoproteins (LDLs) is a key step in the development of atherosclerosis. In this Commentary, we discuss recent recommendations for clinical laboratory measurement of low-density lipoprotein cholesterol (LDL-C) and its utility both for assessing cardiovascular disease risk and as a tool in the management of patients receiving lipid-lowering therapy. C1 [Jialal, I.] Univ Calif Davis, Dept Pathol & Lab Med, Lab Atherosclerosis & Metab Res, Davis, CA 95616 USA. [Jialal, I.] Univ Calif Davis, Dept Internal Med, Davis, CA 95616 USA. [Remaley, A. T.] NHLBI, Lipoprot Metab Sect, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Jialal, I (reprint author), Univ Calif Davis, Dept Pathol & Lab Med, Lab Atherosclerosis & Metab Res, Davis, CA 95616 USA. EM ijialal@ucdavis.edu NR 8 TC 4 Z9 4 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUL PY 2014 VL 96 IS 1 BP 20 EP 22 DI 10.1038/clpt.2014.69 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AJ8WJ UT WOS:000337988500004 PM 24942398 ER PT J AU Karovic, S Wen, Y Karrison, TG Bakris, GL Levine, MR House, LK Wu, K Thomeas, V Rudek, MA Wright, JJ Cohen, EEW Fleming, GF Ratain, MJ Maitland, ML AF Karovic, S. Wen, Y. Karrison, T. G. Bakris, G. L. Levine, M. R. House, L. K. Wu, K. Thomeas, V. Rudek, M. A. Wright, J. J. Cohen, E. E. W. Fleming, G. F. Ratain, M. J. Maitland, M. L. TI Sorafenib Dose Escalation Is Not Uniformly Associated With Blood Pressure Elevations in Normotensive Patients With Advanced Malignancies SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID NITRIC-OXIDE SYNTHASE; ENDOTHELIAL GROWTH-FACTOR; CANCER-PATIENTS; SOLID TUMORS; CORONARY SPASM; HYPERTENSION; BEVACIZUMAB; BIOMARKER; SUNITINIB; POLYMORPHISMS AB Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects. C1 [Karovic, S.; Levine, M. R.; House, L. K.; Wu, K.; Thomeas, V.; Cohen, E. E. W.; Fleming, G. F.; Ratain, M. J.; Maitland, M. L.] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Wen, Y.; Bakris, G. L.; Fleming, G. F.; Ratain, M. J.; Maitland, M. L.] Univ Chicago, Comm Clin Pharmacol & Pharmacogen, Chicago, IL 60637 USA. [Karrison, T. G.; Cohen, E. E. W.; Fleming, G. F.; Ratain, M. J.; Maitland, M. L.] Univ Chicago, Comprehens Canc Ctr, Chicago, IL 60637 USA. [Karrison, T. G.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Bakris, G. L.] Univ Chicago, Dept Med, Sect Endocrinol Diabet & Metab, Chicago, IL 60637 USA. [Rudek, M. A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Wright, J. J.] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Maitland, ML (reprint author), Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. EM mmaitlan@medicine.bsd.uchicago.edu FU US National Institutes of Health (NIH) [K23CA124802]; National Cancer Institute (NCI) [U01CA69852]; Cancer Therapy Evaluation Program of the NCI; National Institute of General Medical Sciences [U01GM61393]; Pharmacogenetics of Anticancer Agents Research Group; University of Chicago Comprehensive Cancer Center; University of Chicago Comprehensive Cancer Center Clinical Pharmacology Core Laboratory; CALGB Foundation Faculty Fellowship; Conquer Cancer Foundation of the American Society of Clinical Oncology; Bayer; Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH) [P30 CA006973, UL1 RR025005, 1S10RR026824-01]; University of Chicago Biological Science Division FX This project was supported by US National Institutes of Health (NIH) grant K23CA124802, a National Cancer Institute (NCI) Career Development Award (M.L.M.), grant U01CA69852 supported by the Cancer Therapy Evaluation Program of the NCI (M.J.R.), National Institute of General Medical Sciences grant U01GM61393, Pharmacogenetics of Anticancer Agents Research Group (M.J.R. and M.L.M), a protocol-specific project award from the University of Chicago Comprehensive Cancer Center, and the University of Chicago Comprehensive Cancer Center Clinical Pharmacology Core Laboratory. Additional support was provided by a CALGB Foundation Faculty Fellowship (M.L.M.), the Conquer Cancer Foundation of the American Society of Clinical Oncology (M.L.M. and M.J.R.), research funding from Bayer and by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 RR025005, and the Shared Instrument Grant (1S10RR026824-01)). Y.W. was supported by an internal grant from the University of Chicago Biological Science Division. This work was presented in part as an abstract at the American Society of Clinical Oncology Annual Meeting, 5 June 2011, Chicago, IL. NR 36 TC 6 Z9 6 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUL PY 2014 VL 96 IS 1 BP 27 EP 35 DI 10.1038/clpt.2014.63 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AJ8WJ UT WOS:000337988500008 PM 24637941 ER PT J AU Mills, KL Tamnes, CK AF Mills, Kathryn L. Tamnes, Christian K. TI Methods and considerations for longitudinal structural brain imaging analysis across development SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Review DE Adolescence; Childhood; DTI; Maturation; MRI; Morphometry ID HUMAN CEREBRAL-CORTEX; MULTIPLE-SCLEROSIS BRAIN; WHITE-MATTER DEVELOPMENT; SURFACE-BASED ANALYSIS; MAGNETIC-RESONANCE; CORTICAL THICKNESS; SEX-DIFFERENCES; LIFE-SPAN; AUTOMATED SEGMENTATION; ALZHEIMERS-DISEASE AB Magnetic resonance imaging (MRI) has allowed the unprecedented capability to measure the human brain in vivo. This technique has paved the way for longitudinal studies exploring brain changes across the entire life span. Results from these studies have given us a glimpse into the remarkably extended and multifaceted development of our brain, converging with evidence from anatomical and histological studies. Ever-evolving techniques and analytical methods provide new avenues to explore and questions to consider, requiring researchers to balance excitement with caution. This review addresses what MRI studies of structural brain development in children and adolescents typically measure and how. We focus on measurements of brain morphometry (e.g., volume, cortical thickness, surface area, folding patterns), as well as measurements derived from diffusion tensor imaging (DTI). By integrating finding from multiple longitudinal investigations, we give an update on current knowledge of structural brain development and how it relates to other aspects of biological development and possible underlying physiological mechanisms. Further, we review and discuss current strategies in image processing, analysis techniques and modeling of brain development. We hope this review will aid current and future longitudinal investigations of brain development, as well as evoke a discussion amongst researchers regarding best practices. Published by Elsevier Ltd. C1 [Mills, Kathryn L.] UCL, Inst Cognit Neurosci, London, England. [Mills, Kathryn L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Tamnes, Christian K.] Univ Oslo, Dept Psychol, Res Grp Lifespan Changes Brain & Cognit, Oslo, Norway. RP Mills, KL (reprint author), UCL Inst Cognit Neurosci, 17 Queen Sq, London WC1N 3AR, England. EM kathryn.l.mills@gmail.com OI Mills, Kathryn/0000-0002-6463-186X FU National Institute of Mental Health Intramural Research program; NIH Graduate Partnership Program; Department of Psychology, University of Oslo FX KLM is supported by the National Institute of Mental Health Intramural Research program and the NIH Graduate Partnership Program. CKT is supported by the Department of Psychology, University of Oslo. NR 143 TC 33 Z9 34 U1 3 U2 22 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 EI 1878-9307 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD JUL PY 2014 VL 9 BP 172 EP 190 DI 10.1016/j.dcn.2014.04.004 PG 19 WC Neurosciences SC Neurosciences & Neurology GA AJ8XB UT WOS:000337990300015 PM 24879112 ER PT J AU Alnaeeli, M Raaka, BM Gavrilova, O Teng, RF Chanturiya, T Noguchi, CT AF Alnaeeli, Mawadda Raaka, Bruce M. Gavrilova, Oksana Teng, Ruifeng Chanturiya, Tatyana Noguchi, Constance Tom TI Erythropoietin Signaling: A Novel Regulator of White Adipose Tissue Inflammation During Diet-Induced Obesity SO DIABETES LA English DT Article ID ALTERNATIVE MACROPHAGE ACTIVATION; INSULIN-RESISTANCE; CEREBRAL-ISCHEMIA; PPAR-GAMMA; MICE; RECRUITMENT; EXPRESSION; PROTECTS; SURVIVAL; DISEASE AB Obesity-induced white adipose tissue (WAT) inflammation and insulin resistance are associated with macrophage (M(sic)) infiltration and phenotypic shift from "anti-inflammatory" M2-like to predominantly "proinflammatory" M1-like cells. Erythropoietin (EPO), a glycoprotein hormone indispensable for erythropoiesis, has biological activities that extend to nonerythroid tissues, including antiapoptotic and anti-inflammatory effects. Using comprehensive in vivo and in vitro analyses in mice, EPO treatment inhibited WAT inflammation, normalized insulin sensitivity, and reduced glucose intolerance. We investigated EPO receptor (EPO-R) expression in WAT and characterized the role of its signaling during obesity-induced inflammation. Remarkably, and prior to any detectable changes in body weight or composition, EPO treatment reduced M1-like M(sic) and increased M2-like M(sic) in WAT, while decreasing inflammatory monocytes. These anti-inflammatory effects were found to be driven, at least in part, by direct EPO-R response in M(sic) via Stat3 activation, where EPO effects on M2 but not M1 M(sic) required interleukin-4 receptor/Stat6. Using obese Delta EpoR mice with EPO-R restricted to erythroid cells, we demonstrated an anti-inflammatory role for endogenous EPO. Collectively, our findings identify EPO-R signaling as a novel regulator of WAT inflammation, extending its nonerythroid activity to encompass effects on both M(sic) infiltration and subset composition in WAT. C1 [Alnaeeli, Mawadda; Noguchi, Constance Tom] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Raaka, Bruce M.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD USA. [Gavrilova, Oksana; Teng, Ruifeng; Chanturiya, Tatyana] NIDDK, Mouse Metab Core Facil, NIH, Bethesda, MD USA. RP Noguchi, CT (reprint author), NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. EM connien@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institutes of Health. NR 50 TC 12 Z9 13 U1 0 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD JUL PY 2014 VL 63 IS 7 BP 2415 EP 2431 DI 10.2337/db13-0883 PG 17 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AJ7YO UT WOS:000337918200030 PM 24647735 ER PT J AU Downward, GS Hu, W Large, D Veld, H Xu, J Reiss, B Wu, GP Wei, FS Chapman, RS Rothman, N Qing, L Vermeulen, R AF Downward, George S. Hu, Wei Large, David Veld, Harry Xu, Jun Reiss, Boris Wu, Guoping Wei, Fusheng Chapman, Robert S. Rothman, Nat Qing, Lan Vermeulen, Roel TI Heterogeneity in coal composition and implications for lung cancer risk in Xuanwei and Fuyuan counties, China SO ENVIRONMENT INTERNATIONAL LA English DT Article DE Solid fuels; Coal; Exposure assessment; Lung cancer ID CURRENT PROGRESS; WEI; COMBUSTION; EXPOSURE; ORIGIN; YUNNAN; FUEL AB Background: Xuanwei and Fuyuan counties in Yunnan Province, China have among the highest lung cancer rates in the country. This has been associated with the domestic combustion of bituminous coal (referred to as "smoky" coal). Additionally, significant geographical variation in cancer rates among smoky coal users has been observed, suggesting heterogeneity in fuel source composition and/or combustion characteristics. Research thus far has indicated that smoky coal emits high levels of polycyclic aromatic hydrocarbons (PAHs) and contains high concentrations of fine grained crystalline quartz, however, much of this research is limited in terms of sample size and geographic scope. In order to more fully characterise geochemical and elemental compositions of smoky and smokeless coal use in Xuanwei and Fuyuan, we carried out a large exposure assessment study in households in this region. Methods: Fuel samples representing smoky and "smokeless" (anthracite, the major alternative coal type in the region) coals were collected from 137 homes in Xuanwei and Fuyuan. Rock-Eval, Leco-CS, XRF analysis and electron microscopy were used to establish hydrocarbon content (to represent volatile organic compounds), major and trace element composition and mineral composition respectively. Heterogeneity in coal characteristics between and within coal types was assessed by the Kruskal-Wallis test Results: 145 coal samples (116 smoky and 29 smokeless coals) were analysed. Statistically significant differences between smoky and smokeless coals with regard to hydrocarbon content, sulfur, trace elements and mineral composition were observed. Of note, smoky coal contained between 5 and 15 times the amount of volatile organic matter and twice the amount of quartz (including respirable quartz) than smokeless coal. Smoky coal generally had lower levels of trace elements (plus aluminium) than smokeless coal. Significant variation was also observed between smoky coal samples from different geographical areas with regard to hydrocarbon content and elemental composition (including aluminium and silicon). Discussion: This paper has identified compositional differences between and within smoky and smokeless coals sourced from Xuanwei and Fuyuan counties. A decreased ratio of aluminium to silicon in smoky coal suggests elevated free silica, a finding consistent with observed higher levels of quartz. Elevated volatile organic matter content in smoky coal (when compared to smokeless coal) is consistent with the geochemical expectations for smoky and smokeless coals. These findings also reflect previous observations of elevated volatile compound emissions (notably PAHs) from smoky coal in the area. The observed heterogeneity in coal composition between and within coal types may provide leads to the observed heterogeneity in cancer risk observed in this area. (C) 2014 Elsevier Ltd. All rights reserved C1 [Downward, George S.; Reiss, Boris; Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, NL-3584 CM Utrecht, Netherlands. [Hu, Wei; Rothman, Nat; Qing, Lan] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Large, David] Univ Nottingham, Dept Chem & Environm Engn, Nottingham NG7 2RD, England. [Veld, Harry] Deltares, Dept Appl Microbiol & Geochem, Utrecht, Netherlands. [Xu, Jun] Univ Hong Kong, Sch Publ Hlth, Dept Community Med, Hong Kong, Hong Kong, Peoples R China. [Wu, Guoping; Wei, Fusheng] China Natl Environm Monitoring Ctr, Beijing, Peoples R China. [Chapman, Robert S.] Chulalongkorn Univ, Coll Publ Hlth Sci, Bangkok, Thailand. RP Downward, GS (reprint author), Univ Utrecht, Inst Risk Assessment Sci, Yalelaan 2, NL-3584 CM Utrecht, Netherlands. EM g.s.downward@uu.nl RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU National Institutes of Health [HHSN261201400122P] FX This project was supported by the National Institutes of Health (HHSN261201400122P) intramural research programme. 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 organisations imply endorsement by the U.S. Government. The authors would like to acknowledge Johan Beekhuizen and Meng Wang from the Institute for Risk Assessment Sciences, Utrecht University for their support in the production of Fig. 1. NR 26 TC 16 Z9 17 U1 4 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD JUL PY 2014 VL 68 BP 94 EP 104 DI 10.1016/j.envint.2014.03.019 PG 11 WC Environmental Sciences SC Environmental Sciences & Ecology GA AJ7JZ UT WOS:000337874300011 PM 24721117 ER PT J AU Savitz, DA Klebanoff, MA Wellenius, GA Jensen, ET Longnecker, MP AF Savitz, David A. Klebanoff, Mark A. Wellenius, Gregory A. Jensen, Elizabeth T. Longnecker, Matthew P. TI Persistent organochlorines and hypertensive disorders of pregnancy SO ENVIRONMENTAL RESEARCH LA English DT Article DE Organochlorines; PCBs; DDT; Gestational hypertension; Preeclampsia ID PERFLUOROOCTANOIC ACID EXPOSURE; POLYCHLORINATED-BIPHENYLS; PREECLAMPSIA; BIRTH; ASSOCIATION; PRETERM AB Although there is indirect evidence to suggest that persistent organochlorines might increase risk of hypertensive disorders of pregnancy, there are no epidemiologic studies directly addressing this question. In this cohort study, sampled from the Collaborative Perinatal Project, 1933 women had complete data on organochlorine measurements, covariates, and pregnancy outcomes. Exposures to organochlorines were divided into quintiles, and levels were much higher in these patients recruited from 1959 to 1965 compared to levels in the general population at present. Among included women, 364 developed gestational hypertension (hypertension without proteinuria) and 131 developed preeclampsia (hypertension with proteinuria). We found essentially no association between serum DDE and total PCBs and risk of either gestational hypertension or preeclampsia. Results for other organochlorines showed varying patterns of results: DDT was inversely associated with risk of gestational hypertension (p for trend <0.001), B-Hexachlorocyclohexane and heptachlor epoxide were inversely related to gestational hypertension (p trend <0.01 and 0.10, respectively), dieldrin had a modestly positive association with gestational hypertension (p for trend = 0.12), and hexachlorobenzene, trans-nonachlor, and oxychlordane yielded results close to the null. Hexachlorobenzene showed an inverse association with preeclampsia (p for trend <0.001). The study suggests that persistent organochlorines present at historically high level are not likely to increase the risk of hypertensive disorders of pregnancy, suggesting that other toxicants that have similar biologic effects are also unlikely to do so. (C) 2014 Elsevier Inc. All rights reserved. C1 [Savitz, David A.; Wellenius, Gregory A.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Klebanoff, Mark A.] Ohio State Univ, Coll Med, Nationwide Childrens Hosp, Dept Pediat, Columbus, OH 43210 USA. [Klebanoff, Mark A.] Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Jensen, Elizabeth T.; Longnecker, Matthew P.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. RP Savitz, DA (reprint author), Brown Univ, Sch Publ Hlth, Dept Epidemiol, 47 George St,Room 302, Providence, RI 02912 USA. EM david_savitz@brown.edu; Mark.Klebanoff@nationwidechildrens.org; Gregory_wellenius@brown.edu; elizabeth.jensen@nih.gov; Longnecl@niehs.nih.gov RI Wellenius, Gregory/A-7105-2012; Jensen, Elizabeth/L-1466-2016; OI Wellenius, Gregory/0000-0003-0427-7376; Longnecker, Matthew/0000-0001-6073-5322 FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. This research was reviewed and approved by the National Institute of Environmental Health Sciences IRB and was found to be exempt from Institutional Review Board review at Brown University. NR 20 TC 5 Z9 5 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD JUL PY 2014 VL 132 BP 1 EP 5 DI 10.1016/j.envres.2014.03.020 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA AJ7FJ UT WOS:000337862300001 PM 24742720 ER PT J AU Cupul-Uicab, LA Terrazas-Medina, EA Hernandez-Avila, M Longnecker, MP AF Cupul-Uicab, Lea A. Terrazas-Medina, Efrain A. Hernandez-Avila, Mauricio Longnecker, Matthew P. TI Prenatal exposure to p,p '-DDE and p,p '-DDT in relation to lower respiratory tract infections in boys from a highly exposed area of Mexico SO ENVIRONMENTAL RESEARCH LA English DT Article DE Boys; Lower respiratory tract infections; p,p '-DDE; p,p '-DDT; Prenatal exposure ID 1,1-DICHLORO-2,2-BIS(P-CHLOROPHENYL)ETHYLENE DDE; CAUSAL-DIAGRAMS; INFANTS; CHILDHOOD; PNEUMONIA; BRONCHIOLITIS; PESTICIDES; RISKS; BLOOD AB Background: Prenatal exposure to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), the major breakdown product of DDT, has been associated with recurrent lower respiratory tract infections (LRTIs) in infants. However, epidemiological investigations are limited. Objective: To assess the association of prenatal exposure to p,p'-DDE and p,p'-DDT with the occurrence of LRTI in boys from Chiapas, a highly exposed area of Mexico. Methods: We analyzed data from 747 singleton boys whose prenatal exposure to p,p'-DDE and p,p'-DDT was determined in maternal serum drawn at delivery (2002-2003). LRTI (i.e., pneumonia, bronchiolitis, and other illness of the bronchi) experienced by the children were reported by their mothers during in-person interviews. The median age of the children when they were last seen was 21.4 months (quartiles 19.1 and 25.3 months). Results: Median exposure to p,p'-DDE in this population was higher (2.7 mu g/g lipid) than recent U.S. levels (0.20 mu g/g). There were 0.19 episodes of LRTI per child-year. After adjusting for potential confounders, children in the highest category of p,p'-DDE (>9.00 mu g/g) exposure compared to those in the lowest (<= 3.00 mu g/g) had an adjusted incidence rate ratio (aIRR) of LRTI of 0.77 (95% confidence interval [CI], 0.41-1.46). The corresponding aIRR for p,p'-DDT (>= 2.00 mu/g compared to <= 0.25 mu g/g) was 0.65 (95% CI: 0.30-139). Conclusion: An association of prenatal exposure to p,p'-DDE and p,p'-DDT with LRTI during childhood was not supported in this population with relatively high levels of exposure. (C) 2014 Elsevier Inc. All rights reserved. C1 [Cupul-Uicab, Lea A.; Terrazas-Medina, Efrain A.; Hernandez-Avila, Mauricio] Natl Inst Publ Hlth, Ctr Populat Hlth Res, Cuernavaca 62100, Morelos, Mexico. [Cupul-Uicab, Lea A.; Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH DHHS USA, Res Triangle Pk, NC 27709 USA. RP Cupul-Uicab, LA (reprint author), Natl Inst Publ Hlth, Ave Univ 655, Cuernavaca 62100, Morelos, Mexico. EM lea.cupul@insp.mx OI Longnecker, Matthew/0000-0001-6073-5322 FU National Institute of Environmental Health Sciences, National Institutes of Health [N01-ES-15467]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; Instituto Nacional de Salud Publica, Cuernavaca, Morelos, Mexico FX This work was supported in part by a contract from the National Institute of Environmental Health Sciences, National Institutes of Health [N01-ES-15467]; in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; and in part by the Instituto Nacional de Salud Publica, Cuernavaca, Morelos, Mexico. NR 36 TC 1 Z9 1 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 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD JUL PY 2014 VL 132 BP 19 EP 23 DI 10.1016/j.envres.2014.03.017 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA AJ7FJ UT WOS:000337862300004 PM 24742723 ER PT J AU Litiere, S de Vries, EGE Seymour, L Sargent, D Shankar, L Bogaerts, J AF Litiere, Saskia de Vries, Elisabeth G. E. Seymour, Lesley Sargent, Dan Shankar, Lalitha Bogaerts, Jan CA RECIST Comm TI The components of progression as explanatory variables for overall survival in the Response Evaluation Criteria in Solid Tumours 1.1 database SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Tumour growth; Time-dependent model; Goodness-of-fit; Breast cancer; Lung cancer; Colorectal cancer ID TRIALS; CANCER AB Purpose: Progressive disease (PD) per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 is defined as growth of measurable target lesions, presence of new lesions or unequivocal progression of non-target disease. In this manuscript we explored whether a more refined categorisation of tumour response and/or these components of progression, varying over time, can improve prediction of overall survival (OS) in the RECIST database. Methods: Data were randomly selected from 13 randomised clinical trials (3758 patients with breast, lung or colorectal cancer). A maximum of five target lesions contributed to the sum of longest diameters. At each measurement time we determined: best target response as best % improvement from baseline; tumour growth of target lesions as worst % change and worst rate of increase (mm/week) from nadir; presence of new lesions and occurrence of non-target PD. OS was analysed by tumour type using Cox regression, adjusting for baseline sum and including these parameters as time-dependent covariates. Results: 36% of patients had new lesions, 28% non-target PD and 49% experienced target lesion growth (median strongest growth 1.5 mm/week). Regardless of tumour type, presence of new lesions (hazard ratio (HR) ranging 1.5-2.3) and non-target PD (HR 1.5-2.0) were strongly associated with worse OS. The explanatory value of tumour growth for OS was low compared to the other components. Conclusion: Modelling target lesion tumour growth did not show a marked improvement in OS prediction over and above the other components. These analyses enable a better understanding of the role of each component in PD evaluation. Work is ongoing to incorporate this information into an updated version of RECIST with enhanced prediction of subsequent survival. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Litiere, Saskia; Bogaerts, Jan] European Org Res Treatment Canc, Brussels, Belgium. [de Vries, Elisabeth G. E.] Univ Groningen, Univ Med Ctr, Dept Med Oncol, Groningen, Netherlands. [Seymour, Lesley] Queens Univ, NCIC Clin Trials Grp, Kingston, ON, Canada. [Sargent, Dan] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Shankar, Lalitha] NCI, Canc Imaging Program, NIH, Bethesda, MA USA. RP Litiere, S (reprint author), European Org Res Treatment Canc, Brussels, Belgium. EM saskia.litiere@eortc.be OI Sargent, Daniel/0000-0002-2684-4741 FU EORTC Charitable Trust FX This publication was supported by the EORTC Charitable Trust. NR 10 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2014 VL 50 IS 10 BP 1847 EP 1853 DI 10.1016/j.ejca.2014.03.014 PG 7 WC Oncology SC Oncology GA AJ7KO UT WOS:000337875800018 PM 24726734 ER PT J AU Bell, DW AF Bell, Daphne W. TI Novel genetic targets in endometrial cancer SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Editorial Material DE endometrial; gene; mutation; uterine ID UTERINE SEROUS CARCINOMA; DNA-DAMAGE RESPONSE; GENOME-WIDE; SOMATIC MUTATIONS; BINDING-PROTEINS; COMPLEX; RNA; IDENTIFICATION; REPRESSOR; CELLS AB Worldwide, similar to 74,000 women die from endometrial cancer each year. Understanding the somatic genomic alterations that drive endometrial tumorigenesis may provide new opportunities to identify targeted therapies for specific subsets of patients. Since 2012, the use of next-generation sequencing to decode the mutational landscape of endometrial tumors has not only confirmed prior knowledge of established genetic targets for serous and endometrioid endometrial carcinomas (ECs), but has also uncovered novel significantly mutated genes, referred to herein as novel genetic targets, which represent candidate cancer genes in these tumors. This editorial summarizes the novel genetic targets that have been identified in serous and endometrioid ECs, according to their unifying functional characteristics. An expert opinion section comments on remaining knowledge gaps that will undoubtedly be filled in future genomic studies of endometrial cancer. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Bell, DW (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM belldaph@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 33 TC 1 Z9 1 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8222 EI 1744-7631 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD JUL PY 2014 VL 18 IS 7 BP 725 EP 730 DI 10.1517/14728222.2014.909414 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AJ5VW UT WOS:000337759300003 PM 24750045 ER PT J AU Coelingh, KL Luke, CJ Jin, H Talaat, KR AF Coelingh, Kathleen L. Luke, Catherine J. Jin, Hong Talaat, Kawsar R. TI Development of live attenuated influenza vaccines against pandemic influenza strains SO EXPERT REVIEW OF VACCINES LA English DT Review DE intranasal influenza vaccine; LAIV; pandemic influenza vaccine ID ANN-ARBOR STRAIN; CELLULAR IMMUNE-RESPONSES; PHASE-I TRIAL; VIRUS VACCINE; H5N1 INFLUENZA; HEALTHY-ADULTS; POSTMARKETING EVALUATION; YOUNG-CHILDREN; SAFETY; FERRETS AB Avian and animal influenza viruses can sporadically transmit to humans, causing outbreaks of varying severity. In some cases, further human-to-human virus transmission does not occur, and the outbreak in humans is limited. In other cases, sustained human-to-human transmission occurs, resulting in worldwide influenza pandemics. Preparation for future pandemics is an important global public health goal. A key objective of preparedness is to gain an understanding of how to design, test, and manufacture effective vaccines that could be stockpiled for use in a pandemic. This review summarizes results of an ongoing collaboration to produce, characterize, and clinically test a library of live attenuated influenza vaccine strains (based on Ann Arbor attenuated Type A strain) containing protective antigens from influenza viruses considered to be of high pandemic potential. C1 [Coelingh, Kathleen L.] AstraZeneca, Gaithersburg, MD 20878 USA. [Luke, Catherine J.] NIH, Bethesda, MD 20892 USA. [Jin, Hong] MedImmune, Mountain View, CA 94043 USA. [Talaat, Kawsar R.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Coelingh, KL (reprint author), AstraZeneca, One MedImmune Way, Gaithersburg, MD 20878 USA. EM coelinghk@medimmune.com FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA; HHS Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority [HHS0100200900021]; MedImmune FX KC is an employee of AstraZeneca, HJ is an employee of MedImmune; both may hold stock or stock options in AstraZeneca, the parent company of MedImmune. CL is a member of the Executive Committee for a Cooperative Research and Development Agreement between NIH and MedImmune. KT has no competing interests to declare. The influenza pandemic vaccine program is conducted as part of a Cooperative Research and Development Agreement between MedImmune and the Laboratory of Infectious Diseases, NIAID. This research was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. The 2009 H1N1pdm LAIV studies were funded in whole or in part with Federal funds from the HHS Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority under Contract HHS0100200900021. 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. Writing assistance was utilized in the production of this manuscript. Editorial assistance was provided by DeRocco SE and Fincke JE of Complete Healthcare Communications, Inc. (Chadds Ford, PA) and was funded by MedImmune. NR 51 TC 18 Z9 19 U1 3 U2 13 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD JUL PY 2014 VL 13 IS 7 BP 855 EP 871 DI 10.1586/14760584.2014.922417 PG 17 WC Immunology SC Immunology GA AJ5XA UT WOS:000337762400005 PM 24867587 ER PT J AU Luke, CJ Subbarao, K AF Luke, Catherine J. Subbarao, Kanta TI Improving pandemic H5N1 influenza vaccines by combining different vaccine platforms SO EXPERT REVIEW OF VACCINES LA English DT Review DE influenza vaccine; pandemic influenza vaccine; prime boost ID T-CELL RESPONSES; VIRUS-LIKE PARTICLE; A VIRUS; IMMUNE-RESPONSES; MF59-ADJUVANTED INFLUENZA; ANTIBODY-RESPONSES; ANTIGENIC VARIANT; REVERSE GENETICS; GLOBAL MORTALITY; BOOSTER RESPONSE AB A variety of platforms are being explored for the development of vaccines for pandemic influenza. Observations that traditional inactivated subvirion vaccines and live-attenuated vaccines against H5 and some H7 influenza viruses were poorly immunogenic spurred efforts to evaluate new approaches, including whole virus vaccines, higher doses of antigen, addition of adjuvants and combinations of different vaccine modalities in heterologous prime-boost regimens to potentiate immune responses. Results from clinical trials of prime-boost regimens have been very promising. Further studies are needed to determine optimal combinations of platforms, intervals between doses of vaccines and the logistics of deployment in pre-pandemic and early pandemic settings. C1 [Luke, Catherine J.; Subbarao, Kanta] NIAID, Emerging Resp Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Subbarao, K (reprint author), NIAID, Emerging Resp Viruses Sect, Infect Dis Lab, NIH, Bldg 33,Room 3E13C-1,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This research was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. CJ Luke is a member of the Executive Committee for a Cooperative Research and Development Agreement between NIH and MedImmune. K Subbarao is Principal Investigator on a Cooperative Research and Development Agreement between NIH and MedImmune for the development of live-attenuated pandemic influenza vaccines. 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 85 TC 12 Z9 12 U1 1 U2 12 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD JUL PY 2014 VL 13 IS 7 BP 873 EP 883 DI 10.1586/14760584.2014.922416 PG 11 WC Immunology SC Immunology GA AJ5XA UT WOS:000337762400006 PM 24855993 ER PT J AU Slominski, AT Kim, TK Takeda, Y Janjetovic, Z Brozyna, AA Skobowiat, C Wang, J Postlethwaite, A Li, W Tuckey, RC Jetten, AM AF Slominski, Andrzej T. Kim, Tae-Kang Takeda, Yukimasa Janjetovic, Zorica Brozyna, Anna A. Skobowiat, Cezary Wang, Jin Postlethwaite, Arnold Li, Wei Tuckey, Robert C. Jetten, Anton M. TI ROR alpha and ROR gamma are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D SO FASEB JOURNAL LA English DT Article DE keratinocytes; melanoma cells; retinoic acid-related nuclear receptors; CYP11A1 ID CYTOCHROME P450SCC CYP11A1; VITAMIN-D-RECEPTOR; IN-VIVO; TRANSCRIPTIONAL ACTIVATION; EPIDERMAL-KERATINOCYTES; INHIBITS PROLIFERATION; ULTRAVIOLET-RADIATION; CHOLESTEROL SULFATE; NUCLEAR RECEPTORS; METABOLISM AB ROR alpha and ROR gamma are expressed in human skin cells that produce the noncalcemic 20-hydroxyvitamin D-3 [20(OH)D-3] and 20,23-dihydroxyvitamin D-3 [20,23(OH)(2)D-3]. Chinese hamster ovary (CHO) cells stably expressing a Tet-on ROR alpha or ROR gamma expression vector and a ROR-responsive element (RORE)-LUC reporter, and a mammalian 2-hybrid model examining the interaction between the ligand binding domain (LBD) of ROR alpha or ROR gamma with an LBD-interacting LXXLL-peptide, were used to study ROR-antagonist activities. These assays revealed that 20(OH)D-3 and 20,23(OH)(2)D-3 function as antagonists of ROR alpha and ROR gamma. Moreover, 20(OH)D-3 inhibited the activation of the promoter of the Bmal1 and G6pase genes, targets of ROR alpha, and 20(OH)D-3 and 20,23(OH)(2)D-3 inhibited Il17 promoter activity in Jurkat cells overexpressing ROR alpha or ROR gamma. Molecular modeling using crystal structures of the LBDs of ROR alpha and ROR gamma revealed docking scores for 20(OH)D-3, 20, 23(OH)(2)D-3 and 1,25(OH)(2)D-3 similar to those of the natural ligands, predicting good binding to the receptor. Notably, 20(OH)D-3, 20,23(OH)(2)D-3, and 1,25(OH)(2)D-3 inhibited RORE-mediated activation of a reporter in keratinocytes and melanoma cells and inhibited IL-17 production by immune cells. Our study identifies a novel signaling pathway, in which 20(OH)D-3 and 20,23(OH)(2)D-3 act as antagonists or inverse agonists of ROR alpha and ROR gamma, that opens new possibilities for local (skin) or systemic regulation. C1 [Slominski, Andrzej T.; Kim, Tae-Kang; Janjetovic, Zorica; Skobowiat, Cezary] Univ Tennessee, Ctr Hlth Sci, Dept Pathol & Lab Med, Memphis, TN 38163 USA. [Slominski, Andrzej T.; Postlethwaite, Arnold] Univ Tennessee, Ctr Hlth Sci, Dept Med, Memphis, TN 38163 USA. [Wang, Jin; Li, Wei] Univ Tennessee, Ctr Hlth Sci, Dept Pharmaceut Sci, Memphis, TN 38163 USA. [Takeda, Yukimasa; Jetten, Anton M.] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Brozyna, Anna A.] Nicolaus Copernicus Univ, Dept Tumor Pathol & Pathomorphol, Prof Franciszek Lukaszczyk Mem Hosp, Oncol Ctr,Ludwik Rydygier Coll Med, Bydgoszcz, Poland. [Postlethwaite, Arnold] Dept Vet Affairs Med Ctr, Memphis, TN USA. [Tuckey, Robert C.] Univ Western Australia, Sch Chem & Biochem, Crawley, WA, Australia. RP Slominski, AT (reprint author), Univ Tennessee, Ctr Hlth Sci, Dept Pathol, 930 Madison Ave,RM525, Memphis, TN 38163 USA. EM aslominski@uthsc.edu; jetten@niehs.nih.gov RI Brozyna, Anna/D-4902-2014; Skobowiat, Cezary/J-5007-2012 OI Brozyna, Anna/0000-0002-3195-9965; Skobowiat, Cezary/0000-0002-3881-0231 FU U.S. National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases [2R06AR052190, 1R01AR056666-01A2]; West Clinic Cancer Foundation; Department of Veterans Affairs Program [1IPIBX00107-01, 1R21AR063242-01A1, 1S10OD010678-01]; National Institute of Environmental Health Sciences, NIH [Z01-ES-101586]; Japanese Society for the Promotion of Science (JSPS) FX The project was supported by grants from the U.S. National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (2R06AR052190 and 1R01AR056666-01A2) and the West Clinic Cancer Foundation to A. T. S.; Department of Veterans Affairs Program Project grant 1IPIBX00107-01 to A. P. and grants 1R21AR063242-01A1 and 1S10OD010678-01 to W. L.; and by grants from the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (Z01-ES-101586), and the Japanese Society for the Promotion of Science (JSPS) to A.M.J. and Y.T. NR 70 TC 40 Z9 40 U1 1 U2 10 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD JUL PY 2014 VL 28 IS 7 BP 2775 EP 2789 DI 10.1096/fj.13-242040 PG 15 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AJ8JN UT WOS:000337949400005 PM 24668754 ER PT J AU Cheng, J Edin, ML Hoopes, SL Li, H Bradbury, JA Graves, JP DeGraff, LM Lih, FB Garcia, V Shaik, JSB Tomer, KB Flake, GP Falck, JR Lee, CR Poloyac, SM Schwartzman, ML Zeldin, DC AF Cheng, Jennifer Edin, Matthew L. Hoopes, Samantha L. Li, Hong Bradbury, J. Alyce Graves, Joan P. DeGraff, Laura M. Lih, Fred B. Garcia, Victor Shaik, Jafar Sadik B. Tomer, Kenneth B. Flake, Gordon P. Falck, John R. Lee, Craig R. Poloyac, Samuel M. Schwartzman, Michal L. Zeldin, Darryl C. TI Vascular characterization of mice with endothelial expression of cytochrome P450 4F2 SO FASEB JOURNAL LA English DT Article DE CYP4F2; 20-HETE; oxidative stress; cellular proliferation; angiogenesis ID URINARY 20-HYDROXYEICOSATETRAENOIC ACID; ANDROGEN-INDUCED HYPERTENSION; BLOOD-PRESSURE; OXIDATIVE STRESS; CELL-PROLIFERATION; 20-HETE SYNTHESIS; ARACHIDONIC-ACID; NADPH-OXIDASE; RENAL INJURY; DYSFUNCTION AB Cytochrome P450 (CYP) 4A and 4F enzymes metabolize arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE). Although CYP4A-derived 20-HETE is known to have prohypertensive and proangiogenic properties, the effects of CYP4F-derived metabolites are not well characterized. To investigate the role of CYP4F2 in vascular disease, we generated mice with endothelial expression of human CYP4F2 (Tie2-CYP4F2-Tr). LC/MS/MS analysis revealed 2-fold increases in 20-HETE levels in tissues and endothelial cells (ECs), relative to wild-type (WT) controls. Tie2-CYP4F2-Tr ECs demonstrated increases in growth (267.1 +/- 33.4 vs. 205.0 +/- 13% at 48 h) and tube formation (7.7 +/- 1.1 vs. 1.6 +/- 0.5 tubes/field) that were 20-HETE dependent and associated with up-regulation of prooxidant NADPH oxidase and proangiogenic VEGF. Increases in VEGF and NADPH oxidase levels were abrogated by inhibitors of NADPH oxidase and MAPK, respectively, suggesting the possibility of crosstalk between pathways. Interestingly, IL-6 levels in Tie2-CYP4F2-Tr mice (18.6 +/- 2.7 vs. 7.9 +/- 2.7 pg/ml) were up-regulated via NADPH oxidase-and 20-HETE-dependent mechanisms. Although Tie2-CYP4F2-Tr aortas displayed increased vasoconstriction, vasorelaxation and blood pressure were unchanged. Our findings indicate that human CYP4F2 significantly increases 20-HETE production, CYP4F2-derived 20-HETE mediates EC proliferation and angiogenesis via VEGF-and NADPH oxidase-dependent manners, and the Tie2-CYP4F2-Tr mouse is a novel model for examining the pathophysiological effects of CYP4F2-derived 20-HETE in the vasculature. C1 [Cheng, Jennifer; Edin, Matthew L.; Hoopes, Samantha L.; Li, Hong; Bradbury, J. Alyce; Graves, Joan P.; DeGraff, Laura M.; Lih, Fred B.; Tomer, Kenneth B.; Flake, Gordon P.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Falck, John R.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Garcia, Victor; Schwartzman, Michal L.] New York Med Coll, Dept Pharmacol, Valhalla, NY 10595 USA. [Lee, Craig R.] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC USA. [Shaik, Jafar Sadik B.; Poloyac, Samuel M.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA USA. RP Zeldin, DC (reprint author), NIEHS, NIH, 111 TW Alexander Dr,Bldg 101,Rm A214, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov RI SHAIK, JAFAR SADIK/A-9638-2010; OI SHAIK, JAFAR SADIK/0000-0001-5776-3138; Edin, Matthew/0000-0002-7042-500X; Lee, Craig/0000-0003-3595-5301 FU U.S. National Institutes of Health (NIH) [DK-38226]; Robert A. Welch Foundation; NIH [GM-088199, HL-34300]; NIH, National Institute of Environmental Health Sciences [Z01 ES050167, Z01 ES025034]; [HL-34300-26A1S1] FX The authors gratefully acknowledge the staff at Xenogen Biosciences (Cranberry, NJ, USA) for assistance with pronuclear injections and generation of the Tie2-CYP4F2-Tr mice. This work was made possible by U.S. National Institutes of Health (NIH) grant DK-38226 and support from the Robert A. Welch Foundation (to J.R.F.), NIH grant GM-088199 (to C. R. L), NIH grant HL-34300 (to M. L. S.), Diversity Supplement Award HL-34300-26A1S1 (to V. G.), and funds from the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES050167 to K. B. T. and Z01 ES025034 to D.C.Z.). NR 44 TC 6 Z9 6 U1 0 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD JUL PY 2014 VL 28 IS 7 BP 2915 EP 2931 DI 10.1096/fj.13-241927 PG 17 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA AJ8JN UT WOS:000337949400016 PM 24668751 ER PT J AU Song, SB Cohen, LG AF Song, Sunbin Cohen, Leonardo G. TI Conscious recall of different aspects of skill memory SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Article DE conscious recall; transition; ordinal; skill learning; implicit; process dissociation procedure; serial reaction time task; sequence learning ID PROCESS-DISSOCIATION PROCEDURE; IMPLICIT; REPRESENTATION; STROKE AB Different mechanisms are involved in the formation of memories necessary for daily living. For example, different memory representations are formed for the practiced transitions between key-presses (i.e., pressing key "2" after "3" in "4-3-2-1") and for the ordinal position of each key press (i.e., pressing key "2" in the third ordinal position in "4-3-2-1") in a motor sequence. Whether the resulting transition-based and ordinal-based memories (Song and Cohen, 2014) can be consciously recalled is unknown. Here, we studied subjects who over a week of training and testing formed transition and ordinal-based memory representations of skill for a 12-item sequence of key-presses. Afterwards, subjects were first asked to recall and type the trained sequence and then to perform random key presses avoiding the trained sequence. The difference in the ability to purposefully recall and avoid a trained sequence represents conscious recall (Destrebecqz and Cleerernans, 2001). We report that (a) the difference in the ability to purposefully recall and to avoid the trained sequence correlated with ordinal based but not with transition based memory; (b) subjects with no ability to recall or avoid the trained sequence formed transition-based but not ordinal-based memories; and (c) subjects with full ability to recall and avoid the trained sequence formed both transition-based and ordinal-based memories. We conclude that ordinal based memory can be voluntarily recalled when transition based memory cannot, documenting a differential capacity to recall memories forming a motor skill. Understanding that different memories form a motor skill, with different neural substrates (Cohen and Squire, 1980), may help develop novel training strategies in neurorehabilitation of patients with brain lesions. C1 [Song, Sunbin; Cohen, Leonardo G.] Natl Inst Neurol Disorders & Stroke, Human Cort Physiol & Neurorehabil Sec, NIH, Bethesda, MD 20892 USA. RP Song, SB (reprint author), Natl Inst Neurol Disorders & Stroke, Human Cort Physiol & Neurorehabil Sec, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM songss@mail.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health. NR 15 TC 0 Z9 0 U1 2 U2 5 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD JUL 1 PY 2014 VL 8 AR 233 DI 10.3389/fnbeh.2014.00233 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AK1SN UT WOS:000338196400001 PM 25071489 ER PT J AU Xu, GL Chen, J Yang, F Li, GQ Zheng, LX Wu, YZ AF Xu, Gui-lian Chen, Jian Yang, Fei Li, Gui-qing Zheng, Li-xin Wu, Yu-zhang TI C5a/C5aR Pathway Is Essential for the Pathogenesis of Murine Viral Fulminant Hepatitis by Way of Potentiating Fgl2/Fibroleukin Expression SO HEPATOLOGY LA English DT Article ID ANAPHYLATOXIN C5A RECEPTOR; KINASE ACTIVATION; VIRUS STRAIN-3; PROTHROMBINASE; INFECTION; LIVER; INHIBITION; PROTEIN; SEPSIS; CELLS AB Viral fulminant hepatitis (FH) remains a serious clinical problem with very high mortality. Lacking understanding of FH pathogenesis has in essence hindered efficient clinical treatment. Inferring from a correlation observed between the genetic differences in the complement component 5 (C5) and the susceptibility of mouse strains to murine hepatitis virus strain-3 (MHV-3) infections, we propose that excessive complement activation plays a critical role in the development of FH. We show that MHV-3 infection causes massive complement activation, along with a rapid increase in serum C5a levels and quick development of FH in susceptible strains. Mice deficient in the C5a receptor (C5aR) or the susceptible strains treated with C5aR antagonists (C5aRa) exhibit significant attenuation of the disease, accompanied by a remarkable reduction of hepatic fibrinogen-like protein 2 (Fgl2), a hallmark protein that causes necrosis of infected livers. In accordance, biopsy of FH patients shows a dramatic increase of Fgl2 expression, which correlates with C5aR up-regulation in the liver. In vitro C5a administration accelerates MHV-3-induced Fgl2 secretion by macrophages. Furthermore, inhibiting ERK1/2 and p38 efficiently blocks C5a-mediated Fgl2 production during viral infections. Conclusion: These data provide evidence that mouse susceptibility to MHV-3-induced FH may rely on C5a/C5aR interactions, for which ERK1/2 and p38 pathways participate in up-regulating Fgl2 expression. Inhibition of C5a/C5aR interactions is expected to be beneficial in the clinical treatment of FH patients. C1 [Xu, Gui-lian; Chen, Jian; Yang, Fei; Li, Gui-qing; Wu, Yu-zhang] Third Mil Med Univ, Coll Basic Med Sci, PLA, Inst Immunol, Chongqing 400038, Peoples R China. [Zheng, Li-xin] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Xu, GL (reprint author), Third Mil Med Univ, Coll Basic Med Sci, PLA, Inst Immunol, 30 Gaotanyan Main St, Chongqing 400038, Peoples R China. EM xuguilian@yahoo.com; yuzhangwu@tmmu.edu.cn FU National Natural Science Foundation of China [31270929, 30930086, 81220108024]; Innovation Team Foundation of Ministry of Education of China [PCSIRT 1052]; U.S. NIAID intramural research programs FX Supported by grants from the National Natural Science Foundation of China (31270929, 30930086, and 81220108024) and the Innovation Team Foundation of Ministry of Education of China (PCSIRT 1052). LXZ is supported by the U.S. NIAID intramural research programs. NR 34 TC 9 Z9 10 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JUL PY 2014 VL 60 IS 1 BP 114 EP 124 DI 10.1002/hep.27114 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AJ8PQ UT WOS:000337969000017 PM 24604562 ER PT J AU Kwon, HJ Won, YS Park, O Chang, BX Duryee, MJ Thiele, GE Matsumoto, A Singh, S Abdelmegeed, MA Song, BJ Kawamoto, T Vasiliou, V Thiele, GM Gao, B AF Kwon, Hyo-Jung Won, Young-Suk Park, Ogyi Chang, Binxia Duryee, Michael J. Thiele, Geoffrey E. Matsumoto, Akiko Singh, Surendra Abdelmegeed, Mohamed A. Song, Byoung-Joon Kawamoto, Toshihiro Vasiliou, Vasilis Thiele, Geoffrey M. Gao, Bin TI Aldehyde Dehydrogenase 2 Deficiency Ameliorates Alcoholic Fatty Liver but Worsens Liver Inflammation and Fibrosis in Mice SO HEPATOLOGY LA English DT Article ID HEPATIC STELLATE CELLS; GENE TARGETING MOUSE; KUPFFER CELLS; KNOCKOUT MICE; ISCHEMIA/REPERFUSION INJURY; SIGNAL TRANSDUCER; TRANSCRIPTION 3; DISEASE; ACETALDEHYDE; METABOLISM AB Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that metabolizes acetaldehyde produced from alcohol metabolism. Approximately 40-50% of East Asians carry an inactive ALDH2 gene and exhibit acetaldehyde accumulation after alcohol consumption. However, the role of ALDH2 deficiency in the pathogenesis of alcoholic liver injury remains obscure. In the present study, wild-type and ALDH2(-/-) mice were subjected to ethanol feeding and/or carbon tetrachloride (CCl4) treatment, and liver injury was assessed. Compared with wild-type mice, ethanol-fed ALDH2(-/-) mice had higher levels of malondialdehyde-acetaldehyde (MAA) adduct and greater hepatic inflammation, with higher hepatic interleukin (IL)-6 expression but surprisingly lower levels of steatosis and serum alanine aminotransferase (ALT). Higher IL-6 levels were also detected in ethanol-treated precision-cut liver slices from ALDH2(-/-) mice and in Kupffer cells isolated from ethanol-fed ALDH2(-/-) mice than those levels in wild-type mice. In vitro incubation with MAA enhanced the lipopolysaccharide (LPS)-mediated stimulation of IL-6 production in Kupffer cells. In agreement with these findings, hepatic activation of the major IL-6 downstream signaling molecule signal transducer and activator of transcription 3 (STAT3) was higher in ethanol-fed ALDH2(-/-) mice than in wild-type mice. An additional deletion of hepatic STAT3 increased steatosis and hepatocellular damage in ALDH2(-/-) mice. Finally, ethanol-fed ALDH2(-/-) mice were more prone to CCl4-induced liver inflammation and fibrosis than ethanol-fed wild-type mice. Conclusion: ALDH2(-/-) mice are resistant to ethanol-induced steatosis but prone to inflammation and fibrosis by way of MAA-mediated paracrine activation of IL-6 in Kupffer cells. These findings suggest that alcohol, by way of acetaldehyde and its associated adducts, stimulates hepatic inflammation and fibrosis independent from causing hepatocyte death, and that ALDH2-deficient individuals may be resistant to steatosis and blood ALT elevation, but are prone to liver inflammation and fibrosis following alcohol consumption. C1 [Kwon, Hyo-Jung; Won, Young-Suk; Park, Ogyi; Chang, Binxia; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Kwon, Hyo-Jung] Chungnam Natl Univ, Coll Vet Med, Taejon, South Korea. [Won, Young-Suk] Korea Res Inst Biosci & Biotechnol, Lab Anim Resource Ctr, Chungbuk, South Korea. [Duryee, Michael J.; Thiele, Geoffrey E.; Thiele, Geoffrey M.] Omaha VA Med Ctr, Expt Immunol Lab, Omaha, NE USA. [Duryee, Michael J.; Thiele, Geoffrey E.; Thiele, Geoffrey M.] Univ Nebraska Med Ctr, Omaha, NE USA. [Matsumoto, Akiko] Saga Univ, Sch Med, Dept Social Med, Saga 840, Japan. [Singh, Surendra; Vasiliou, Vasilis] Univ Colorado, Dept Pharmaceut Sci, Aurora, CO USA. [Abdelmegeed, Mohamed A.; Song, Byoung-Joon] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Kawamoto, Toshihiro] Univ Occupat & Environm Hlth, Dept Environm Hlth, Kitakyushu, Fukuoka 807, Japan. RP Gao, B (reprint author), NIAAA, Lab Liver Dis, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov OI Thiele, Geoffrey/0000-0001-5688-8596 FU NIAAA, NIH; [1R24AA022057] FX Supported by the intramural program of the NIAAA, NIH (to B. G.) and 1R24AA022057 (to V.V.). NR 40 TC 36 Z9 37 U1 3 U2 36 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JUL PY 2014 VL 60 IS 1 BP 146 EP 157 DI 10.1002/hep.27036 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AJ8PQ UT WOS:000337969000020 PM 24492981 ER PT J AU Feng, DC AF Feng, Dechun TI Interleukin-22, Liver Progenitor Cells, and Liver Cancer SO HEPATOLOGY LA English DT Letter ID HEPATOCELLULAR-CARCINOMA; HEPATITIS; ACTIVATION; STAT3; MICE C1 NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. RP Feng, DC (reprint author), NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD JUL PY 2014 VL 60 IS 1 BP 427 EP 428 DI 10.1002/hep.26899 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AJ8PQ UT WOS:000337969000044 PM 24306993 ER PT J AU Lippincott-Schwartz, J AF Lippincott-Schwartz, Jennifer TI In Focus: Single-Molecule Super-Resolution Microscopy Foreword SO HISTOCHEMISTRY AND CELL BIOLOGY LA English DT Editorial Material C1 Eugene Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20817 USA. RP Lippincott-Schwartz, J (reprint author), Eugene Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20817 USA. EM lippincj@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 0 TC 0 Z9 0 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0948-6143 EI 1432-119X J9 HISTOCHEM CELL BIOL JI Histochem. Cell Biol. PD JUL PY 2014 VL 142 IS 1 BP 1 EP 2 DI 10.1007/s00418-014-1228-8 PG 2 WC Cell Biology; Microscopy SC Cell Biology; Microscopy GA AK5WY UT WOS:000338498700001 PM 24928602 ER PT J AU Weiss, JM Alvord, WG Quinones, OA Stauffer, JK Wiltrout, RH AF Weiss, Jonathan M. Alvord, W. Gregory Quinones, Octavio A. Stauffer, Jimmy K. Wiltrout, Robert H. TI CD40 expression in renal cell carcinoma is associated with tumor apoptosis, CD8(+) T cell frequency and patient survival SO HUMAN IMMUNOLOGY LA English DT Article DE CD40; Apoptosis; CD8; Renal cell carcinoma; Survival ID CARBONIC-ANHYDRASE IX; GROWTH-INHIBITORY ACTIVITY; PROXIMAL TUBULE CELLS; CANCER-THERAPY; ACTIVATION; INTERLEUKIN-2; RECRUITMENT; PROGNOSIS; LIGAND; TISSUE AB The co-stimulatory molecule, CD40, is expressed in renal cell carcinoma (RCC) and a variety of inflammatory diseases in the kidney. We investigated the relationship between tumor-associated CD40 expression, immune milieu of the tumor microenvironment, tumor stage and survival of patients with RCC. The expression of CD40, TUNEL and CD8 in human renal cell carcinomas was analyzed by immunohistochemistry performed on tissue samples obtained at the time of surgery. Computer-assisted quantitation of protein expression was used to analyze results in connection with patient survival and tumor stage. We show for the first time that tumor-associated CD40 expression is associated with prolonged survival in RCC patients. Tumor apoptosis (TUNEL) and CD8 immunostaining were also associated with patient survival. No relation was observed between CD40 expression and tumor stage. Our results suggest CD40 may be a prognostic biomarker indicative of prolonged RCC patient survival. Strategies that up-regulate CD40 expression in some RCC patients may thus improve survival, supporting further studies of agonistic CD40 antibodies in RCC. (C) 2014 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics. C1 [Weiss, Jonathan M.; Stauffer, Jimmy K.; Wiltrout, Robert H.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Alvord, W. Gregory; Quinones, Octavio A.] Data Management Serv Inc, Frederick Natl Lab Canc Res, Stat Consulting, Frederick, MD USA. RP Weiss, JM (reprint author), NCI, Bldg 560,Rm 31-18, Frederick, MD 21702 USA. EM weissjo@mail.nih.gov FU Intramural Research Program of NIH/NCI FX This project was funded in whole or part by the Intramural Research Program of NIH/NCI. We thank Donna Butcher of the Pathology/Histotechnology Laboratory (NCI) for immunohistochemical staining. NR 47 TC 4 Z9 4 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 EI 1879-1166 J9 HUM IMMUNOL JI Hum. Immunol. PD JUL PY 2014 VL 75 IS 7 BP 614 EP 620 DI 10.1016/j.humimm.2014.04.018 PG 7 WC Immunology SC Immunology GA AJ8ER UT WOS:000337936000004 PM 24801648 ER PT J AU Zago, CA Jacob, CMA Diniz, EMD Lovisolo, SM Zerbini, MCN Dorna, M Watanabe, L Fernandes, JF Rocha, V Oliveira, JB Carneiro-Sampaio, M AF Zago, Claudia Augusta Abe Jacob, Cristina Miuki de Albuquerque Diniz, Edna Maria Lovisolo, Silvana Maria Nogueira Zerbini, Maria Claudia Dorna, Mayra Watanabe, Leticia Fernandes, Juliana Folloni Rocha, Vanderson Oliveira, Joao Bosco Carneiro-Sampaio, Magda TI Autoimmune manifestations in SCID due to IL7R mutations: Omenn syndrome and cytopenias SO HUMAN IMMUNOLOGY LA English DT Article DE IL7R alpha deficiency; SCID; Omenn syndrome; Autoimmune cytopenias; Eosinophilic myocarditis; Primary immunodeficiencies ID SEVERE COMBINED IMMUNODEFICIENCY; DEFICIENCY; GENE AB B+NK+SCID (severe combined immunodeficiency) due to IL7R alpha deficiency represents approximately 10% of American SCID cases. To better understand the spectrum of autoimmune disorders associated with IL7R alpha deficiency, we describe two unrelated IL7R alpha-deficient female SCID infants whose clinical picture was dominated by autoimmune manifestations: one with intrauterine Omenn syndrome (OS) and another with persistent thrombocytopenic purpura since 4 months of age. The OS baby harbored a homozygous p.C118Y mutation in IL7R. She presented dense eosinophilic infiltrates in several organs, including pancarditis, which may have contributed to her death (on the 2nd day of life). B cells were observed in lymph nodes, spleen, bone marrow and thymus. The second patient harbored compound heterozygous p.01 8Y and p.I121NfsX8 mutations. She underwent a successful unrelated cord blood transplant. In conclusion, early OS can be observed in patients with IL7R mutations, and autoimmune cytopenias could also complicate the clinical course of SCID babies with this type of defect. (C) 2014 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics. C1 [Zago, Claudia Augusta; Abe Jacob, Cristina Miuki; de Albuquerque Diniz, Edna Maria; Dorna, Mayra; Watanabe, Leticia; Fernandes, Juliana Folloni; Rocha, Vanderson; Carneiro-Sampaio, Magda] Univ Sao Paulo, Fac Med, Dept Pediat, BR-05403900 Sao Paulo, Brazil. [de Albuquerque Diniz, Edna Maria; Lovisolo, Silvana Maria; Nogueira Zerbini, Maria Claudia] Univ Sao Paulo, Hosp Univ HU, BR-05403900 Sao Paulo, Brazil. [Oliveira, Joao Bosco] Serv Immunol, NIH, Bethesda, MD USA. RP Carneiro-Sampaio, M (reprint author), Univ Sao Paulo, Inst Crianca, Hosp Clin, Fac Med, Av Dr Eneas Carvalho Aguiar,647, BR-05403900 Sao Paulo, Brazil. EM magdascs@usp.br RI Zerbini, Maria Claudia/D-1586-2012; OI Zerbini, Maria Claudia/0000-0002-7408-9816; Oliveira, Joao/0000-0001-9388-8173 FU FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo) [2008/58238-4, 2009/53864-7] FX The authors thank the teams at Hospital Universitario, Instituto da Crianca, and hematopoietic stem cell transplantation unit at ITACI, that carefully assisted the infants described in this paper. We also thank Cristina Maria Podesta Guimaraes and Mariza Kazue Umetzu Yoshikawa for technical assistance. The study was sponsored by FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo) - Grants 2008/58238-4 and 2009/53864-7. NR 30 TC 5 Z9 5 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 EI 1879-1166 J9 HUM IMMUNOL JI Hum. Immunol. PD JUL PY 2014 VL 75 IS 7 BP 662 EP 666 DI 10.1016/j.humimm.2014.04.006 PG 5 WC Immunology SC Immunology GA AJ8ER UT WOS:000337936000011 PM 24759676 ER PT J AU Woody, GE Bruce, D Korthuis, PT Chhatre, S Poole, S Hillhouse, M Jacobs, P Sorensen, J Saxon, AJ Metzger, D Ling, W AF Woody, George E. Bruce, Douglas Korthuis, P. Todd Chhatre, Sumedha Poole, Sabrina Hillhouse, Maureen Jacobs, Petra Sorensen, James Saxon, Andrew J. Metzger, David Ling, Walter TI HIV Risk Reduction With Buprenorphine-Naloxone or Methadone: Findings From a Randomized Trial SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; risk reduction; buprenorphine; methadone ID HUMAN-IMMUNODEFICIENCY-VIRUS; SUBSTANCE-ABUSE TREATMENT; INTRAVENOUS-DRUG-USERS; OUT-OF-TREATMENT; OPIOID DEPENDENCE; MAINTENANCE TREATMENT; PRIMARY-CARE; FOLLOW-UP; BEHAVIORS; PREVENTION AB Objectives:Compare HIV injecting and sex risk in patients being treated with methadone (MET) or buprenorphine-naloxone (BUP).Methods:Secondary analysis from a study of liver enzyme changes in patients randomized to MET or BUP who completed 24 weeks of treatment and had 4 or more blood draws. The initial 1:1 randomization was changed to 2:1 (BUP:MET) after 18 months due to higher dropout in BUP. The Risk Behavior Survey measured HIV risk before 30 days at baseline and weeks 12 and 24.Results:Among 529 patients randomized to MET, 391 (74%) were completers; among 740 randomized to BUP, 340 (46%) were completers; 700 completed the Risk Behavior Survey. There were significant reductions in injecting risk (P < 0.0008) with no differences between groups in mean number of times reported injecting heroin, speedball, other opiates, and number of injections; or percent who shared needles; did not clean shared needles with bleach; shared cookers; or engaged in front/back loading of syringes. The percent having multiple sex partners decreased equally in both groups (P < 0.03). For males on BUP, the sex risk composite increased; for males on MET, the sex risk decreased resulting in significant group differences over time (P < 0.03). For females, there was a significant reduction in sex risk (P < 0.02) with no group differences.Conclusions:Among MET and BUP patients who remained in treatment, HIV injecting risk was equally and markedly reduced; however, MET retained more patients. Sex risk was equally and significantly reduced among females in both treatment conditions, but it increased for males on BUP and decreased for males on MET. C1 [Woody, George E.; Chhatre, Sumedha; Poole, Sabrina; Metzger, David] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Woody, George E.; Chhatre, Sumedha; Poole, Sabrina; Metzger, David] Treatment Res Inst, Philadelphia, PA 19106 USA. [Bruce, Douglas] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Hillhouse, Maureen; Ling, Walter] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Jacobs, Petra] NIDA, Bethesda, MD 20892 USA. [Sorensen, James] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Saxon, Andrew J.] Vet Affairs Puget Sound Hlth Care Syst, Dept Psychiat, Seattle, WA USA. RP Woody, GE (reprint author), Treatment Res Inst, 150 South Independence Mall W, Philadelphia, PA 19106 USA. EM woody@tresearch.org FU NIDA [U10-DA 13045, U10-DA013714, U10 DA-13043, KO5 DA-17009] FX Supported by NIDA grants: U10-DA 13045 (W.L.); U10-DA013714 (D.D.); U10 DA-13043, KO5 DA-17009 (G.W.). NR 46 TC 12 Z9 12 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2014 VL 66 IS 3 BP 288 EP 293 DI 10.1097/QAI.0000000000000165 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AJ9JL UT WOS:000338025800011 PM 24751432 ER PT J AU Ghartey, J Kovacs, A Burk, RD Massad, LS Minkoff, H Xie, XH D'souza, G Xue, XN Watts, DH Levine, AM Einstein, MH Colie, C Anastos, K Eltoum, IE Herold, BC Palefsky, JM Strickler, HD AF Ghartey, Jeny Kovacs, Andrea Burk, Robert D. Massad, L. Stewart Minkoff, Howard Xie, Xianhong D'souza, Gypsyamber Xue, Xiaonan Watts, D. Heather Levine, Alexandra M. Einstein, Mark H. Colie, Christine Anastos, Kathryn Eltoum, Isam-Eldin Herold, Betsy C. Palefsky, Joel M. Strickler, Howard D. TI Genital Tract HIV RNA Levels and Their Associations With Human Papillomavirus Infection and Risk of Cervical Precancer SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE genital tract HIV viral load; cervical neoplasia; HPV natural history ID HUMAN-IMMUNODEFICIENCY-VIRUS; WOMENS INTERAGENCY HIV; INTRAEPITHELIAL NEOPLASIA; MENSTRUAL-CYCLE; ANTIRETROVIRAL THERAPY; VAGINAL SECRETIONS; BSCC TERMINOLOGY; NATURAL-HISTORY; TYPE-1 RNA; CYTOLOGY AB Objective:Plasma HIV RNA levels have been associated with the risk of human papillomavirus (HPV) and cervical neoplasia in HIV-seropositive women. However, little is known regarding local genital tract HIV RNA levels and their relation with cervical HPV and neoplasia.Design/Methods:In an HIV-seropositive women's cohort with semiannual follow-up, we conducted a nested case-control study of genital tract HIV RNA levels and their relation with incident high-grade squamous intraepithelial lesions (HSIL) subclassified as severe (severe HSIL), as provided for under the Bethesda 2001 classification system. Specifically, 66 incidents of severe HSIL were matched to 130 controls by age, CD4(+) count, highly active antiretroviral therapy use, and other factors. We also studied HPV prevalence, incident detection, and persistence in a random sample of 250 subjects.Results:Risk of severe HSIL was associated with genital tract HIV RNA levels (odds ratio comparing HIV RNA the median among women with detectable levels versus undetectable, 2.96; 95% confidence interval: 0.99 to 8.84; P-trend = 0.03). However, this association became nonsignificant (P-trend = 0.51) after adjustment for plasma HIV RNA levels. There was also no association between genital tract HIV RNA levels and the prevalence of any HPV or oncogenic HPV. However, the incident detection of any HPV (P-trend = 0.02) and persistence of oncogenic HPV (P-trend = 0.04) were associated with genital tract HIV RNA levels, after controlling plasma HIV RNA levels.Conclusions:These prospective data suggest that genital tract HIV RNA levels are not a significant independent risk factor for cervical precancer in HIV-seropositive women, but they leave open the possibility that they may modestly influence HPV infection, an early stage of cervical tumorigenesis. C1 [Ghartey, Jeny; Einstein, Mark H.; Anastos, Kathryn] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10467 USA. [Ghartey, Jeny; Einstein, Mark H.; Anastos, Kathryn; Herold, Betsy C.] Montefiore Med Ctr, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10461 USA. [Kovacs, Andrea] Univ So Calif, Dept Pediat, Los Angeles, CA 90089 USA. [Burk, Robert D.; Herold, Betsy C.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Massad, L. Stewart] Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. [Minkoff, Howard] Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. [Xie, Xianhong; Xue, Xiaonan; Strickler, Howard D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [D'souza, Gypsyamber] Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Watts, D. Heather] NICHHD, US Dept HHS, Bethesda, MD 20892 USA. [Levine, Alexandra M.] City Hope Natl Med Ctr, Dept Hematol, Duarte, CA 91010 USA. [Colie, Christine] Georgetown Univ, Med Ctr, Dept Obstet & Gynecol, Washington, DC 20007 USA. [Eltoum, Isam-Eldin] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Palefsky, Joel M.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Ghartey, J (reprint author), Montefiore Med Ctr, Albert Einstein Coll Med, 1300 Morris Pk Ave,Block 307, Bronx, NY 10461 USA. EM jenyghartey@gmail.com FU National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [UO1-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources (UCSF-CTSI) [UL1 RR024131]; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Einstein-Montefiore Center for AIDS Research [5P30AI051519-08]; Einstein-Montefiore Clinical and Translational Science Award [1ULIRR025750, KL2RR025749]; NIAID [R33AI079763, R01-CA-085178] FX The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32632). The study is cofunded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI grant number UL1 RR024131). This project has also been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health (HHSN261200800001E), the Einstein-Montefiore Center for AIDS Research (5P30AI051519-08), Einstein-Montefiore Clinical and Translational Science Award (1ULIRR025750 and KL2RR025749 to J.G.), and NIAID (R33AI079763 to B.C.H. and R01-CA-085178 to H.D.S.). NR 34 TC 3 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2014 VL 66 IS 3 BP 316 EP 323 DI 10.1097/QAI.0000000000000157 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AJ9JL UT WOS:000338025800015 PM 24694931 ER PT J AU Marfeo, EE Ni, PS Chan, L Rasch, EK Jette, AM AF Marfeo, Elizabeth E. Ni, Pengsheng Chan, Leighton Rasch, Elizabeth K. Jette, Alan M. TI Combining agreement and frequency rating scales to optimize psychometrics in measuring behavioral health functioning SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE Scale usage; Response styles; Measurement development; Patient-reported outcomes; Work; Disability evaluation ID ITEM RESPONSE THEORY; WORK DISABILITY EVALUATION; INFORMATION-SYSTEM PROMIS AB Objective: The goal of this article was to investigate optimal functioning of using frequency vs. agreement rating scales in two subdomains of the newly developed Work Disability Functional Assessment Battery: the Mood & Emotions and Behavioral Control scales. Study Design and Setting: A psychometric study comparing rating scale performance embedded in a cross-sectional survey used for developing a new instrument to measure behavioral health functioning among adults applying for disability benefits in the United States was performed. Results: Within the sample of 1,017 respondents, the range of response category endorsement was similar for both frequency and agreement item types for both scales. There were fewer missing values in the frequency items than the agreement items. Both frequency and agreement items showed acceptable reliability. The frequency items demonstrated optimal effectiveness around the mean +/- 1-2 standard deviation score range; the agreement items performed better at the extreme score ranges. Conclusion: Findings suggest an optimal response format requires a mix of both agreement-based and frequency-based items. Frequency items perform better in the normal range of responses, capturing specific behaviors, reactions, or situations that may elicit a specific response. Agreement items do better for those whose scores are more extreme and capture subjective content related to general attitudes, behaviors, or feelings of work-related behavioral health functioning. (C) 2014 Elsevier Inc. All rights reserved. C1 [Marfeo, Elizabeth E.; Ni, Pengsheng; Jette, Alan M.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Hlth & Disabil Res Inst, Boston, MA 02118 USA. [Chan, Leighton; Rasch, Elizabeth K.] NIH, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Marfeo, EE (reprint author), Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Hlth & Disabil Res Inst, 715 Albany St,T5W, Boston, MA 02118 USA. EM emarfeo@bu.edu FU SSA-NIH Interagency Agreements under NIH [HHSN269200900004C, HHSN269201000011C, HHSN269201100009I]; NIH Intramural Research Program FX This project was funded through SSA-NIH Interagency Agreements under NIH contract numbers HHSN269200900004C, HHSN269201000011C, and HHSN269201100009I and through the NIH Intramural Research Program. NR 17 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-4356 EI 1878-5921 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD JUL PY 2014 VL 67 IS 7 BP 781 EP 784 DI 10.1016/j.jclinepi.2014.02.005 PG 4 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AJ8UP UT WOS:000337983600008 PM 24751176 ER PT J AU Jiang, H Sidhu, R Fujiwara, H De Meulder, M de Vries, R Gong, Y Kao, M Porter, FD Yanjanin, NM Carillo-Carasco, N Xu, X Ottinger, E Woolery, M Ory, DS Jiang, XT AF Jiang, Hui Sidhu, Rohini Fujiwara, Hideji De Meulder, Marc de Vries, Ronald Gong, Yong Kao, Mark Porter, Forbes D. Yanjanin, Nicole M. Carillo-Carasco, Nuria Xu, Xin Ottinger, Elizabeth Woolery, Myra Ory, Daniel S. Jiang, Xuntian TI Development and validation of sensitive LC-MS/MS assays for quantification of HP-beta-CD in human plasma and CSF SO JOURNAL OF LIPID RESEARCH LA English DT Article DE 2-hydroxypropyl-beta-cyclodextrin; ultra performance liquid chromatography; two-dimensional liquid chromatography; in-source fragmentation; liquid chromatography-tandem mass spectrometry; Niemann-Pick C; cerebrospinal fluid ID TANDEM MASS-SPECTROMETRY; DISEASE TYPE-C; EVERY ORGAN; CYCLODEXTRIN; CHROMATOGRAPHY; CHOLESTEROL; IONIZATION; MOUSE; 2-HYDROXYPROPYL-BETA-CYCLODEXTRIN; METABOLISM AB 2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of Niemann-Pick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder. Development of a sensitive quantitative LC-MS/MS assay to monitor the pharmacokinetics (PKs) of HP-beta-CD required for clinical trials has been challenging owing to the dispersity of the HP-beta-CD. To support a phase 1 clinical trial for ICV delivery of HP-beta-CD in NPC1 patients, novel methods for quantification of HP-beta-CD in human plasma and cerebrospinal fluid (CSF) using LC-MS/MS were developed and validated: a 2D-LC-in-source fragmentation-MS/MS (2D-LC-IF-MS/MS) assay and a reversed phase ultra performance LC-MS/MS (RP-UPLC-MS/MS) assay. In both assays, protein precipitation and "dilute and shoot" procedures were used to process plasma and CSF, respectively. The assays were fully validated and in close agreement, and allowed determination of PK parameters for HP-beta-CD. The LC-MS/MS methods are similar to 100-fold more sensitive than the current HPLC assay, and were successfully employed to analyze HP-beta-CD in human plasma and CSF samples to support the phase 1 clinical trial of HP-beta-CD in NPC1 patients. C1 [Jiang, Hui; Sidhu, Rohini; Fujiwara, Hideji; Ory, Daniel S.; Jiang, Xuntian] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63130 USA. [De Meulder, Marc; de Vries, Ronald] Janssen Res & Dev, Beerse, Belgium. [Gong, Yong; Kao, Mark] Janssen Res & Dev, Spring House, PA USA. [Porter, Forbes D.; Yanjanin, Nicole M.; Carillo-Carasco, Nuria] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Xu, Xin; Ottinger, Elizabeth] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Woolery, Myra] NIH, Dept Nursing, Bethesda, MD 20892 USA. RP Jiang, XT (reprint author), Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63130 USA. EM xjiang@wustl.edu RI Carrillo-Carrasco, Nuria/B-9034-2009; Sidhu, Rohini/G-3547-2012 OI Carrillo-Carrasco, Nuria/0000-0003-0374-0808; FU Bench to Bedside Program; Office of Rare Diseases Research, Therapies for Rare and Neglected Diseases (TRND) Program in the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH); NIH [1ZIAHD008824-07]; Dana's Angels Research Trust FX The 2D-LC-IF-MS/MS assay was performed in the Metabolomics Facility at Washington University (P30 DK020579). This work was supported by the Bench to Bedside Program, the Office of Rare Diseases Research, Therapies for Rare and Neglected Diseases (TRND) Program in the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH), and NIH Grant 1ZIAHD008824-07 (F. D. P.). Additional support was provided by a grant from Dana's Angels Research Trust (D.S.O). NR 23 TC 7 Z9 7 U1 2 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD JUL PY 2014 VL 55 IS 7 BP 1537 EP 1548 DI 10.1194/jlr.D050278 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AJ9GZ UT WOS:000338017400032 PM 24868096 ER PT J AU Bai, RL Koay, CG Hutchinson, E Basser, PJ AF Bai, Ruiliang Koay, Cheng Guan Hutchinson, Elizabeth Basser, Peter J. TI A framework for accurate determination of the T-2 distribution from multiple echo magnitude MRI images SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE T-2 distribution; MRI; Multi-echo; Magnitude; Rician; Gaussian; Signal; Probability integral transform ID MAGNETIC-RESONANCE IMAGES; RAT SPINAL-CORD; PHASE CORRECTION; NMR RELAXATION; MYELIN WATER; MULTIEXPONENTIAL T-2; NOISE VARIANCE; WHITE-MATTER; RESOLUTION; DIFFUSION AB Measurement of the T-2 distribution in tissues provides biologically relevant information about normal and abnormal microstructure and organization. Typically, the T-2 distribution is obtained by fitting the magnitude MR images acquired by a multi-echo MRI pulse sequence using an inverse Laplace transform (ILT) algorithm. It is well known that the ideal magnitude MR signal follows a Rician distribution. Unfortunately, studies attempting to establish the validity and efficacy of the ILT algorithm assume that these input signals are Gaussian distributed. Violation of the normality (or Gaussian) assumption introduces unexpected artifacts, including spurious cerebrospinal fluid (CSF)-like long T-2 components; bias of the true geometric mean T-2 values and in the relative fractions of various components; and blurring of nearby T-2 peaks in the T-2 distribution. Here we apply and extend our previously proposed magnitude signal transformation framework to map noisy Rician-distributed magnitude multi-echo MRI signals into Gaussian-distributed signals with high accuracy and precision. We then perform an ILT on the transformed data to obtain an accurate T-2 distribution. Additionally, we demonstrate, by simulations and experiments, that this approach corrects the aforementioned artifacts in magnitude multi-echo MR images over a large range of signal-to-noise ratios. Published by Elsevier Inc. C1 [Bai, Ruiliang; Hutchinson, Elizabeth; Basser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet, PPITS, NIH, Bethesda, MD 20892 USA. [Bai, Ruiliang] Univ Maryland, Inst Phys Sci & Technol, Biophys Program, College Pk, MD 20740 USA. [Koay, Cheng Guan] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med Phys, Madison, WI 53705 USA. RP Bai, RL (reprint author), NICHD, Sect Tissue Biophys & Biomimet, PPITS, NIH, Bethesda, MD 20892 USA. EM ruiliang.bai@nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. Thanks to Mr. R.R. Clevenger, Mr. T.J. Hunt, and Mrs. Joni Taylor from LAMS, NHLBI for obtaining the spinal cord specimens and Ms. L. Salak for editing the manuscript. We are also grateful to our colleagues Dr. M.E. Komlosh for assistance with the experiments and preparing samples and Dr. A. Avram for useful discussions. NR 51 TC 8 Z9 8 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 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD JUL PY 2014 VL 244 BP 53 EP 63 DI 10.1016/j.jmr.2014.04.016 PG 11 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA AK0IF UT WOS:000338095400008 PM 24859198 ER PT J AU Tycko, R AF Tycko, Robert TI Remote sensing of sample temperatures in nuclear magnetic resonance using photoluminescence of semiconductor quantum dots SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Magic-angle spinning; Dynamic nuclear polarization; Low-temperature NMR; Remote sensing; Quantum dots ID 25 K; NMR; POLARIZATION; THERMOMETER AB Knowledge of sample temperatures during nuclear magnetic resonance (NMR) measurements is important for acquisition of optimal NMR data and proper interpretation of the data. Sample temperatures can be difficult to measure accurately for a variety of reasons, especially because it is generally not possible to make direct contact to the NMR sample during the measurements. Here I show that sample temperatures during magic-angle spinning (MAS) NMR measurements can be determined from temperature-dependent photoluminescence signals of semiconductor quantum dots that are deposited in a thin film on the outer surface of the MAS rotor, using a simple optical fiber-based setup to excite and collect photoluminescence. The accuracy and precision of such temperature measurements can be better than 5 K over a temperature range that extends from approximately 50 K (-223 degrees C) to well above 310 K (37 degrees C). Importantly, quantum dot photoluminescence can be monitored continuously while NMR measurements are in progress. While this technique is likely to be particularly valuable in low-temperature MAS NMR experiments, including experiments involving dynamic nuclear polarization, it may also be useful in high-temperature MAS NMR and other forms of magnetic resonance. Published by Elsevier Inc. C1 [Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 17 TC 3 Z9 3 U1 2 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD JUL PY 2014 VL 244 BP 64 EP 67 DI 10.1016/j.jmr.2014.04.021 PG 4 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA AK0IF UT WOS:000338095400009 PM 24859817 ER PT J AU Yau, WM Thurber, KR Tycko, R AF Yau, Wai-Ming Thurber, Kent R. Tycko, Robert TI Synthesis and evaluation of nitroxide-based oligoradicals for low-temperature dynamic nuclear polarization in solid state NMR SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Magic-angle spinning; Cross-effect DNP; Hyperpolarization; Electron paramagnetic resonance ID MAGNETIC-RESONANCE; 25 K; BIRADICALS; DNP; MELITTIN; SPECTROSCOPY; NANOPARTICLES; C-13 AB We describe the synthesis of new nitroxide-based biradical, triradical, and tetraradical compounds and the evaluation of their performance as paramagnetic dopants in dynamic nuclear polarization (DNP) experiments in solid state nuclear magnetic resonance (NMR) spectroscopy with magic-angle spinning (MAS). Under our experimental conditions, which include temperatures in the 25-30 K range, a 9.4 T magnetic field, MAS frequencies of 6.2-6.8 kHz, and microwave irradiation at 264.0 GHz from a 800 mW extended interaction oscillator source, the most effective compounds are triradicals that are related to the previously-described compound DOTOPA-TEMPO (see Thurber et al., 2010), but have improved solubility in glycerol/water solvent near neutral pH. Using these compounds at 30 mM total nitroxide concentration, we observe DNP enhancement factors of 92-128 for cross-polarized C-13 NMR signals from N-15,C-13-labeled melittin in partially protonated glycerol/water, and build-up times of 2.6-3.8 s for H-1 spin polarizations. Net sensitivity enhancements with biradical and tetraradical dopants, taking into account absolute C-13 NMR signal amplitudes and build-up times, are approximately 2-4 times lower than with the best triradicals. Published by Elsevier Inc. C1 [Yau, Wai-Ming; Thurber, Kent R.; Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. We thank Dr. Kan-Nian Hu for helpful discussions regarding the synthesis and properties of oligoradicals and Dr. John R. Lloyd for assistance with mass spectrometry. NR 43 TC 10 Z9 10 U1 6 U2 42 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD JUL PY 2014 VL 244 BP 98 EP 106 DI 10.1016/j.jmr.2014.05.002 PG 9 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA AK0IF UT WOS:000338095400014 PM 24887201 ER PT J AU Yu, ZH Yu, PP Chen, HZ Geller, HM AF Yu, Zhihua Yu, Panpan Chen, Hongzhuan Geller, Herbert M. TI Targeted inhibition of KCa3.1 attenuates TGF-beta-induced reactive astrogliosis through the Smad2/3 signaling pathway SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE astrocyte; chondroitin sulfate proteoglycans; culture; GFAP; mouse ID CHONDROITIN SULFATE PROTEOGLYCANS; FIBRILLARY ACIDIC PROTEIN; SPINAL-CORD-INJURY; GROWTH-FACTOR; K+ CHANNELS; GLIAL SCAR; ASTROCYTES; RAT; IMMUNOFLUORESCENCE; REGENERATION AB Reactive astrogliosis, characterized by cellular hypertrophy and various alterations in gene expression and proliferative phenotypes, is considered to contribute to brain injuries and diseases as diverse as trauma, neurodegeneration, and ischemia. KCa3.1 (intermediate-conductance calcium-activated potassium channel), a potassium channel protein, has been reported to be up-regulated in reactive astrocytes after spinal cord injury in vivo. However, little is known regarding the exact role of KCa3.1 in reactive astrogliosis. To elucidate the role of KCa3.1 in regulating reactive astrogliosis, we investigated the effects of either blocking or knockout of KCa3.1 channels on the production of astrogliosis and astrocytic proliferation in response to transforming growth factor (TGF)- in primary cultures of mouse astrocytes. We found that TGF- increased KCa3.1 protein expression in astrocytes, with a concomitant marked increase in the expression of reactive astrogliosis, including glial fibrillary acidic protein and chondroitin sulfate proteoglycans. These changes were significantly attenuated by the KCa3.1 inhibitor 1-((2-chlorophenyl) (diphenyl)methyl)-1H-pyrazole (TRAM-34). Similarly, the increase in glial fibrillary acidic protein and chondroitin sulfate proteoglycans in response to TGF- was attenuated in KCa3.1-/- astrocytes. TRAM-34 also suppressed astrocytic proliferation. In addition, the TGF--induced phosphorylation of Smad2 and Smad3 proteins was reduced with either inhibition of KCa3.1 with TRAM-34 or in KCa3.1-/- astrocytes. These findings highlight a novel role for the KCa3.1 channel in reactive astrogliosis phenotypic modulation and provide a potential target for therapeutic intervention for brain injuries. Reactive astrogliosis is characterized by the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans. We demonstrate that either pharmacological blockade or knockout of KCa3.1 channels reduces reactive gliosis in cultured astrocytes caused by TGF-, and also reduces TGF--induced phosphorylation of Smad2/3. C1 [Yu, Zhihua; Chen, Hongzhuan] Shanghai Jiao Tong Univ, Sch Med, Inst Med Sci, Dept Pharmacol, Shanghai 200030, Peoples R China. [Yu, Zhihua; Yu, Panpan; Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Geller, HM (reprint author), NHLBI, Dev Neurobiol Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. EM geller@helix.nih.gov FU National Basic Research Program of China [2010CB529806]; National Natural Science Foundation of China [81102491]; Division of Intramural Research of the National Heart, Lung, and Blood Institute of NIH FX This work was supported by National Basic Research Program of China grant 2010CB529806, and National Natural Science Foundation of China grant 81102491 and the Division of Intramural Research of the National Heart, Lung, and Blood Institute of NIH. The assistance of the Light Microscopy Core Facility of the National Heart, Lung, and Blood Institute, NIH is greatly appreciated. We thank Dr James Melvin and Dr. Marcelo A. Catalan Gaete (National Institute of Dental and Craniofacial Research, NIH) for kindly providing the KCa3.1-/- mice. NR 40 TC 10 Z9 10 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2014 VL 130 IS 1 BP 41 EP 49 DI 10.1111/jnc.12710 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AJ8KN UT WOS:000337952800005 PM 24606313 ER PT J AU Lungu, C Malone, P Wu, T Ghosh, P McElroy, B Zaghloul, K Patterson, T Hallett, M Levine, Z AF Lungu, C. Malone, P. Wu, T. Ghosh, P. McElroy, B. Zaghloul, K. Patterson, T. Hallett, M. Levine, Z. TI Temporal macrodynamics and microdynamics of the postoperative impedance at the tissue-electrode interface in deep brain stimulation patients SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID PARKINSONS-DISEASE; ELECTRICAL-PROPERTIES AB Objective To study the temporal dynamics of tissue impedance after deep brain stimulation (DBS). Background DBS therapy commonly employs a constant voltage approach, and current delivery to the tissue is a function of electrode-tissue impedance. It is presumed that impedance fluctuates early postimplantation, with implications for variations in current delivery and therapeutic efficacy. We hypothesised that the largest variation will be recorded early after surgery, followed by stabilisation. Methods Review of impedance checks of implanted DBS systems at standard parameters during the first five months postimplantation. All measurement time points were binned into 1-week periods, and we used repeated measures analysis of variance with Tukey pairwise multiple comparisons correction. The analysis was repeated after normalising impedance values for each subject to that patient's baseline value. Results There was an initial (non-significant) drop in impedance at week 1, followed by significant increase at week 3 (p=0.0002). There were no further significant differences in impedance values at subsequent time points. Analysis of normalised data showed a significant difference between the initial measurement in postoperative week 1 (normalised value 1) and week 3 (normalised value 1.73, p<0.0001), with no further difference among the subsequent weekly points during the 5-month follow-up. No significant hourly variations were found at any time points. Conclusions We found major changes in impedance within the first month postimplantation, with no further variation. This is an important confirmation in patients of this temporal dynamics of the impedance of implanted DBS hardware, with potential therapeutic implications. C1 [Lungu, C.; Malone, P.; Ghosh, P.; McElroy, B.] NINDS, NIH Parkinson Clin, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Wu, T.] NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. [Zaghloul, K.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Patterson, T.] Marshall Univ, Dept Neurosci, Huntington, WV USA. [Hallett, M.] NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Levine, Z.] Holy Cross Hosp, Dept Neurosurg, Silver Spring, MD USA. RP Lungu, C (reprint author), NINDS, NIH Parkinson Clin, Off Clin Director, NIH, Bldg 10,Rm 7D37,MSC 1428,10 Ctr Dr, Bethesda, MD 20892 USA. EM lunguci@ninds.nih.gov NR 18 TC 5 Z9 5 U1 0 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD JUL PY 2014 VL 85 IS 7 BP 816 EP 819 DI 10.1136/jnnp-2013-306066 PG 4 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA AJ7YX UT WOS:000337919300020 PM 24218525 ER PT J AU Semba, RD Gebauer, SK Baer, DJ Sun, K Turner, R Silber, HA Talegawkar, S Ferrucci, L Novotny, JA AF Semba, Richard D. Gebauer, Sarah K. Baer, David J. Sun, Kai Turner, Randi Silber, Harry A. Talegawkar, Sameera Ferrucci, Luigi Novotny, Janet A. TI Dietary Intake of Advanced Glycation End Products Did Not Affect Endothelial Function and Inflammation in Healthy Adults in a Randomized Controlled Trial SO JOURNAL OF NUTRITION LA English DT Article ID CARDIOVASCULAR-DISEASE MORTALITY; DENSITY-LIPOPROTEIN CHOLESTEROL; EPSILON-CARBOXYMETHYL-LYSINE; SERUM-LEVELS; DIABETES-MELLITUS; OXIDATIVE STRESS; RISK-FACTORS; FOODS; ATHEROSCLEROSIS; ENDPRODUCTS AB When food is heated to high temperatures, the characteristic "browning" generates advanced glycation end products (AGEs). AGEs are associated with an increased risk of cardiovascular disease, diabetes, and other adverse outcomes. Whether dietary AGEs are absorbed and are harmful to human health remains highly controversial. The objective of this study was to compare the effects of a diet high or low in AGEs on endothelial function, circulating AGEs, inflammatory mediators, and circulating receptors for AGEs in healthy adults. A randomized, parallel-arm, controlled dietary intervention was conducted for 6 wk with 24 healthy adults, aged 50-69 y, that compared isocaloric, food-equivalent diets that were prepared at either high or mild temperatures. Peripheral arterial tonometry, serum and urine carboxmethyl-lysine (CM L), inflammatory mediators (interleukin-6, C-reactive protein, vascular adhesion molecule-1, and tumor necrosis factor-a receptors I and II), soluble receptor for AGEs, and endogenous secretory receptor for AGEs were measured at baseline and after 6 wk of dietary intervention. In the low-AGE diet group, the following changed from baseline to 6 wk (mean +/- SE): serum CM L from 763 +/- 24 to 679 +/- 29 ng/mL (P = 0.03) and urine CML from 1.37 +/- 1.47 to 0.77 +/- 2.01 mu g/mL creatinine (P = 0.02). There were no significant changes in serum and urinary CML concentrations from baseline to follow-up in the high-AGE diet group. A high- or low-AGE diet had no significant impact on peripheral arterial tonometry or any inflammatory mediators after 6 wk of dietary intervention. In healthy middle-aged to older adults, consumption of a diet high or low in AGEs for 6 wk had no impact on endothelial function and inflammatory mediators, 2 precursors of cardiovascular disease. This trial was registered at clinicaltrials.gov as NCT01402973. C1 [Semba, Richard D.; Sun, Kai; Turner, Randi; Silber, Harry A.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Semba, Richard D.; Sun, Kai; Turner, Randi; Silber, Harry A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Gebauer, Sarah K.; Baer, David J.; Novotny, Janet A.] USDA, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. [Talegawkar, Sameera] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu FU NIH [R01 AG027012, R01 HL094507]; Intramural Research Program, National Institute on Aging; USDA Beltsville Human Nutrition Research Center FX Supported by NIH grants R01 AG027012 and R01 HL094507, the Intramural Research Program, National Institute on Aging, and the USDA Beltsville Human Nutrition Research Center. NR 33 TC 14 Z9 14 U1 0 U2 11 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD JUL PY 2014 VL 144 IS 7 BP 1037 EP 1042 DI 10.3945/jn.113.189480 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AJ8UU UT WOS:000337984200007 PM 24744309 ER PT J AU Feeney, MJ Dwyer, J Hasler-Lewis, CM Milner, JA Noakes, M Rowe, S Wach, M Beelman, RB Caldwel, J Cantorna, MT Castlebury, LA Chang, ST Cheskin, LJ Clemens, R Drescher, G Fulgoni, VL Haytowitz, DB Hubbard, VS Law, D Miller, AM Minor, B Percival, SS Riscuta, G Schneeman, B Thornsbury, S Toner, CD Woteki, CE Wu, DY AF Feeney, Mary Jo Dwyer, Johanna Hasler-Lewis, Clare M. Milner, John A. Noakes, Manny Rowe, Sylvia Wach, Mark Beelman, Robert B. Caldwel, Joe Cantorna, Margherita T. Castlebury, Lisa A. Chang, Shu-Ting Cheskin, Lawrence J. Clemens, Roger Drescher, Greg Fulgoni, Victor L., III Haytowitz, David B. Hubbard, Van S. Law, David Miller, Amy Myrdal Minor, Bart Percival, Susan S. Riscuta, Gabriela Schneeman, Barbara Thornsbury, Suzanne Toner, Cheryl D. Woteki, Catherine E. Wu, Dayong TI Mushrooms and Health Summit Proceedings SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Mushrooms and Health Summit CY SEP 09-10, 2013 CL Washington, DC SP Mushroom Council ID WHITE BUTTON MUSHROOMS; AGARICUS-BISPORUS; ERGOTHIONEINE TRANSPORTER; DIETARY SUPPLEMENTATION; CULTIVATED MUSHROOMS; EDIBLE MUSHROOMS; MICE; CARCINOGENESIS; INFLAMMATION; ACCELERATE AB The Mushroom Council convened the Mushrooms and Health Summit in Washington, DC, on 9-10 September 2013. The proceedings are synthesized in this article. Although mushrooms have long been regarded as health-promoting foods, research specific to their role in a healthful diet and in health promotion has advanced in the past decade. The earliest mushroom cultivation was documented in China, which remains among the top global mushroom producers, along with the United States, Italy, The Netherlands, and Poland. Although considered a vegetable in dietary advice, mushrooms are fungi, set apart by vitamin B-12 in very low quantity but in the same form found in meat, ergosterol converted with UV light to vitamin D-2, and conjugated linoleic acid. Mushrooms are a rare source of ergothioneine as well as selenium, fiber, and several other vitamins and minerals. Some preclinical and clinical studies suggest impacts of mushrooms on cognition, weight management, oral health, and cancer risk. Preliminary evidence suggests that mushrooms may support healthy immune and inflammatory responses through interaction with the gut microbiota, enhancing development of adaptive immunity, and improved immune cell functionality. In addition to imparting direct nutritional and health benefits, analysis of U.S. food intake survey data reveals that mushrooms are associated with higher dietary quality. Also, early sensory research suggests that mushrooms blended with meats and lower sodium dishes are well liked and may help to reduce intakes of red meat and salt without compromising taste. As research progresses on the specific health effects of mushrooms, there is a need for effective communication efforts to leverage mushrooms to improve overall dietary quality. C1 [Feeney, Mary Jo] Consultant Food & Agr Ind, Los Altos, CA 94022 USA. [Dwyer, Johanna] Tufts Univ, Tufts Med Sch, Boston, MA 02111 USA. [Dwyer, Johanna] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Hasler-Lewis, Clare M.] Univ Calif Davis, Robert Mondavi Inst Wine & Food Sci, Davis, CA 95616 USA. [Milner, John A.] ARS, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD USA. [Noakes, Manny] Commonwealth Sci & Ind Res Org, Adelaide, SA, Australia. [Rowe, Sylvia] SR Strategy LLC, Washington, DC USA. [Wach, Mark] Sylvan Inc, Kittanning, PA USA. [Beelman, Robert B.] Penn State Univ, Dept Food Sci, Ctr Plant & Mushroom Prod Hlth, University Pk, PA 16802 USA. [Caldwel, Joe] Monterey Mushrooms Inc, Watsonville, CA USA. [Cantorna, Margherita T.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Castlebury, Lisa A.] ARS, Systemat Mycol & Microbiol Lab, USDA, Beltsville, MD USA. [Chang, Shu-Ting] Chinese Univ Hong Kong, McKellar, ACT, Australia. [Cheskin, Lawrence J.] Johns Hopkins Bloomberg Sch Publ Hlth, Johns Hopkins Weight Management Ctr, Baltimore, MD USA. [Cheskin, Lawrence J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. [Clemens, Roger] Univ So Calif, Sch Pharm, Int Ctr Regulatory Sci, Los Angeles, CA USA. [Drescher, Greg] Culinary Inst Amer, Hyde Pk, NY USA. [Fulgoni, Victor L., III] Nutr Impact LLC, Battle Creek, MI USA. [Haytowitz, David B.] ARS, Nutr Data Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD USA. [Hubbard, Van S.] NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. [Hubbard, Van S.] NIDDK, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Law, David] Gourmet Mushrooms Inc, Sebastopol, CA USA. [Miller, Amy Myrdal] Culinary Inst Amer, St Helena, CA USA. [Minor, Bart] Mushroom Council, San Jose, CA USA. [Percival, Susan S.] Univ Florida, Dept Food Sci & Human Nutr, Gainesville, FL 32611 USA. [Riscuta, Gabriela] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Rockville, MD USA. [Schneeman, Barbara] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. [Thornsbury, Suzanne] Serv Econ Res, Market & Trade Econ Div, USDA, Washington, DC USA. [Toner, Cheryl D.] CDT Consulting LLC, Herndon, VA USA. [Woteki, Catherine E.] USDA, Washington, DC 20250 USA. [Wu, Dayong] Tufts Univ, Nutr Immunol Lab, Jean Mayer USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Wu, Dayong] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. RP Feeney, MJ (reprint author), Consultant Food & Agr Ind, Los Altos, CA 94022 USA. EM mj@feeney.us.com OI Dwyer, Johanna/0000-0002-0783-1769 NR 72 TC 7 Z9 7 U1 8 U2 55 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD JUL PY 2014 VL 144 IS 7 BP 1128S EP 1136S DI 10.3945/jn.114.190728 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AJ8UU UT WOS:000337984200020 PM 24812070 ER PT J AU Moshesh, M Peddada, SD Cooper, T Baird, D AF Moshesh, Malana Peddada, Shyamal D. Cooper, Tracy Baird, Donna TI Intraobserver Variability in Fibroid Size Measurements Estimated Effects on Assessing Fibroid Growth SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE coefficient of variation; fibroid; growth; gynecologic ultrasound; sonography; variability ID 3-DIMENSIONAL ULTRASOUND; TRANSVAGINAL ULTRASONOGRAPHY; UTERINE LEIOMYOMATA; VOLUME MEASUREMENTS; ACCURACY; RELIABILITY; EXPERIENCE; DIAGNOSIS AB Objectives-To evaluate intraobserver variability of fibroid sonographic measurements and apply this factor to fibroid growth assessment. Methods-Study participants were African American women aged 23 to 34 years who had never had a diagnosis of uterine fibroids. All participants underwent transvaginal sonography to screen for the presence of previously undiagnosed fibroids (>= 0.5 cm in diameter). The diameters of up to 6 fibroids were measured in 3 perpendicular planes at 3 separate times during the examinations by experienced sonographers. Intraobserver variability as measured by the coefficient of variation (CV) for fibroid diameter and volume was calculated for each fibroid, and factors associated with the CV were assessed by regression models. The impact of variability on growth assessment was determined. Results-Ninety-six of 300 women screened were found to have at least 1 fibroid, yielding a total of 174 fibroids for this analysis. The mean CV for the 3 measurements of fibroid maximum diameter was 5.9%. The mean CV for fibroid volume was 12.7%. Fibroid size contributed significantly to intraobserver variability (P = .04), with greater variability for smaller fibroids. Fibroid type (submucosal, intramural, or subserosal) was not important. Fibroids from the same woman tended to have similar measurement variability when assessed for volume but not for maximum diameter. Calculations showed that when following up fibroids, as much as a 20% increase in diameter could be due to measurement error, not "true growth." Conclusions-A small fibroid must have a greater change in size than a large fibroid to conclude that it is growing, but even for small fibroids an increase in diameter of greater than 20% is likely to indicate true growth, not measurement variability. C1 [Moshesh, Malana; Baird, Donna] Natl Inst Environm Hlth, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Peddada, Shyamal D.] Natl Inst Environm Hlth, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Cooper, Tracy] Henry Ford Hlth Syst, Div Ultrasound, Dept Radiol, Detroit, MI USA. RP Baird, D (reprint author), Natl Inst Environm Hlth, Epidemiol Branch, 111T W Alexander Dr, Res Triangle Pk, NC 27709 USA. EM baird@niehs.nih.gov RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU National Institutes of Health; National Institute of Environmental Health Sciences; American Recovery and Reinvestment Act FX We thank Grace Kissling, PhD, and Zongli Xu, PhD, for helpful comments on an earlier draft of the manuscript and Melissa Williams, Deborah Cousins, and Sue Edelstein for assistance with the images. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, and American Recovery and Reinvestment Act funds designated for National Institutes of Health research. NR 22 TC 3 Z9 3 U1 0 U2 4 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD JUL PY 2014 VL 33 IS 7 BP 1217 EP 1224 DI 10.7863/ultra.33.7.1217 PG 8 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA AJ9CB UT WOS:000338003300012 PM 24958408 ER PT J AU Le Couteur, DG Simpson, SJ de Cabo, R AF Le Couteur, David G. Simpson, Stephen J. de Cabo, Rafael TI Are Glycans the Holy Grail for Biomarkers of Aging? (Comment on: Glycans Are a Novel Biomarker of Chronological and Biological Age by Kristic et al.) SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material DE Biomarkers of aging; Glycans AB Posttranslational modifications of circulating proteins such as immunoglobulins may prove to be important biomarkers of aging. C1 [Le Couteur, David G.] Univ Sydney, Ctr Educ & Res Ageing, Sydney, NSW 2139, Australia. [Le Couteur, David G.] Univ Sydney, ANZAC Res Inst, Sydney, NSW 2139, Australia. [Le Couteur, David G.] Concord Repatriat Gen Hosp, Sydney, NSW 2139, Australia. [Le Couteur, David G.; Simpson, Stephen J.] Univ Sydney, Charles Perkins Ctr, Sydney, NSW 2006, Australia. [Simpson, Stephen J.] Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia. [de Cabo, Rafael] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. RP Le Couteur, DG (reprint author), Univ Sydney, Ctr Educ & Res Ageing, Hosp Rd, Sydney, NSW 2139, Australia. EM david.lecouteur@sydney.edu.au RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 NR 13 TC 1 Z9 1 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2014 VL 69 IS 7 BP 777 EP 778 DI 10.1093/gerona/glt202 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AJ9DG UT WOS:000338006400001 PM 24325897 ER PT J AU Stenholm, S Guralnik, JM Bandinelli, S Ferrucci, L AF Stenholm, Sari Guralnik, Jack M. Bandinelli, Stefania Ferrucci, Luigi TI The Prognostic Value of Repeated Measures of Lower Extremity Performance: Should We Measure More Than Once? SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Aging; Disability; Measurement; Mobility; Physical performance; Walking speed ID PHYSICAL PERFORMANCE; SUBSEQUENT DISABILITY; OLDER PERSONS; GAIT SPEED; VALIDITY; QUESTIONNAIRE; PREDICTOR; MORTALITY; BATTERY; DECLINE AB Lower extremity physical performance measured at one point in time is a powerful predictor of future disability. Whether information on previous lower extremity performance adds independent information to disability prediction compared to a single measure alone is unknown. Data are from community-dwelling men and women aged greater than or equal to 65 years enrolled in the Invecchiare in Chianti study who were free of mobility and activities of daily living (ADL) disability at baseline and at 3-year follow-up (n = 891). Walking speed and Short Physical Performance Battery were examined at baseline and at the 3-year follow-up (zero-time). Logistic regression analysis was used to examine the associations between physical performance measures and incident mobility and ADL disability detected at the 6-year and 9-year follow-up. Walking speed and Short Physical Performance Battery score assessed at the zero-time strongly predicted development of mobility and ADL disability during the subsequent 6 years independent of walking speed/Short Physical Performance Battery score 3 years prior. Current lower extremity performance is a strong risk factor for subsequent mobility and ADL disability and is independent of performance 3 years prior, which has negligible independent prognostic value. C1 [Stenholm, Sari] Univ Turku, Dept Publ Hlth, Turku, Finland. [Stenholm, Sari] Natl Inst Hlth & Welf, Dept Hlth Funct Capac & Welf, Turku, Finland. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Stenholm, S (reprint author), Univ Turku, Dept Publ Hlth, Lemminkaisenkatu 1, Turun 20014, Finland. EM sari.stenholm@utu.fi FU Academy of Finland [273850, 264944]; Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland; Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002, 1 Z01 AG001050-01] FX This work was supported by a grants from the Academy of Finland (273850 and 264944) and in part by the Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland. The InCHIANTI study baseline (1998-2000) was supported as a "targeted project" by the Italian Ministry of Health (ICS110.1/RF97.71) and in part by the U.S. National Institute on Aging (263 MD 9164, 263 MD 821336); the InCHIANTI Follow-up 1 (2001-2003) was funded by the U.S. National Institute on Aging (N.1-AG-1-1, N.1-AG-1-2111); the InCHIANTI Follow-up 2 study (2004-2006) was financed by the U.S. National Institute on Aging (N01-AG-5-0002) and the InCHIANTI Follow-up 3 study (2007-2008) was financed by the U.S. National Institute on Aging (1 Z01 AG001050-01). NR 20 TC 4 Z9 4 U1 3 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2014 VL 69 IS 7 BP 894 EP 899 DI 10.1093/gerona/glt175 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AJ9DG UT WOS:000338006400014 PM 24270061 ER PT J AU Kaup, AR Simonsick, EM Harris, TB Satterfield, S Metti, AL Ayonayon, HN Rubin, SM Yaffe, K AF Kaup, Allison R. Simonsick, Eleanor M. Harris, Tamara B. Satterfield, Suzanne Metti, Andrea L. Ayonayon, Hilsa N. Rubin, Susan M. Yaffe, Kristine TI Older Adults With Limited Literacy Are at Increased Risk for Likely Dementia SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Cognitive aging; Risk factors; Epidemiology ID ETHNICALLY DIVERSE ELDERS; POPULATION-BASED COHORT; HEALTH LITERACY; COGNITIVE DECLINE; BODY-COMPOSITION; READING-ABILITY; SOCIOECONOMIC-STATUS; ALZHEIMERS-DISEASE; EDUCATION; MORTALITY AB Low literacy is common among the elderly and possibly more reflective of educational attainment than years of school completed. We examined the association between literacy and risk of likely dementia in older adults. Participants were 2,458 black and white elders (aged 71-82) from the Health, Aging and Body Composition study, who completed the Rapid Estimate of Adult Literacy in Medicine and were followed for 8 years. Participants were free of dementia at baseline; incidence of likely dementia was defined by hospital records, prescription for dementia medication, or decline in Modified Mini-Mental State Examination score. We conducted Cox proportional hazard models to evaluate the association between literacy and incidence of likely dementia. Demographics, education, income, comorbidities, lifestyle variables, and apolipoprotein E (APOE) epsilon 4 status were included in adjusted analyses. Twenty-three percent of participants had limited literacy (< 9th-grade level). Limited literacy, as opposed to adequate literacy (a parts per thousand yen9th-grade level), was associated with greater incidence of likely dementia (25.5% vs17.0%; unadjusted hazard ratio [HR] = 1.75, 95% confidence interval 1.44-2.13); this association remained significant after adjustment. There was a trend for an interaction between literacy and APOE epsilon 4 status (p = .07); the association between limited literacy and greater incidence of likely dementia was strong among epsilon 4 noncarriers (unadjusted HR = 1.85) but nonsignificant among epsilon 4 carriers (unadjusted HR = 1.25). Limited literacy is an important risk factor for likely dementia, especially among APOE epsilon 4-negative older adults, and may prove fruitful to target in interventions aimed at reducing dementia risk. C1 [Kaup, Allison R.; Yaffe, Kristine] San Francisco VA Med Ctr, Sierra Pacific Mental Illness Res Educ & Clin Ctr, San Francisco, CA 94121 USA. [Kaup, Allison R.; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Simonsick, Eleanor M.] Harbor Hosp, Translat Gerontol Branch, NIA, Baltimore, MD USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Metti, Andrea L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Ayonayon, Hilsa N.; Rubin, Susan M.; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Kaup, AR (reprint author), San Francisco VA Med Ctr, 4150 Clement St,116H, San Francisco, CA 94121 USA. EM allison.kaup@ucsf.edu FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, K24AG031155]; National Institute of Nursing Research [R01-NR012459]; Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This work was supported by the National Institute on Aging (N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; R01-AG028050, K24AG031155 to K.Y.) and National Institute of Nursing Research (R01-NR012459). This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Writing of this manuscript was supported by Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the San Francisco Veterans Affairs Medical Center, and the Department of Veterans Affairs Sierra-Pacific Mental Illness Research, Education, and Clinical Center. NR 39 TC 10 Z9 11 U1 2 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2014 VL 69 IS 7 BP 900 EP 906 DI 10.1093/gerona/glt176 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AJ9DG UT WOS:000338006400015 PM 24158765 ER PT J AU Zhang, XA Fang, YL Zhao, YD Zheng, WM AF Zhang, Xinan Fang, Yile Zhao, Yingdong Zheng, Weiming TI Mathematical modeling the pathway of human breast cancer SO MATHEMATICAL BIOSCIENCES LA English DT Article DE Breast cancer; Tumorigenesis; Mathematical model ID GENETIC INSTABILITY; CARCINOGENESIS; MUTATION; DYNAMICS; BRCA1 AB In order to understand the mechanism of human breast cancer we use the growth rates of clonal expansion of intermediate cells and mutation rates as parameters and build two-six stage models to fit the age-specific incidence of breast cancers in the surveillance, epidemiology, and end results (SEER) registry. We propose four types of different mechanisms for the human breast cancer and test those mechanisms by Chi-square test. Our results suggest that loss of functions of instability genes is an early event in the tumorigenesis, which is useful for early diagnosis of breast cancer. The clonal expansion of intermediate cells must depend on the hormone expression level of females, which implies that it may be effective for females to receive hormone blocking therapy for breast cancer before their menopause. (C) 2014 Elsevier Inc. All rights reserved. C1 [Zhang, Xinan] Cent China Normal Univ, Sch Math & Stat, Wuhan 430079, Peoples R China. [Fang, Yile] Huazhong Univ Sci & Technol, Dept Elect & Elect Eduat, Wuchang Branch, Wuhan 430064, Peoples R China. [Zhao, Yingdong] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Zheng, Weiming] Tsinghua Univ, Dept Comp Sci & Technol, Beijing 100084, Peoples R China. RP Zhang, XA (reprint author), Cent China Normal Univ, Sch Math & Stat, Wuhan 430079, Peoples R China. EM zhangxinan@hotmail.com FU National Natural Science Foundation of China [11371161, 11071275, 11228104]; Special Fund for Basic Scientific Research of Central Colleges [CCNU10B01005] FX This work is supported by the National Natural Science Foundation of China (Nos. 11371161, 11071275, 11228104), and by the Special Fund for Basic Scientific Research of Central Colleges (CCNU10B01005). XZ thanks Dr. Richard Simon for his guidance when XZ was a postdoctoral fellow in Biometric Research Branch of National Cancer Institute, NIH, USA. We thank the reviewers very much for their very good suggestions on the manuscript. NR 29 TC 0 Z9 1 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-5564 EI 1879-3134 J9 MATH BIOSCI JI Math. Biosci. PD JUL PY 2014 VL 253 BP 25 EP 29 DI 10.1016/j.mbs.2014.03.011 PG 5 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA AJ7JX UT WOS:000337874100004 PM 24680645 ER PT J AU Yabroff, KR Guy, GP Ekwueme, DU McNeel, T Rozjabek, HM Dowling, E Li, CY Virgo, KS AF Yabroff, K. Robin Guy, Gery P., Jr. Ekwueme, Donatus U. McNeel, Timothy Rozjabek, Heather M. Dowling, Emily Li, Chunyu Virgo, Katherine S. TI Annual Patient Time Costs Associated With Medical Care Among Cancer Survivors in the United States SO MEDICAL CARE LA English DT Article DE cost of illness; costs and cost analysis; utilization; neoplasms; Medical Expenditure Panel Survey ID HEALTH INTERVIEW SURVEY; 2ND PRIMARY CANCERS; BREAST-CANCER; ECONOMIC BURDEN; COLONOSCOPY; PREVALENCE; SURGERY; ADULTS; TRAVEL AB Background:Although patient time costs are recommended for inclusion in cost-effectiveness analyses, these data are not routinely collected. We used nationally representative data and a medical service-based approach to estimate the annual patient time costs among cancer survivors.Methods:We identified adult 6699 cancer survivors and 86,412 individuals without a cancer history ages 18 years or more from 2008-2011 Medical Expenditure Panel Survey (MEPS). Service use was categorized as hospitalizations, emergency room use, provider visits, ambulatory surgery, chemotherapy, and radiation therapy. Service time estimates were applied to frequencies for each service category and the US median wage rate in 2011 was used to value time. We evaluated the association between cancer survivorship and service use frequencies and patient time costs with multivariable regression models, stratified by age group (18-64 and 65+ y). Sensitivity analyses evaluated different approaches for valuing time.Results:Cancer survivors were more likely to have hospitalizations, emergency room visits, ambulatory surgeries, and provider visits in the past year than individuals without a cancer history in adjusted analyses (P<0.05). Annual patient time was higher for cancer survivors than individuals without a cancer history among those aged 18-64 years (30.2 vs. 13.6 h; P<0.001) and 65+ years (55.1 vs. 36.6 h; P<0.001), as were annual patient time costs (18-64 y: $500 vs. $226; P<0.001 and 65+ y: $913 vs. $607; P<0.001).Conclusions:Cancer survivors had greater annual medical service use and patient time costs than individuals without a cancer history. This medical service-based approach for estimating annual time costs can also be applied to other conditions. C1 [Yabroff, K. Robin; Rozjabek, Heather M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Guy, Gery P., Jr.; Ekwueme, Donatus U.; Li, Chunyu] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Canc Prevent & Control, Atlanta, GA USA. [McNeel, Timothy] Informat Management Serv Inc, Rockville, MD USA. [Dowling, Emily] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Virgo, Katherine S.] Emory Univ, Dept Hlth Policy & Management, Atlanta, GA 30322 USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, 9609 Med Ctr Dr 3E436, Rockville, MD 20850 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 FU Intramural NIH HHS [Z99 CA999999] NR 38 TC 7 Z9 7 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD JUL PY 2014 VL 52 IS 7 BP 594 EP 601 DI 10.1097/MLR.0000000000000151 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AJ5TI UT WOS:000337750800006 PM 24926706 ER PT J AU Liu, JF Wang, SJ Linguraru, MG Yao, JH Summers, RM AF Liu, Jianfei Wang, Shijun Linguraru, Marius George Yao, Jianhua Summers, Ronald M. TI Tumor sensitive matching flow: A variational method to detecting and segmenting perihepatic and perisplenic ovarian cancer metastases on contrast-enhanced abdominal CT SO MEDICAL IMAGE ANALYSIS LA English DT Article DE Ovarian cancer Metastases; Tumor sensitive matching flow; Dynamic shape prior; Level set ID LEVEL SET SEGMENTATION; OPTICAL-FLOW; IMAGE SEGMENTATION; ACTIVE CONTOURS; SHAPE PRIORS; TEXTURE; MODELS; LIVER; CLASSIFICATION; REGISTRATION AB Accurate automated segmentation and detection of ovarian cancer metastases may improve the diagnosis and prognosis of women with ovarian cancer. In this paper, we focus on an important subset of ovarian cancer metastases that spread to the surface of the liver and spleen. Automated ovarian cancer metastasis detection and segmentation are very challenging problems to solve. These metastases have a wide variety of shapes and intensity values similar to that of the liver, spleen and adjacent soft tissues. To address these challenges, this paper presents a variational approach, called tumor sensitive matching flow (TSMF), to detect and segment perihepatic and perisplenic ovarian cancer metastases. TSMF is an image motion field that only highlights metastasis-caused deformation on the surface of liver and spleen while dampening all other image motion between the patient image and the atlas image. It provides several benefits: (1) juxtaposing the roles of image matching and metastasis classification within a variational framework; (2) only requiring a small set of features from a few patient images to train a metastasis-likelihood function for classification; and (3) dynamically creating shape priors for geodesic active contour (GAC) to prevent inaccurate metastasis segmentation. We compared the TSMF to an organ surface partition (OSP) baseline approach. At a false positive rate of 2 per patient, the sensitivities of TSMF and OSP were 87% and 17% (p < 0.001), respectively. In a comparison of the segmentations conducted using TSMF-constrained GAC and conventional GAC, the volume overlap rates were 73 +/- 9% and 46 +/- 26% (p < 0.001) and average surface distances were 2.4 +/- 1.2 mm and 7.0 +/- 6.0 mm (p < 0.001), respectively. These encouraging results demonstrate that TSMF could accurately detect and segment ovarian cancer metastases. (C) 2014 Published by Elsevier B.V. C1 [Liu, Jianfei; Wang, Shijun; Yao, Jianhua; Summers, Ronald M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Linguraru, Marius George] Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC 20010 USA. [Linguraru, Marius George] George Washington Univ, Sch Med & Hlth Sci, Dept Radiol, Washington, DC 20052 USA. [Linguraru, Marius George] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA. RP Summers, RM (reprint author), NIH, Ctr Clin, Imaging Biomarkers & Comp Aided Diag Lab, Dept Radiol & Imaging Sci, Bldg 10 Room 1C224D MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov FU Intramural Research Program of the National Institutes of Health, Clinical Center FX This work was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center. The authors thank Brandon Peplinski for data annotation. NR 82 TC 3 Z9 3 U1 6 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD JUL PY 2014 VL 18 IS 5 BP 725 EP 739 DI 10.1016/j.media.2014.04.001 PG 15 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AJ7KN UT WOS:000337875700003 PM 24835180 ER PT J AU Loth, DW Artigas, MS Gharib, SA Wain, LV Franceschini, N Koch, B Pottinger, TD Smith, AV Duan, Q Oldmeadow, C Lee, MK Strachan, DP James, AL Huffman, JE Vitart, V Ramasamy, A Wareham, NJ Kaprio, J Wang, XQ Trochet, H Kahonen, M Flexeder, C Albrecht, E Lopez, LM de Jong, K Thyagarajan, B Alves, AC Enroth, S Omenaas, E Joshi, PK Fall, T Vinuela, A Launer, LJ Loehr, LR Fornage, M Li, G Wik, JB Tang, WB Manichaikul, A Lahousse, L Harris, TB North, KE Rudnicka, AR Hui, J Gu, XJ Lumley, T Wright, AF Hastie, ND Campbell, S Kumar, R Pin, I Scott, RA Pietilainen, KH Surakka, I Liu, YM Holliday, EG Schulz, H Heinrich, J Davies, G Vonk, JM Wojczynski, M Pouta, A Johansson, A Wild, SH Ingelsson, E Rivadeneira, F Vozke, H Hysi, PG Eiriksdottir, G Morrison, AC Rotter, JI Gao, W Postma, DS White, WB Rich, SS Hofman, A Aspelund, T Couper, D Smith, LJ Psaty, BM Lohman, K Burchard, EG Uitterlinden, AG Garcia, M Joubert, BR McArdle, WL Musk, AB Hansel, N Heckbert, SR Zgaga, L van Meurs, JBJ Navarro, P Rudan, I Oh, YM Redline, S Jarvis, DL Zhao, JH Rantanen, T O'Connor, GT Ripatti, S Scott, RJ Karrasch, S Grallert, H Gaddis, NC Starr, JM Wijmenga, C Minster, RL Lederer, DJ Pekkanen, J Gyllensten, U Campbe, H Morris, AP Glaser, S Hammond, CJ Burkart, KM Beilby, J Kritchevsky, SB Gucinason, V Hancock, DB Williams, D Polasek, O Zemunik, T Kolcic, I Petrini, MF Wjst, M Kim, WJ Porteous, DJ Scotland, G Smith, BH Villanen, A Heliovaara, M Attia, JR Sayers, I Hampel, R Gieger, C Deary, IJ Boezen, HM Newman, A Jarvelin, MR Wilson, JF Lind, L Stricker, BH Teumer, A Spector, TD Melen, E Peters, MJ Lange, LA Barr, RG Bracke, KR Verhamme, FM Sung, J Hiemstra, PS Cassano, PA Sood, A Hayward, C Dupuis, J Hall, IP Brusselle, GG Tobin, MD London, SJ AF Loth, Daan W. Artigas, Maria Soler Gharib, Sina A. Wain, Louise V. Franceschini, Nora Koch, Beate Pottinger, Tess D. Smith, Albert Vernon Duan, Qing Oldmeadow, Chris Lee, Mi Kyeong Strachan, David P. James, Alan L. Huffman, Jennifer E. Vitart, Veronique Ramasamy, Adaikalavan Wareham, Nicholas J. Kaprio, Jaakko Wang, Xin-Qun Trochet, Holly Kaonen, Mika Flexeder, Claudia Albrecht, Eva Lopez, Lorna M. de Jong, Kim Thyagarajan, Bharat Alves, Alexessander Couto Enroth, Stefan Omenaas, Ernst Joshi, Peter K. Fall, Tove Vinuela, Ana Launer, Lenore J. Loehr, Laura R. Fornage, Myriam Li, Guo Wik, Jemma B. Tang, Wenbo Manichaikul, Ani Lahousse, Lies Harris, Tamara B. North, Kari E. Rudnicka, Alicja R. Hui, Jennie Gu, Xiangjun Lumley, Thomas Wright, Alan F. Hastie, Nicholas D. Campbell, Susan Kumar, Rajesh Pin, Isabelle Scott, Robert A. Pietilainen, Kirsi H. Surakka, Ida Liu, Yongmei Holliday, Elizabeth G. Schulz, Holger Heinrich, Joachim Davies, Gail Vonk, Judith M. Wojczynski, Mary Pouta, Anneli Johansson, Asa Wild, Sarah H. Ingelsson, Erik Rivadeneira, Fernando Voezke, Henry Hysi, Pirro G. Eiriksdottir, Gudny Morrison, Alanna C. Rotter, Jerome I. Gao, Wei Postma, Dirkje S. White, Wendy B. Rich, Stephen S. Hofman, Albert Aspelund, Thor Couper, David Smith, Lewis J. Psaty, Bruce M. Lohman, Kurt Burchard, Esteban G. Uitterlinden, Andre G. Garcia, Melissa Joubert, Bonnie R. McArdle, Wendy L. Musk, A. Bill Hansel, Nadia Heckbert, Susan R. Zgaga, Lina van Meurs, Joyce B. J. Navarro, Pau Rudan, Igor Oh, Yeon-Mok Redline, Susan Jarvis, Deborah L. Zhao, Jing Hua Rantanen, Taina O'Connor, George T. Ripatti, Samuli Scott, Rodney J. Karrasch, Stefan Grallert, Harald Gaddis, Nathan C. Starr, John M. Wijmenga, Cisca Minster, Ryan L. Lederer, David J. Pekkanen, Juha Gyllensten, Ulf Campbe, Harry Morris, Andrew P. Glaeser, Sven Hammond, Christopher J. Burkart, Kristin M. Beilby, John Kritchevsky, Stephen B. Gucinason, Vilrnundur Hancock, Dana B. Williams, Dale Polasek, Ozren Zemunik, Tatijana Kolcic, Ivana Petrini, Marcy F. Wjst, Matthias Kim, Woo Jin Porteous, David J. Scotland, Generation Smith, Blair H. Villanen, Anne Heliovaara, Markku Attia, John R. Sayers, Ian Hampel, Regina Gieger, Christian Deary, Ian J. Boezen, H. Marike Newman, Anne Jarvelin, Marjo-Riitta Wilson, James F. Lind, Lars Stricker, Bruno H. Teumer, Alexander Spector, Timothy D. Melen, Erik Peters, Marjolein J. Lange, Leslie A. Barr, R. Graham Bracke, Ken R. Verhamme, Fien M. Sung, Joohon Hiemstra, Pieter S. Cassano, Patricia A. Sood, Akshay Hayward, Caroline Dupuis, Josee Hall, Ian P. Brusselle, Guy G. Tobin, Martin D. London, Stephanie J. TI Genome-wide association analysis identifies six new loci associated with forced vital capacity SO NATURE GENETICS LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; LUNG-FUNCTION; GENE-EXPRESSION; HEALTHY TWIN; HERITABILITY; DISEASE; TRAITS; CELLS; MORTALITY; FAMILY AB Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 x 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease. C1 [Loth, Daan W.; Lahousse, Lies; Hofman, Albert; Uitterlinden, Andre G.; Stricker, Bruno H.; Brusselle, Guy G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Loth, Daan W.; Stricker, Bruno H.] Netherlands Hlth Care Inspectorate, The Hague, Netherlands. [Artigas, Maria Soler; Wain, Louise V.; Tobin, Martin D.] Univ Leicester, Dept Hlth Sci, Genet Epidemiol Grp, Leicester, Leics, England. [Artigas, Maria Soler; Wain, Louise V.; Tobin, Martin D.] Glenfield Hosp, NIHR, Leicester Resp Biomed Res Unit, Leicester, Leics, England. [Gharib, Sina A.] Univ Washington, Ctr Lung Biol, Computat Med Core, Seattle, WA 98195 USA. [Gharib, Sina A.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Franceschini, Nora; Loehr, Laura R.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Franceschini, Nora; Loehr, Laura R.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Koch, Beate; Glaeser, Sven] Univ Hosp Greifswald, Dept Internal Med, Greifswald, Germany. [Pottinger, Tess D.; Lederer, David J.; Burkart, Kristin M.; Barr, R. Graham] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA. [Smith, Albert Vernon; Eiriksdottir, Gudny; Aspelund, Thor; Gucinason, Vilrnundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert Vernon; Aspelund, Thor; Gucinason, Vilrnundur] Univ Iceland, Reykjavik, Iceland. [Duan, Qing; Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Oldmeadow, Chris; Holliday, Elizabeth G.; Scott, Rodney J.; Attia, John R.] Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW 2300, Australia. [Oldmeadow, Chris; Holliday, Elizabeth G.; Scott, Rodney J.; Attia, John R.] Univ Newcastle, Fac Hlth, Newcastle, NSW 2300, Australia. [Lee, Mi Kyeong; Sung, Joohon] Seoul Natl Univ, Inst Hlth & Environm, Seoul, South Korea. [Strachan, David P.; Rudnicka, Alicja R.] St Georges Univ London, Div Populat Hlth Sci & Educ, London, England. [James, Alan L.] West Australian Sleep Disorders Res Inst, Inst Hlth & Environm Pulm Physiol & Sleep Med, Nedlands, WA, Australia. [James, Alan L.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [James, Alan L.] Busselton Populat Med Res Inst, Busselton, WA, Australia. [Huffman, Jennifer E.; Vitart, Veronique; Trochet, Holly; Wright, Alan F.; Hastie, Nicholas D.; Campbell, Susan; Navarro, Pau; Hayward, Caroline] Univ Edinburgh, MRC, IGMM, Human Genet Unit, Edinburgh, Midlothian, Scotland. [Ramasamy, Adaikalavan; Jarvis, Deborah L.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Resp Epidemiol & Publ Hlth Grp, London, England. [Ramasamy, Adaikalavan; Alves, Alexessander Couto; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Ctr Environm & Hlth, MRC HPA,Dept Epidemiol & Biostat, London, England. [Wareham, Nicholas J.; Scott, Robert A.; Zhao, Jing Hua] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England. [Kaprio, Jaakko] Univ Helsinki, Hjelt Inst, Dept Publ Hlth, Helsinki, Finland. [Kaprio, Jaakko; Heliovaara, Markku] Natl Inst Hlth & Welf THL, Helsinki, Finland. [Kaprio, Jaakko; Pietilainen, Kirsi H.; Surakka, Ida; Ripatti, Samuli] Univ Helsinki, FIMM, Helsinki, Finland. [Wang, Xin-Qun; Manichaikul, Ani] Univ Virginia, Dept Publ Hlth Sci, Div Biostat & Epidemiol, Charlottesville, VA USA. [Kaonen, Mika] Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Kaonen, Mika] Tampere Univ Hosp, Tampere, Finland. [Flexeder, Claudia; Schulz, Holger; Heinrich, Joachim; Karrasch, Stefan] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 1, Neuherberg, Germany. [Albrecht, Eva; Gieger, Christian] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany. [Lopez, Lorna M.; Davies, Gail; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Lopez, Lorna M.; Davies, Gail; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland. [de Jong, Kim; Vonk, Judith M.; Boezen, H. Marike] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [de Jong, Kim; Vonk, Judith M.; Postma, Dirkje S.; Boezen, H. Marike] Univ Groningen, Univ Med Ctr Groningen, GRIAC, Groningen, Netherlands. [Thyagarajan, Bharat] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Enroth, Stefan; Johansson, Asa; Gyllensten, Ulf] Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, Uppsala, Sweden. [Enroth, Stefan; Fall, Tove; Johansson, Asa; Ingelsson, Erik; Gyllensten, Ulf] Uppsala Univ, Sci Life Lab, Uppsala, Sweden. [Omenaas, Ernst] Haukeland Hosp, Clin Res Ctr, N-5021 Bergen, Norway. [Omenaas, Ernst] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Joshi, Peter K.; Wild, Sarah H.; Rudan, Igor; Campbe, Harry; Wilson, James F.] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Fall, Tove; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Vinuela, Ana; Hysi, Pirro G.; Hammond, Christopher J.; Spector, Timothy D.] Kings Coll London, Dept Twins Res & Genet Epidemiol, London, England. [Launer, Lenore J.; Harris, Tamara B.; Garcia, Melissa] NIA, US NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Fornage, Myriam; Gu, Xiangjun] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam; Gu, Xiangjun] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Li, Guo; Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Wik, Jemma B.] Pfizer Global Res & Dev, Precis Med, Cambridge, MA USA. [Tang, Wenbo; Cassano, Patricia A.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Manichaikul, Ani; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA USA. [Lahousse, Lies; Bracke, Ken R.; Verhamme, Fien M.; Brusselle, Guy G.] Ghent Univ Hosp, Dept Resp Med, Ghent, Belgium. [Hui, Jennie; Beilby, John] PathWest Lab Med Washington, Nedlands, WA, Australia. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Kumar, Rajesh; Smith, Lewis J.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Pin, Isabelle] CHU Grenoble, F-38043 Grenoble, France. [Pin, Isabelle] Inst Albert Bonniot, INSERM U823, Grenoble, France. [Pin, Isabelle] Univ Grenoble 1, Grenoble, France. [Pietilainen, Kirsi H.] Univ Helsinki, Res Programs Unit, Obes Res Unit, Helsinki, Finland. [Pietilainen, Kirsi H.] Univ Helsinki, Cent Hosp, Dept Med, Div Internal Med, Helsinki, Finland. [Surakka, Ida; Ripatti, Samuli] Natl Inst Hlth & Welf THL, Helsinki, Finland. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Heinrich, Joachim] CPC M, Munich, Germany. [Davies, Gail; Porteous, David J.] Univ Edinburgh, MRC IGMM, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh, Midlothian, Scotland. [Davies, Gail] MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Wojczynski, Mary] Washington Univ, Dept Stat Gen, St Louis, MO USA. [Pouta, Anneli] Natl Inst Hlth & Welf, Oulu, Finland. [Pouta, Anneli] Univ Oulu, Univ Hosp Oulu, Dept Clin Sci Obstet & Gynecol, Oulu, Finland. [Johansson, Asa] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden. [Ingelsson, Erik] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Rivadeneira, Fernando; Uitterlinden, Andre G.; van Meurs, Joyce B. J.; Stricker, Bruno H.; Peters, Marjolein J.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Rivadeneira, Fernando; Hofman, Albert; Uitterlinden, Andre G.; van Meurs, Joyce B. J.; Stricker, Bruno H.; Peters, Marjolein J.] NGI, NCHA, Rotterdam, Netherlands. [Voezke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Morrison, Alanna C.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Rotter, Jerome I.] Univ Calif Los Angeles, Harbor Med Ctr, Biomed Res Inst, Torrance, CA 90509 USA. [Rotter, Jerome I.] Univ Calif Los Angeles, Harbor Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Gao, Wei; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Postma, Dirkje S.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, Groningen, Netherlands. [White, Wendy B.] Tougaloo Coll, Jackson, MS USA. [Couper, David] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Lohman, Kurt] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Burchard, Esteban G.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Burchard, Esteban G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Joubert, Bonnie R.; Hancock, Dana B.; London, Stephanie J.] US Dept HHS, Epidemiol Branch, NIEHS, US NIH, Res Triangle Pk, NC 27709 USA. [McArdle, Wendy L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Musk, A. Bill] Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia. [Hansel, Nadia] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Zgaga, Lina] Trinity Coll Dublin, Dept Publ Hlth & Primary Care, Dublin, Ireland. [Zgaga, Lina] Univ Zagreb, Sch Med, Adrija Stampar Sch Publ Hlth, Zagreb 41001, Croatia. [Oh, Yeon-Mok] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pulm & Crit Care Med, Seoul, South Korea. [Oh, Yeon-Mok] Univ Ulsan, Coll Med, Asan Med Ctr, Clin Res Ctr Chron Obstruct Airway Dis, Seoul, South Korea. [Redline, Susan] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Jarvis, Deborah L.] Univ London Imperial Coll Sci Technol & Med, MRC PHE Ctr Environm & Hlth, London, England. [Rantanen, Taina; Villanen, Anne] Univ Jyvaskyla, Gerontol Res Ctr, Dept Hlth Sci, Jyvaskyla, Finland. [O'Connor, George T.; Morris, Andrew P.] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [O'Connor, George T.; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ripatti, Samuli] Wellcome Trust Sanger Inst, Genet Epidemiol Grp, Hinxton, England. [Karrasch, Stefan] Univ Munich, Inst & Outpatient Clin Occupat Social & Environ M, Munich, Germany. [Karrasch, Stefan] Univ Munich, Klinikum Rechts Isar, Univ Hosp, Inst Gen Practice, Munich, Germany. [Grallert, Harald] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Gaddis, Nathan C.] Res Triangle Inst Int, Res Comp Div, Res Triangle Pk, NC USA. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Minster, Ryan L.] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Lederer, David J.; Barr, R. Graham] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Pekkanen, Juha] Natl Inst Hlth & Welf THL, Dept Environm Hlth, Kuopio, Finland. [Pekkanen, Juha] Univ Eastern Finland, Kuopio, Finland. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Hancock, Dana B.] Res Triangle Inst Int, Behav Hlth Epidemiol Program, Res Triangle Pk, NC USA. [Williams, Dale] Florida Int Univ, Miami, FL 33199 USA. [Polasek, Ozren; Kolcic, Ivana] Univ Split, Sch Med, Dept Publ Hlth, Split, Croatia. [Zemunik, Tatijana] Univ Split, Sch Med, Dept Med Biol, Split, Croatia. [Petrini, Marcy F.] Univ Mississippi, Med Ctr, Dept Med, Div Pulm Crit Care & Sleep Med, Jackson, MS 39216 USA. [Wjst, Matthias] Helmholtz Zentrum Munchen HMGU, CPC, Munich, Germany. [Kim, Woo Jin] Kangwon Natl Univ, Kangwon Natl Univ Hosp, Sch Med, Dept Internal Med, Chunchon, South Korea. [Kim, Woo Jin] Kangwon Natl Univ, Kangwon Natl Univ Hosp, Sch Med, Environm Hlth Ctr, Chunchon, South Korea. [Scotland, Generation] Univ Med Sch, Natl Hlth Serv, Dundee, Scotland. [Scotland, Generation] Univ Med Sch, Natl Hlth Serv, Edinburgh, Midlothian, Scotland. [Scotland, Generation] Univ Med Sch, Natl Hlth Serv, Glasgow, Lanark, Scotland. [Smith, Blair H.] Univ Dundee, Med Res Inst, Dundee, Scotland. [Sayers, Ian; Hall, Ian P.] Univ Nottingham, Div Therapeut & Mol Med, Nottingham NG7 2RD, England. [Hampel, Regina] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [Newman, Anne] Univ Pittsburgh, Ctr Aging & Populat Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Children & Young People & Families, Oulu, Finland. [Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Teumer, Alexander] Univ Med Greifswald, Interfac Inst Genet & Funct Gen, Dept Genet & Funct Genom, Greifswald, Germany. [Melen, Erik] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Melen, Erik] Sachs Childrens Hosp, Stockholm, Sweden. [Sung, Joohon] Seoul Natl Univ, Sch Publ Hlth, Dept Epidemiol, Complex Dis & Genet Epidemiol Branch, Seoul, South Korea. [Hiemstra, Pieter S.] Leiden Univ, Med Ctr, Dept Pulmonol, Leiden, Netherlands. [Cassano, Patricia A.] Weill Cornell Med Coll, Dept Publ Hlth, Div Biostat & Epidemiol, New York, NY USA. [Sood, Akshay] Univ New Mexico, Sch Med, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Brusselle, Guy G.] Erasmus MC, Dept Resp Med, Rotterdam, Netherlands. RP London, SJ (reprint author), US Dept HHS, Epidemiol Branch, NIEHS, US NIH, Res Triangle Pk, NC 27709 USA. EM mt47@le.ac.uk; london2@niehs.nih.gov RI Newman, Anne B./C-6408-2013; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Hayward, Caroline/M-8818-2016; Rantanen, Taina/O-6579-2016; Wijmenga, Cisca/D-2173-2009; Kolcic, Ivana/E-2713-2017; Rivadeneira, Fernando/O-5385-2015; Soler Artigas, Maria/L-6529-2013; Fall, Tove/O-7226-2014; Ramasamy, Adaikalavan/G-2632-2010; Grallert, Harald/B-3424-2013; Schulz, Holger/J-5643-2015; Gudnason, Vilmundur/K-6885-2015; Aspelund, Thor/C-5983-2008; Ripatti, Samuli/H-9446-2014; Enroth, Stefan/C-7396-2009; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011 OI London, Stephanie/0000-0003-4911-5290; Wain, Louise/0000-0003-4951-1867; Pottinger, Tess/0000-0003-0647-5712; Gieger, Christian/0000-0001-6986-9554; Lee, Mi Kyeong/0000-0002-3036-3684; Pekkanen, Juha/0000-0002-1083-8777; Bracke, Ken/0000-0001-5906-4605; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Navarro, Pau/0000-0001-5576-8584; Hammond, Christopher/0000-0002-3227-2620; Smith, Blair/0000-0002-5362-9430; Kaprio, Jaakko/0000-0002-3716-2455; Johansson, Asa/0000-0002-2915-4498; Lahousse, Lies/0000-0002-3494-4363; Viljanen, Anne/0000-0002-8428-3604; Hall, Ian/0000-0001-9933-3216; Newman, Anne B./0000-0002-0106-1150; Peters, Marjolein/0000-0003-3167-9063; Vinuela, Ana/0000-0003-3771-8537; Zgaga, Lina/0000-0003-4089-9703; Hancock, Dana/0000-0003-2240-3604; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Hayward, Caroline/0000-0002-9405-9550; Rantanen, Taina/0000-0002-1604-1945; Kolcic, Ivana/0000-0001-7918-6052; Wijmenga, Cisca/0000-0002-5635-1614; Alves, Alex/0000-0001-8519-7356; Smith, Lewis J/0000-0002-4728-1562; Gaddis, Nathan/0000-0001-5205-7138; Joshi, Peter/0000-0002-6361-5059; Rivadeneira, Fernando/0000-0001-9435-9441; Soler Artigas, Maria/0000-0002-3213-1107; Ramasamy, Adaikalavan/0000-0002-7598-2892; Schulz, Holger/0000-0002-1157-200X; Gudnason, Vilmundur/0000-0001-5696-0084; Aspelund, Thor/0000-0002-7998-5433; Ripatti, Samuli/0000-0002-0504-1202; Enroth, Stefan/0000-0002-5056-9137; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862 FU Biotechnology and Biological Sciences Research Council [BB/F019394/1]; Chief Scientist Office [CZB/4/505, CZB/4/710, CZD/16/6/4, ETM/55]; Department of Health [SRF/01/010]; Intramural NIH HHS [Z01 ES043012-10]; Medical Research Council [MR/L016400/1, G0100266, G0700704, G0701863, G0902313, G1000861, MC_PC_U127561128, MC_PC_U127592696, MC_U106179471, MC_UU_12015/1, MR/K026992/1]; NCATS NIH HHS [UL1 TR000124, UL1 TR001079]; NHLBI NIH HHS [N01 HC095159, R01 HL077612, R01 HL103676]; NIA NIH HHS [R01 AG023629, U01 AG023746, U01 AG023749]; NIDDK NIH HHS [P30 DK058404, P30 DK063491]; NIMH NIH HHS [R25 MH083620] NR 46 TC 32 Z9 33 U1 3 U2 33 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUL PY 2014 VL 46 IS 7 BP 669 EP 677 DI 10.1038/ng.3011 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA AK0HP UT WOS:000338093800006 PM 24929828 ER PT J AU Wang, YF Mckay, JD Rafnar, T Wang, ZM Timofeeva, MN Broderick, P Zong, XC Laplana, M Wei, YY Han, YH Lloyd, A Delahaye-Sourdeix, M Chubb, D Gaborieau, V Wheeler, W Chatterjee, N Thorleifsson, G Sulem, P Liu, G Kaaks, R Henrion, M Kinnersley, B Vallee, M LeCalvez-Kelm, F Stevens, VL Gapstur, SM Chen, WV Zaridze, D Szeszenia-Dabrowska, N Lissowska, J Rudnai, P Fabianova, E Mates, D Bencko, V Foretova, L Janout, V Krokan, HE Gabrielsen, ME Skorpen, F Vatten, L Njolstad, I Chen, C Goodman, G Benhamou, S Vooder, T Valk, K Nelis, M Metspalu, A Lener, M Lubinski, J Johansson, M Vineis, P Agudo, A Clavel-Chapelon, F Bueno-de-Mesquita, HB Trichopoulos, D Khaw, KT Johansson, M Weiderpass, E Tjonneland, A Riboli, E Lathrop, M Scelo, G Albanes, D Caporaso, NE Ye, YQ Gu, J Wu, XF Spitz, MR Dienemann, H Rosenberger, A Su, L Matakidou, A Eisen, T Stefansson, K Risch, A Chanock, SJ Christiani, DC Hung, RJ Brennan, P Landi, MT Houlston, RS Amos, CI AF Wang, Yufei Mckay, James D. Rafnar, Thorunn Wang, Zhaoming Timofeeva, Maria N. Broderick, Peter Zong, Xuchen Laplana, Marina Wei, Yongyue Han, Younghun Lloyd, Amy Delahaye-Sourdeix, Manon Chubb, Daniel Gaborieau, Valerie Wheeler, William Chatterjee, Nilanjan Thorleifsson, Gudmar Sulem, Patrick Liu, Geoffrey Kaaks, Rudolf Henrion, Marc Kinnersley, Ben Vallee, Maxime LeCalvez-Kelm, Florence Stevens, Victoria L. Gapstur, Susan M. Chen, Wei V. Zaridze, David Szeszenia-Dabrowska, Neonilia Lissowska, Jolanta Rudnai, Peter Fabianova, Eleonora Mates, Dana Bencko, Vladimir Foretova, Lenka Janout, Vladimir Krokan, Hans E. Gabrielsen, Maiken Elvestad Skorpen, Frank Vatten, Lars Njolstad, Inger Chen, Chu Goodman, Gary Benhamou, Simone Vooder, Tonu Valk, Kristjan Nelis, Mari Metspalu, Andres Lener, Marcin Lubinski, Jan Johansson, Mattias Vineis, Paolo Agudo, Antonio Clavel-Chapelon, Francoise Bueno-de-Mesquita, H. Bas Trichopoulos, Dimitrios Khaw, Kay-Tee Johansson, Mikael Weiderpass, Elisabete Tjonneland, Anne Riboli, Elio Lathrop, Mark Scelo, Ghislaine Albanes, Demetrius Caporaso, Neil E. Ye, Yuanqing Gu, Jian Wu, Xifeng Spitz, Margaret R. Dienemann, Hendrik Rosenberger, Albert Su, Li Matakidou, Athena Eisen, Timothy Stefansson, Kari Risch, Angela Chanock, Stephen J. Christiani, David C. Hung, Rayjean J. Brennan, Paul Landi, Maria Teresa Houlston, Richard S. Amos, Christopher I. TI Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON GENETIC-VARIATION; POLYMORPHIC STOP CODON; SUSCEPTIBILITY LOCUS; DNA-DAMAGE; ADENOCARCINOMA; MUTATIONS; METAANALYSIS; POPULATIONS; CARCINOMA AB We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 x 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 x 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 x 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data. C1 [Broderick, Peter; Lloyd, Amy; Chubb, Daniel; Henrion, Marc; Kinnersley, Ben; Houlston, Richard S.] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Mckay, James D.; Timofeeva, Maria N.; Delahaye-Sourdeix, Manon; Gaborieau, Valerie; Vallee, Maxime; LeCalvez-Kelm, Florence; Johansson, Mattias; Scelo, Ghislaine; Brennan, Paul] WHO, IARC, Lyon, France. [Rafnar, Thorunn; Thorleifsson, Gudmar; Sulem, Patrick; Stefansson, Kari] Amgen Inc, deCODE Genet, Reykjavik, Iceland. [Wang, Zhaoming; Chatterjee, Nilanjan; Albanes, Demetrius; Caporaso, Neil E.; Chanock, Stephen J.; Landi, Maria Teresa] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zong, Xuchen; Hung, Rayjean J.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Laplana, Marina; Risch, Angela] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany. [Wei, Yongyue; Su, Li; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Han, Younghun; Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Ctr Genom Med, Lebanon, NH 03756 USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD USA. [Liu, Geoffrey] Univ Hlth Network, Princess Margaret Hosp, Toronto, ON, Canada. [Kaaks, Rudolf] DKFZ, Div Canc Epidemiol, Heidelberg, Germany. [Kaaks, Rudolf; Dienemann, Hendrik; Risch, Angela] TLRC H, Heidelberg, Germany. [Stevens, Victoria L.; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Chen, Wei V.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Zaridze, David] Russian NN Blokhin Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Fabianova, Eleonora] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Mates, Dana] Natl Inst Publ Hlth, Bucharest, Romania. [Bencko, Vladimir] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Janout, Vladimir] Palacky Univ, CR-77147 Olomouc, Czech Republic. [Krokan, Hans E.; Gabrielsen, Maiken Elvestad] Norwegian Univ Sci & Technol, Dept Lab Med, Childrens & Womens Hlth, N-7034 Trondheim, Norway. [Skorpen, Frank] Norwegian Univ Sci & Technol, Fac Med, Childrens & Womens Hlth, Dept Lab Med, N-7034 Trondheim, Norway. [Vatten, Lars] Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth & Gen Practice, N-7034 Trondheim, Norway. [Njolstad, Inger] Univ Tromso, Dept Community Med, Tromso, Norway. [Chen, Chu; Goodman, Gary] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Benhamou, Simone] INSERM U946, Paris, France. [Vooder, Tonu] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Valk, Kristjan] Univ Bergen, Dept Biomed, Bergen, Norway. [Nelis, Mari; Metspalu, Andres] Inst Mol & Cell Biol, Estonian Genome Ctr, Tartu, Estonia. [Nelis, Mari] Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland. [Lener, Marcin; Lubinski, Jan] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Vineis, Paolo; Bueno-de-Mesquita, H. Bas; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Vineis, Paolo] HuGeF Fdn, Unit Mol & Genet Epidemiol, Turin, Italy. [Agudo, Antonio] Catalan Inst Oncol, Canc Epidemiol Res Program, Unit Nutr Environm & Canc, Barcelona, Spain. [Clavel-Chapelon, Francoise] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Nutr Hormones & Womens Hlth Team, U1018, Villejuif, France. [Clavel-Chapelon, Francoise] Univ Paris 11, UMRS 1018, Villejuif, France. [Clavel-Chapelon, Francoise] Inst Gustave Roussy, Villejuif, France. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Khaw, Kay-Tee] Univ Cambridge, Addenbrookes Hosp, Clin Gerontol Unit, Sch Clin Med, Cambridge CB2 2QQ, England. [Johansson, Mikael] Umea Univ, Dept Radiat Sci, Umea, Sverige, Sweden. [Weiderpass, Elisabete] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Tjonneland, Anne] Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Lathrop, Mark] CEPH, Paris, France. [Ye, Yuanqing; Gu, Jian; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Spitz, Margaret R.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Rosenberger, Albert] Thoraxklin Univ Hosp Heidelberg, Dept Thorac Surg, Heidelberg, Germany. [Rosenberger, Albert] Univ Gottingen, Dept Genet Epidemiol, D-37073 Gottingen, Germany. [Matakidou, Athena] Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England. [Eisen, Timothy] Cambridge Univ Hosp Natl Hlth Serv Fdn Trust, Dept Oncol, Cambridge, England. [Eisen, Timothy] Addenbrookes Hosp, Cambridge, England. RP Houlston, RS (reprint author), Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. EM landim@mail.nih.gov; richard.houlston@icr.ac.uk RI Laplana, Marina/G-2653-2010; Janout, Vladimir/M-5133-2014; Hung, Rayjean/A-7439-2013; Agudo, Antonio/J-1805-2016; Benhamou, Simone/K-6554-2015; Weiderpass, Elisabete/M-4029-2016; Liu, Geoffrey/N-4421-2016; Risch, Angela/H-2669-2013; OI Houlston, Richard/0000-0002-5268-0242; Laplana, Marina/0000-0002-2548-0704; Weiderpass, Elisabete/0000-0003-2237-0128; Risch, Angela/0000-0002-8026-5505; Broderick, Peter/0000-0002-8348-5829; Agudo, Antonio/0000-0001-9900-5677; Henrion, Marc/0000-0003-1242-839X; mates, dana/0000-0002-6219-9807; Kinnersley, Ben/0000-0003-1783-6296 FU National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital; NIH [U19CA148127, R01CA055769, 5R01CA127219, 5R01CA133996, 5R01CA121197, R01-CA111703, U01-CA63673, P50 CA70907, R01CA121197, RO1 CA127219, U19 CA148127, RO1 CA55769, CA074386, CA092824, CA090578, DA17932]; Cancer Research UK [C1298/A8780, C1298/A8362]; National Cancer Research Network (NCRN); HEAL; Sanofi-Aventis; National Health Service; National Institute for Health Research Biomedical Research Centre; Sir John Fisher Foundation; Canadian Cancer Society Research Institute [020214]; Ontario Institute of Cancer; Cancer Care Ontario Chair; Alan Brown Chair; Lusi Wong Programs at the Princess Margaret Hospital Foundation; Deutsche Krebshilfe [70-2387, 70-2919]; German Federal Ministry of Education and Research (EPIC-Heidelberg); Institut National du Cancer, France; European Community [LSHG-CT-2005-512113]; Norwegian Cancer Association; Functional Genomics Programme of Research Council of Norway; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; Fred Hutchinson Cancer Research Center; US NCI [R01 CA092039]; FP7 grant [REGPOT 245536]; Estonian Government [SF0180142s08]; EU European Regional Development Fund in the frame of Centre of Excellence in Genomics and Estonian Research Infrastructure's Roadmap; University of Tartu [SP1GVARENG]; IARC Postdoctoral Fellowship; Intramural Research Program of the NIH; NCI, US Public Health Service contracts NCI [N01-CN-45165, N01-RC-45035, N01-RC-37004, NO1-CN-25514, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476, NO1-CN-25404]; American Cancer Society; NIH Genes, Environment and Health Initiative [HG-06-033-NCI-01, RO1HL091172-01]; genotyping at the Johns Hopkins University Center for Inherited Disease Research [U01HG004438, NIH HHSN268200782096C]; study coordination at the GENEVA Coordination Center [U01 HG004446]; Cancer Prevention Research Institute of Texas [RP100443] FX We thank all individuals who participated in this study. We are also grateful to the patients, clinicians and allied health care professions. We thank Z. Chen and K. Boyle for sample handling and data management of the Toronto study, and L. Admas and L.R. Zhang for field recruitment. We thank L. Su, Y. Zhao, G. Liu, J. Wain, R. Heist and K. Asomaning for providing computing support at MDACC. We thank G. Thomas and Synergy Lyon Cancer (Lyon France) for high performance computing support and J. Olivier and A. Chabrier for IARC's PGM ion torrent sequencing optimization and TaqMan genotyping, respectively. We thank D. Goldgar for sharing information from The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) on sequence variation in BRCA2 from familial breast cancer analysis. We acknowledge the Icelandic Cancer Registry (http://www.krabbameinsskrads/indexen.jsp?id=summary) for assistance in the ascertainment of the Icelandic patients with lung cancer. The ICR study made use of genotyping data from the Wellcome Trust Case-Control Consortium 2 (WTCCC2); a full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. We acknowledge The Cancer Genome Atlas (TCGA) for their contribution of lung cancer genomic data to this study (TCGA Project Number 3230). We also acknowledge support from the National Institute for Health Research Biomedical Research Centre at the Royal Marsden Hospital. This study was supported by the NIH (U19CA148127, R01CA055769, 5R01CA127219, 5R01CA133996 and 5R01CA121197). The work performed at ICR was supported by Cancer Research UK (C1298/A8780 and C1298/A8362), National Cancer Research Network (NCRN), HEAL, Sanofi-Aventis and National Health Service funding to the Royal Marsden Hospital and Institute of Cancer Research, as well as the National Institute for Health Research Biomedical Research Centre. B.K. was the recipient of a Sir John Fisher Foundation PhD studentship. Work at ICR was also supported by NIH GM103534 and the Institute for Quantitative Biomedical Sciences at Dartmouth to C.I.A. The work performed in Toronto was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The work performed at Heidelberg was supported by Deutsche Krebshilfe (70-2387 and 70-2919) and the German Federal Ministry of Education and Research (EPIC-Heidelberg). The work performed at IARC was supported by the Institut National du Cancer, France, the European Community (LSHG-CT-2005-512113), the Norwegian Cancer Association, the Functional Genomics Programme of Research Council of Norway, the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101), the NIH (R01-CA111703 and U01-CA63673), the Fred Hutchinson Cancer Research Center, the US NCI (R01 CA092039), an FP7 grant (REGPOT 245536), the Estonian Government (SF0180142s08), the EU European Regional Development Fund in the frame of Centre of Excellence in Genomics and Estonian Research Infrastructure's Roadmap and the University of Tartu (SP1GVARENG) and an IARC Postdoctoral Fellowship (M.N.T.).; Work at the NCI was supported by the Intramural Research Program of the NIH, the NCI, US Public Health Service contracts NCI (N0I-CN-45165, N01-RC-45035, N01-RC-37004, NO1-CN-25514, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476 and NO1-CN-25404), the American Cancer Society, the NIH Genes, Environment and Health Initiative in part by HG-06-033-NCI-01 and RO1HL091172-01, genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446). Work was also supported by NIH grants (P50 CA70907, R01CAl21197, RO1 CAl27219, U19 CA148127 and RO1 CA55769) and a Cancer Prevention Research Institute of Texas grant (RP100443). Genotyping was provided by the Center for Inherited Disease Research (CIDR). Work performed at Harvard was supported by the NIH (CA074386, CA092824 and CA090578). The Icelandic study was supported in part by NIH DA17932. NR 37 TC 65 Z9 67 U1 1 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUL PY 2014 VL 46 IS 7 BP 736 EP 741 DI 10.1038/ng.3002 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA AK0HP UT WOS:000338093800016 PM 24880342 ER PT J AU Gregoriou, GG Rossi, AF Ungerleider, LG Desimone, R AF Gregoriou, Georgia G. Rossi, Andrew F. Ungerleider, Leslie G. Desimone, Robert TI Lesions of prefrontal cortex reduce attentional modulation of neuronal responses and synchrony in V4 SO NATURE NEUROSCIENCE LA English DT Article ID SELECTIVE VISUAL-ATTENTION; MACAQUE AREA V4; POSTERIOR PARIETAL CORTEX; TOP-DOWN; NEURAL MECHANISMS; RHESUS-MONKEY; FRONTAL-LOBE; COVERT ATTENTION; SIGNALS; CONNECTIONS AB It is widely held that the frontal eye field (FEF) in prefrontal cortex (PFC) modulates processing in visual cortex with attention, although the evidence that it is necessary is equivocal. To help identify critical sources of attentional feedback to area V4, we surgically removed the entire lateral PFC, including the FEF, in one hemisphere and transected the corpus callosum and anterior commissure in two macaques. This deprived V4 of PFC input in one hemisphere while keeping the other hemisphere intact. In the absence of PFC, attentional effects on neuronal responses and synchrony in V4 were substantially reduced and the remaining effects of attention were delayed in time, indicating a critical role for PFC. Conversely, distracters captured attention and influenced V4 responses. However, because the effects of attention in V4 were not eliminated by PFC lesions, other sources of top-down attentional control signals to visual cortex must exist outside of PFC. C1 [Gregoriou, Georgia G.] Univ Crete, Fac Med, Dept Basic Sci, Iraklion, Greece. [Gregoriou, Georgia G.] Fdn Res & Technol Hellas, Inst Appl & Computat Math, Iraklion, Greece. [Rossi, Andrew F.] US Natl Inst Hlth, Div Neurosci & Basic Behav Sci, NIMH, Bethesda, MD USA. [Ungerleider, Leslie G.] US Natl Inst Hlth, Lab Brain & Cognit, NIMH, Bethesda, MD 20892 USA. [Desimone, Robert] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. RP Gregoriou, GG (reprint author), Univ Crete, Fac Med, Dept Basic Sci, Iraklion, Greece. EM gregoriou@med.uoc.gr RI Gregoriou, Georgia/F-7759-2011 OI Gregoriou, Georgia/0000-0002-4002-6657 FU National Institute of Mental Health Intramural Research Program and US National Institutes of Health [R01EY017292]; European Community's Seventh Framework Programme [PIRG05-GA-2009-246761] FX We thank G. Pielli for help with the animal training and R. Saunders for assistance with the surgical procedures. This work was supported by the National Institute of Mental Health Intramural Research Program and US National Institutes of Health grant R01EY017292 (R.D.). G.G.G. was partially supported by the European Community's Seventh Framework Programme (Grant PIRG05-GA-2009-246761). NR 50 TC 33 Z9 33 U1 3 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD JUL PY 2014 VL 17 IS 7 BP 1003 EP 1011 DI 10.1038/nn.3742 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AK0IX UT WOS:000338097200018 PM 24929661 ER PT J AU Mabuchi, K Schneider, AB AF Mabuchi, Kiyohiko Schneider, Arthur B. TI Do nuclear power plants increase the risk of thyroid cancer? SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Editorial Material ID STATION ACCIDENT; RADIATION; EXPOSURE AB The major accident at the Chernobyl nuclear power plant has resulted in an increased risk of thyroid cancer in exposed individuals. A new report attempts to quantify the risk of thyroid cancer associated with living near nuclear facilities; however, the findings are inconclusive due to flaws in the study design. C1 [Mabuchi, Kiyohiko] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Schneider, Arthur B.] Univ Illinois, Sect Endocrinol Diabet & Metab, Chicago, IL 60616 USA. RP Mabuchi, K (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM mabuchik@mail.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 EI 1759-5037 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD JUL PY 2014 VL 10 IS 7 BP 385 EP 387 DI 10.1038/nrendo.2014.59 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AK0IT UT WOS:000338096800004 PM 24776732 ER PT J AU Virk-Baker, MK Nagy, TR Barnes, S Groopman, J AF Virk-Baker, Mandeep K. Nagy, Tim R. Barnes, Stephen Groopman, John TI Dietary Acrylamide and Human Cancer: A Systematic Review of Literature SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID RENAL-CELL CANCER; HEMOGLOBIN ADDUCT LEVELS; ITALIAN CASE-CONTROL; UK WOMENS COHORT; LONG-TERM USE; BREAST-CANCER; PROSTATE-CANCER; SWEDISH WOMEN; OVARIAN-CANCER; LUNG-CANCER AB Cancer remains the second leading cause of death in the United States, and the number of cases is expected to continue to rise worldwide. Cancer prevention strategies are crucial for reducing the cancer burden. The carcinogenic potential of dietary acrylamide exposure from cooked foods is unknown. Acrylamide is a by-product of the common Maillard reaction where reducing sugars (i.e., fructose and glucose) react with the amino acid, asparagine. Based on the evidence of acrylamide carcinogenicity in animals, the International Agency for Research on Cancer has classified acrylamide as a group 2A carcinogen for humans. Since the discovery of acrylamide in foods in 2002, a number of studies have explored its potential as a human carcinogen. This article outlines a systematic review of dietary acrylamide and human cancer, acrylamide exposure and internal dose, exposure assessment methods in the epidemiologic studies, existing data gaps, and future directions. A majority of the studies reported no statistically significant association between dietary acrylamide intake and various cancers, and few studies reported increased risk for renal, endometrial, and ovarian cancers; however, the exposure assessment has been inadequate leading to potential misclassification or underestimation of exposure. Future studies with improved dietary acrylamide exposure assessment are encouraged. C1 [Virk-Baker, Mandeep K.] NCI, Canc Prevent Div, NIH, Rockville, MD 20892 USA. [Nagy, Tim R.] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Barnes, Stephen] Univ Alabama Birmingham, Dept Pharmacol & Toxicol, Birmingham, AL USA. [Groopman, John] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. RP Virk-Baker, MK (reprint author), NCI, Canc Prevent Div, NIH, 9609 Med Ctr Dr, Rockville, MD 20892 USA. EM mandeep.virk-baker@nih.gov FU International Life Sciences Institute (ILSI) North America Technical Committee on Food and Chemical Safety Fellowship Award; Cancer Prevention Fellowship Program at the National Cancer Institute; National Institutes of Health (NIH) [P30 DK056336, P30 DK079626]; NIH [U54 CA100949, R21 AT004661]; [R25 CA047888]; [P30 CA006973]; [P01 ES006052] FX This work was funded by the International Life Sciences Institute (ILSI) North America Technical Committee on Food and Chemical Safety Fellowship Award. ILSI North America is a public, nonprofit foundation that provides a forum to advance understanding of scientific issues related to the nutritional quality and safety of the food supply by sponsoring research programs, workshops, and publications. This work was also supported by the R25 CA047888.; M. K. Virk-Baker is supported by the Cancer Prevention Fellowship Program at the National Cancer Institute. T. R. Nagy is supported by National Institutes of Health (NIH) grant awards P30 DK056336 and P30 DK079626. S. Barnes is supported by the NIH grant awards U54 CA100949 and R21 AT004661. J. Groopman is supported by P30 CA006973 and P01 ES006052. NR 82 TC 8 Z9 8 U1 10 U2 64 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0163-5581 EI 1532-7914 J9 NUTR CANCER JI Nutr. Cancer PD JUL PY 2014 VL 66 IS 5 BP 774 EP 790 DI 10.1080/01635581.2014.916323 PG 17 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA AJ9DC UT WOS:000338006000002 PM 24875401 ER EF