FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Chaigne-Delalande, B Li, FY O'Connor, GM Lukacs, MJ Jiang, P Zheng, LX Shatzer, A Biancalana, M Pittaluga, S Matthews, HF Jancel, TJ Bleesing, JJ Marsh, RA Kuijpers, TW Nichols, KE Lucas, CL Nagpal, S Mehmet, H Su, HC Cohen, JI Uzel, G Lenardo, MJ AF Chaigne-Delalande, Benjamin Li, Feng-Yen O'Connor, Geraldine M. Lukacs, Marshall J. Jiang, Ping Zheng, Lixin Shatzer, Amber Biancalana, Matthew Pittaluga, Stefania Matthews, Helen F. Jancel, Timothy J. Bleesing, Jack J. Marsh, Rebecca A. Kuijpers, Taco W. Nichols, Kim E. Lucas, Carrie L. Nagpal, Sunil Mehmet, Huseyin Su, Helen C. Cohen, Jeffrey I. Uzel, Gulbu Lenardo, Michael J. TI Mg2+ Regulates Cytotoxic Functions of NK and CD8 T Cells in Chronic EBV Infection Through NKG2D SO SCIENCE LA English DT Article ID EPSTEIN-BARR-VIRUS; LINKED LYMPHOPROLIFERATIVE DISEASE; NATURAL-KILLER-CELLS; IMMUNE SURVEILLANCE; MAGNESIUM; MAGT1; IMMUNODEFICIENCY; ACTIVATION; TRPM7; COSTIMULATION AB The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free magnesium (Mg2+) concentrations. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. We show that decreased intracellular free Mg2+ causes defective expression of the natural killer activating receptor NKG2D in natural killer (NK) and CD8(+) T cells and impairs cytolytic responses against EBV. Notably, magnesium supplementation in MAGT1-deficient patients restores intracellular free Mg2+ and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, these findings reveal a specific molecular function of free basal intracellular Mg2+ in eukaryotic cells. C1 [Chaigne-Delalande, Benjamin; Li, Feng-Yen; Lukacs, Marshall J.; Jiang, Ping; Zheng, Lixin; Biancalana, Matthew; Matthews, Helen F.; Lucas, Carrie L.; Lenardo, Michael J.] NIAID, Mol Dev Immune Syst Sect, Lymphocyte Mol Genet Unit, Immunol Lab,NIH, Bethesda, MD 20892 USA. [Li, Feng-Yen] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94143 USA. [O'Connor, Geraldine M.; Cohen, Jeffrey I.] Frederick Natl Lab Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD 21702 USA. [Shatzer, Amber] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Pittaluga, Stefania] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Jancel, Timothy J.] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Bleesing, Jack J.; Marsh, Rebecca A.] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA. [Kuijpers, Taco W.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Nichols, Kim E.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Nagpal, Sunil; Mehmet, Huseyin] Merck Res Labs, Resp & Immunol Div, Boston, MA USA. [Su, Helen C.] NIAID, Immunol Dis Unit, Lab Host Def, NIH, Bethesda, MD 20892 USA. [Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Mol Dev Immune Syst Sect, Lymphocyte Mol Genet Unit, Immunol Lab,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lenardo@nih.gov RI Su, Helen/H-9541-2015; OI Su, Helen/0000-0002-5582-9110; Biancalana, Matthew/0000-0002-1078-1838 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Cancer Institute, NIH; Medical Scientist Training Program at the University of California-San Francisco; NIH; Pharmacology Research Associate Training (PRAT) program; National Institute of General Medical Sciences, NIH FX This research was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases and the National Cancer Institute, NIH. We thank H. Malech, A. Snow, J. Niemela, G. Fahle, and T. Dimaggio for assistance in various aspects of the research and patient evaluation and S. Holland for clinical insights and support. We also thank R. Germain, P. Schwartzberg, R. Siegel, T. Waldmann, K. Schafer-Weaver, C. Kanellopoulou, S. Muljo, D. McVicar, J. Milner, R. Baker, and S. Holland for critically reading the manuscript. We thank E. Long and S. Rajagopalan for sharing antibodies and cell lines and helpful assistance with NK experiments; we also thank K. Dowdell, R. Orentas, and B. Lafont for sharing reagents and D. Douek, D. Price, and M. Quigley for assistance with tetramer staining. We are grateful to Merck Research Laboratories for generous support in kind of reagents and materials, and to P. R. Vagelos and R. Vessey for fostering the collaboration. F.-Y.L. was supported by the Medical Scientist Training Program at the University of California-San Francisco and the NIH M.D./Ph.D. Partnership program, and thanks K. Shannon and J. Toutolmin for support and encouragement. We also acknowledge support by the Pharmacology Research Associate Training (PRAT) program (to C. L. L.), National Institute of General Medical Sciences, NIH. The data presented in this paper are tabulated in the main paper and in the supplementary materials. NR 37 TC 68 Z9 70 U1 3 U2 34 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 12 PY 2013 VL 341 IS 6142 BP 186 EP 191 DI 10.1126/science.1240094 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185KA UT WOS:000321965300046 PM 23846901 ER PT J AU Gotts, SJ Saad, ZS Jo, HJ Wallace, GL Cox, RW Martin, A AF Gotts, Stephen J. Saad, Ziad S. Jo, Hang Joon Wallace, Gregory L. Cox, Robert W. Martin, Alex TI The perils of global signal regression for group comparisons: a case study of Autism Spectrum Disorders SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE functional connectivity; typically developing; artifact; resting-state fMRI; GCOR; global correlation ID RESTING-STATE FMRI; FUNCTIONAL CONNECTIVITY MRI; BOLD SIGNAL; DIAGNOSTIC INTERVIEW; RESPONSE FUNCTION; HEAD MOTION; BRAIN; FLUCTUATIONS; NETWORKS; IMPACT AB We have previously argued from a theoretical basis that the standard practice of regression of the Global Signal from the fMRI time series in functional connectivity studies is ill advised, particularly when comparing groups of participants. Here we demonstrate in resting-state data from participants with an Autism Spectrum Disorder and matched controls that these concerns are also well founded in real data. Using the prior theoretical work to formulate predictions, we show: (1) rather than simply altering the mean or range of correlation values amongst pairs of brain regions, Global Signal Regression systematically alters the rank ordering of values in addition to introducing negative values, (2) it leads to a reversal in the direction of group correlation differences relative to other preprocessing approaches, with a higher incidence of both long-range and local correlation differences that favor the Autism Spectrum Disorder group, (3) the strongest group differences under other preprocessing approaches are the ones most altered by Global Signal Regression, and (4) locations showing group differences no longer agree with those showing correlations with behavioral symptoms within the Autism Spectrum Disorder group. The correlation matrices of both participant groups under Global Signal Regression were well predicted by our previous mathematical analyses, demonstrating that there is nothing mysterious about these results. Finally, when independent physiological nuisance measures are lacking, we provide a simple alternative approach for assessing and lessening the influence of global correlations on group comparisons that replicates our previous findings. While this alternative performs less well for symptom correlations than our favored preprocessing approach that includes removal of independent physiological measures, it is preferable to the use of Global Signal Regression, which prevents unequivocal conclusions about the direction or location of group differences. C1 [Gotts, Stephen J.; Wallace, Gregory L.; Martin, Alex] NIMH, Sect Cognit Neuropsychol, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Saad, Ziad S.; Jo, Hang Joon; Cox, Robert W.] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. RP Gotts, SJ (reprint author), NIMH, Lab Brain & Cognit, NIH, Bldg 10,Rm 4C-217, Bethesda, MD 20892 USA. EM gottss@mail.nih.gov RI JO, HANG JOON/D-1775-2011; OI JO, HANG JOON/0000-0002-9180-3831; Wallace, Gregory/0000-0003-0329-5054 FU National Institute of Mental Health, NIH, Division of Intramural Research FX The authors would like to thank Lauren Kenworthy, John Strang, and Rafael Oliveras-Rentas for guidance and aid in ASD participating testing, and Kelly Barnes and Dale Stevens for useful discussions. This study was supported by the National Institute of Mental Health, NIH, Division of Intramural Research, and it was conducted under NIH Clinical Study Protocol 10-M-0027 (ClinicalTrials.gov ID: NCT01031407). NR 68 TC 68 Z9 68 U1 4 U2 19 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD JUL 12 PY 2013 VL 7 AR 356 DI 10.3389/fnhum.2013.00356 PG 20 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 181UH UT WOS:000321693700001 PM 23874279 ER PT J AU Kim, J Kim, SK Kim, HK Mattson, MP Hyun, DH AF Kim, Jiyeong Kim, Su-Kyung Kim, Hwa-Kyung Mattson, Mark P. Hyun, Dong-Hoon TI Mitochondrial Function in Human Neuroblastoma Cells Is Up-Regulated and Protected by NQO1, a Plasma Membrane Redox Enzyme SO PLOS ONE LA English DT Article ID OXYGEN SPECIES GENERATION; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; ELECTRON-TRANSPORT; HYDROGEN-PEROXIDE; COENZYME-Q; PARKINSONS-DISEASE; CEREBRAL-ISCHEMIA; POTENT INDUCTION; PHASE-2 ENZYMES AB Background: Recent findings suggest that NADH-dependent enzymes of the plasma membrane redox system (PMRS) play roles in the maintenance of cell bioenergetics and oxidative state. Neurons and tumor cells exhibit differential vulnerability to oxidative and metabolic stress, with important implications for the development of therapeutic interventions that promote either cell survival (neurons) or death (cancer cells). Methods and Findings: Here we used human neuroblastoma cells with low or high levels of the PMRS enzyme NADH-quinone oxidoreductase 1 (NQO1) to investigate how the PMRS modulates mitochondrial functions and cell survival. Cells with elevated NQO1 levels exhibited higher levels of oxygen consumption and ATP production, and lower production of reactive oxygen species. Cells overexpressing NQO1 were more resistant to being damaged by the mitochondrial toxins rotenone and antimycin A, and exhibited less oxidative/nitrative damage and less apoptotic cell death. Cells with basal levels of NQO1 resulted in increased oxidative damage to proteins and cellular vulnerability to mitochondrial toxins. Thus, mitochondrial functions are enhanced and oxidative stress is reduced as a result of elevated PMRS activity, enabling cells to maintain redox homeostasis under conditions of metabolic and energetic stress. Conclusion: These findings suggest that NQO1 is a potential target for the development of therapeutic agents for either preventing neuronal degeneration or promoting the death of neural tumor cells. C1 [Kim, Jiyeong; Kim, Su-Kyung; Kim, Hwa-Kyung; Hyun, Dong-Hoon] Ewha Womans Univ, Coll Nat Sci, Dept Life Sci, Seoul, South Korea. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Hyun, DH (reprint author), Ewha Womans Univ, Coll Nat Sci, Dept Life Sci, Seoul, South Korea. EM hyundh@ewha.ac.kr FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology, South Korea [NRF-2010-003064]; Intramural Research Program of the National Institute on Aging FX This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2010-003064), South Korea. This work was also funded, in part, by the Intramural Research Program of the National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 3 Z9 3 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 11 PY 2013 VL 8 IS 7 AR e69030 DI 10.1371/journal.pone.0069030 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 188UA UT WOS:000322218800060 PM 23874855 ER PT J AU Laeyendecker, O Piwowar-Manning, E Fiamma, A Kulich, M Donnell, D Bassuk, D Mullis, CE Chin, C Swanson, P Hackett, J Clarke, W Marzinke, M Szekeres, G Gray, G Richter, L Alexandre, MW Chariyalertsak, S Chingono, A Celentano, DD Morin, SF Sweat, M Coates, T Eshleman, SH AF Laeyendecker, Oliver Piwowar-Manning, Estelle Fiamma, Agnes Kulich, Michal Donnell, Deborah Bassuk, Deb Mullis, Caroline E. Chin, Craig Swanson, Priscilla Hackett, John, Jr. Clarke, William Marzinke, Mark Szekeres, Greg Gray, Glenda Richter, Linda Alexandre, Michel W. Chariyalertsak, Suwat Chingono, Alfred Celentano, David D. Morin, Stephen F. Sweat, Michael Coates, Thomas Eshleman, Susan H. TI Estimation of HIV Incidence in a Large, Community-Based, Randomized Clinical Trial: NIMH Project Accept (HIV Prevention Trials Network 043) SO PLOS ONE LA English DT Article ID SUB-SAHARAN AFRICA; UNITED-STATES; THAILAND; INTERVENTION; RISK AB Background: National Institute of Mental Health Project Accept (HIV Prevention Trials Network [HPTN] 043) is a large, Phase III, community-randomized, HIV prevention trial conducted in 48 matched communities in Africa and Thailand. The study intervention included enhanced community-based voluntary counseling and testing. The primary endpoint was HIV incidence, assessed in a single, cross-sectional, post-intervention survey of >50,000 participants. Methods: HIV rapid tests were performed in-country. HIV status was confirmed at a central laboratory in the United States. HIV incidence was estimated using a multi-assay algorithm (MAA) that included the BED capture immunoassay, an avidity assay, CD4 cell count, and HIV viral load. Results: Data from Thailand was not used in the endpoint analysis because HIV prevalence was low. Overall, 7,361 HIV infections were identified (4 acute, 3 early, and 7,354 established infections). Samples from established infections were analyzed using the MAA; 467 MAA positive samples were identified; 29 of those samples were excluded because they contained antiretroviral drugs. HIV prevalence was 16.5% (range at study sites: 5.93% to 30.8%). HIV incidence was 1.60% (range at study sites: 0.78% to 3.90%). Conclusions: In this community-randomized trial, a MAA was used to estimate HIV incidence in a single, cross-sectional post-intervention survey. Results from this analysis were subsequently used to compare HIV incidence in the control and intervention communities. C1 [Laeyendecker, Oliver] NIAID, Immunoregulat Lab, NIH, Baltimore, MD USA. [Laeyendecker, Oliver; Mullis, Caroline E.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Piwowar-Manning, Estelle; Clarke, William; Marzinke, Mark; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Fiamma, Agnes; Coates, Thomas] Univ Calif Los Angeles, Program Global Hlth, Los Angeles, CA USA. [Kulich, Michal] Charles Univ Prague, Fac Math & Phys, Dept Probabil & Stat, Prague, Czech Republic. [Donnell, Deborah; Bassuk, Deb; Chin, Craig] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Donnell, Deborah] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Swanson, Priscilla; Hackett, John, Jr.] Abbott Diagnost, Infect Dis Res, Abbott Pk, IL USA. [Gray, Glenda] Univ Witwatersrand, Chris Hani Baragwanath Hosp, Perinatal HIV Res Unit, Johannesburg, South Africa. [Richter, Linda] Human Sci Res Council, Durban, South Africa. [Alexandre, Michel W.] Muhimbili Univ Hlth & Allied Sci, Dept Microbiol & Immunol, Dar Es Salaam, Tanzania. [Chariyalertsak, Suwat] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai 50000, Thailand. [Chingono, Alfred] Univ Zimbabwe, Sch Med, Dept Psychiat, Harare, Zimbabwe. [Celentano, David D.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Morin, Stephen F.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Sweat, Michael] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. RP Eshleman, SH (reprint author), NIAID, Immunoregulat Lab, NIH, Baltimore, MD USA. EM seshlem@jhmi.edu RI Kulich, Michal/B-1483-2013; OI Kulich, Michal/0000-0002-2812-8968; Laeyendecker, Oliver/0000-0002-6429-4760; Donnell, Deborah/0000-0002-0587-7480 FU U.S. National Institute of Mental Health (NIMH) as a cooperative agreement [U01MH066687]; Johns Hopkins University [U01-MH066688]; Medical University of South Carolina [U01-MH066701]; University of California, San Francisco - SFM, PI [U01-MH066702]; HPTN Protocol [U01-AI068613/UM1-AI068613, U01-AI068617/UM1-AI068617, U01-AI068619/UM1-AI068619]; Division of AIDS of the U.S. National Institute of Allergy and Infectious Diseases (NIAID); Office of AIDS Research of the U.S. National Institutes of Health (NIH); Division of Intramural Research, NIAID, NIH [R01-AI095068] FX This research was sponsored by the U.S. National Institute of Mental Health (NIMH) as a cooperative agreement, through contracts U01MH066687 (Johns Hopkins University - DC, PI); U01-MH066688 (Medical University of South Carolina - MS, PI); U01-MH066701 (University of California, Los Angeles - TC, PI); and U01-MH066702 (University of California, San Francisco - SFM, PI). In addition, this work was supported as HPTN Protocol 043 through contracts U01-AI068613/UM1-AI068613 (HPTN Network Laboratory - SHE, PI); U01-AI068617/UM1-AI068617 (SCHARP - DD, PI); and U01-AI068619/UM1-AI068619 (HPTN - Sten Vermund/Wafaa El-Sadr, PIs) of the Division of AIDS of the U.S. National Institute of Allergy and Infectious Diseases (NIAID); and by the Office of AIDS Research of the U.S. National Institutes of Health (NIH). Additional support was provided through R01-AI095068 (SHE/Ron Brookmeyer - PIs), and by the Division of Intramural Research, NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 15 Z9 15 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 11 PY 2013 VL 8 IS 7 AR e68349 DI 10.1371/journal.pone.0068349 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 188UA UT WOS:000322218800027 PM 23874597 ER PT J AU Hu, X Compton, JR AbdulHameed, MDM Marchand, CL Robertson, KL Leary, DH Jadhav, A Hershfield, JR Wallqvist, A Friedlander, AM Legler, PM AF Hu, Xin Compton, Jaimee R. AbdulHameed, Mohamed Diwan M. Marchand, Charles L. Robertson, Kelly L. Leary, Dagmar H. Jadhav, Ajit Hershfield, Jeremy R. Wallqvist, Anders Friedlander, Arthur M. Legler, Patricia M. TI 3-Substituted lndole Inhibitors Against Francisella tularensis Fabl Identified by Structure-Based Virtual Screening SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CARRIER PROTEIN REDUCTASE; ENOYL-ACP REDUCTASE; RESISTANCE-DETERMINING REGION; IN-VITRO ACTIVITY; ESCHERICHIA-COLI; STREPTOCOCCUS-PNEUMONIAE; STAPHYLOCOCCUS-AUREUS; YERSINIA-PESTIS; MYCOBACTERIUM-TUBERCULOSIS; ANTIBACTERIAL AGENTS AB In this study, we describe novel inhibitors against Francisella tularensis SchuS4 FabI identified from structure-based in silico screening with integrated molecular dynamics simulations to account for induced fit of a flexible loop crucial for inhibitor binding. Two 3-substituted indoles, 54 and 57, preferentially bound the NAD(+) form of the enzyme and inhibited growth of F. tularensis SchuS4 at concentrations near that of their measured K-i. While 57 was species-specific, 54 showed a broader spectrum of growth inhibition against F. tularensis, Bacillus anthracis, and Staphylococcus aureus. Binding interaction analysis in conjunction with site-directed mutagenesis revealed key residues and elements that contribute to inhibitor binding and species specificity. Mutation of Arg-96, a poorly conserved residue opposite the loop, was unexpectedly found to enhance inhibitor binding in the R96G and R96M variants. This residue may affect the stability and closure of the flexible loop to enhance inhibitor (or substrate) binding. C1 [Compton, Jaimee R.; Robertson, Kelly L.; Leary, Dagmar H.; Legler, Patricia M.] USN, Ctr Biomol Sci & Engn, Res Labs, Washington, DC 20375 USA. [Compton, Jaimee R.] Nova Res Inc, Alexandria, VA 22308 USA. [Hu, Xin; Jadhav, Ajit] Natl Ctr Adv Translat Sci, NIH Chem Genom Ctr, Rockville, MD 20850 USA. [Marchand, Charles L.; Hershfield, Jeremy R.; Friedlander, Arthur M.] USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [AbdulHameed, Mohamed Diwan M.; Wallqvist, Anders] USA, Biotechnol HPC Software Applicat Inst, Telemed & Adv Technol Res Ctr, Med Res & Mat Command, Ft Detrick, MD 21702 USA. RP Legler, PM (reprint author), USN, Ctr Biomol Sci & Engn, Res Labs, Washington, DC 20375 USA. EM patricia.legler@nrl.navy.mil RI AbdulHameed, Mohamed Diwan M/O-3088-2015 OI AbdulHameed, Mohamed Diwan M/0000-0003-1483-4084 FU U.S. Defense Threat Reduction Agency [TMTI0004_09_BH_T, CBM.THERB.02.11.RD.012] FX We would like to acknowledge Greg Tawa for helpful discussions and Peter J. Tonge for supplying the initial plasmid DNA construct. We would also like to acknowledge Lynda Miller and Stephanie Halasohoris for excellent technical help. This work was funded by the U.S. Defense Threat Reduction Agency awards TMTI0004_09_BH_T and CBM.THERB.02.11.RD.012. The opinions or assertions contained herein belong to the authors and are not necessarily the official views of the U.S. Army, U.S. Navy or the U.S. Department of Defense. NR 74 TC 9 Z9 9 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 11 PY 2013 VL 56 IS 13 BP 5275 EP 5287 DI 10.1021/jm4001242 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 184IV UT WOS:000321884200005 PM 23815100 ER PT J AU Masaoka, T Chung, S Caboni, P Rausch, JW Wilson, JA Taskent-Sezgin, H Beutler, JA Tocco, G Le Grice, SFJ AF Masaoka, Takashi Chung, Suhman Caboni, Pierluigi Rausch, Jason W. Wilson, Jennifer A. Taskent-Sezgin, Humeyra Beutler, John A. Tocco, Graziella Le Grice, Stuart F. J. TI Exploiting Drug-Resistant Enzymes as Tools To Identify Thienopyrimidinone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROMOTE PROTEIN STABILITY; INTEGRASE INHIBITORS; STRUCTURAL BASIS; AIDS; DIMERIZATION; MECHANISM; DISCOVERY; TARGET; ASSAY AB The thienopyrimidinone 5,6-dimethyl-2-(4-nitrophenyl)thieno[2,3-d]pyrimidin-4(3H)-one (DNTP) occupies the interface between the 066 ribonuclease H (RNase H) domain and p51 thumb of human immunodeficiency virus reverse transcriptase (HIV RT), thereby inducing a conformational change incompatible with catalysis. Here, we combined biochemical characterization of 39 DNTP derivatives with antiviral testing of selected compounds. In addition to wild-type HIV-1 RT, derivatives were evaluated with rationally designed, p66/p51 heterodimers exhibiting high-level DNTP sensitivity or resistance. This strategy identified 3',4'-dihydroxyphenyl (catechol) substituted, thienopyrimidinones with submicromolar in vitro activity against both wild type HIV-1 RT and drug-resistant variants. Thermal shift analysis indicates that, in contrast to active site RNase H inhibitors, thienopyrimidinones destabilize the enzyme, in some instances reducing the T-m by 5 degrees C. Importantly, catechol-containing thienopyrimidinones also inhibit HIV-1 replication in cells. Our data strengthen the case for allosteric inhibition of HIV RNase H activity, providing a platform for designing improved antagonists for use in combination antiviral therapy. C1 [Masaoka, Takashi; Chung, Suhman; Rausch, Jason W.; Taskent-Sezgin, Humeyra; Le Grice, Stuart F. J.] NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Caboni, Pierluigi; Tocco, Graziella] Univ Cagliari, Dept Life & Environm Sci, Unit Drug Sci, I-09124 Cagliari, Italy. [Wilson, Jennifer A.; Beutler, John A.] NCI, Mol Targets Lab, Frederick, MD 21702 USA. RP Le Grice, SFJ (reprint author), NCI, RT Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM legrices@mail.nih.gov FU National Cancer Institute, National Institutes of Health; Ministero dell'Universita, dell'Istruzione e della Ricerca MIUR; Fondazione Banco di Sardegna FX We thank Dr. Wei Yang, NIH, for communication of crystallographic data on HIV-1 RT containing compound 9 prior to publication. T.M., S.C., J.A.W., H.T.-S., J.W.R., J.A.B. and S.F.J.L.G. were supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. G.T. was supported by Ministero dell'Universita, dell'Istruzione e della Ricerca MIUR- PRIN 2008 and Fondazione Banco di Sardegna. NR 29 TC 15 Z9 16 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 11 PY 2013 VL 56 IS 13 BP 5436 EP 5445 DI 10.1021/jm400405z PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 184IV UT WOS:000321884200016 PM 23631411 ER PT J AU Wu, SP Costello, R Hofmann, JN Korde, N Mailankody, S Purdue, M Landgren, O AF Wu, S. Peter Costello, Rene Hofmann, Jonathan N. Korde, Neha Mailankody, Sham Purdue, Mark Landgren, Ola TI MGUS prevalence in a cohort of AML patients SO BLOOD LA English DT Letter ID ACUTE MYELOID-LEUKEMIA; MULTIPLE-MYELOMA; LIGHT-CHAINS; MELPHALAN; RISK C1 [Wu, S. Peter; Costello, Rene; Korde, Neha; Mailankody, Sham; Landgren, Ola] NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Hofmann, Jonathan N.; Purdue, Mark] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Wu, SP (reprint author), NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NR 14 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 11 PY 2013 VL 122 IS 2 BP 294 EP 295 DI 10.1182/blood-2013-04-497859 PG 8 WC Hematology SC Hematology GA 184QY UT WOS:000321909600020 PM 23847188 ER PT J AU Carss, KJ Stevens, E Foley, AR Cirak, S Riemersma, M Torelli, S Hoischen, A Willer, T van Scherpenzeel, M Moore, SA Messina, S Bertini, E Bonnemann, CG Abdenur, JE Grosmann, CM Kesari, A Punetha, J Quinlivan, R Waddell, LB Young, HK Wraige, E Yau, S Brodd, L Feng, L Sewry, C MacArthur, DG North, KN Hoffinan, E Stemple, DL Hurles, ME van Bokhoven, H Campbell, KP Lefeber, DJ Lin, YY Muntoni, F AF Carss, Keren J. Stevens, Elizabeth Foley, A. Reghan Cirak, Sebahattin Riemersma, Moniek Torelli, Silvia Hoischen, Alexander Willer, Tobias van Scherpenzeel, Monique Moore, Steven A. Messina, Sonia Bertini, Enrico Boennemann, Carsten G. Abdenur, Jose E. Grosmann, Carla M. Kesari, Akanchha Punetha, Jaya Quinlivan, Ros Waddell, Leigh B. Young, Helen K. Wraige, Elizabeth Yau, Shu Brodd, Lina Feng, Lucy Sewry, Caroline MacArthur, Daniel G. North, Kathryn N. Hoffinan, Eric Stemple, Derek L. Hurles, Matthew E. van Bokhoven, Hans Campbell, Kevin P. Lefeber, Dirk J. Lin, Yung-Yao Muntoni, Francesco CA UK10K consortium TI Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of alpha-Dystroglycan SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID WALKER-WARBURG-SYNDROME; CELL-WALL INTEGRITY; O-GLYCAN STRUCTURES; DEFECTIVE GLYCOSYLATION; ABNORMAL GLYCOSYLATION; GLYCOPROTEIN COMPLEX; SKELETAL-MUSCLE; GENE; ZEBRAFISH; LAMININ AB Congenital muscular dystrophies with hypoglycosylation of alpha-dystroglycan (alpha-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of alpha-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated alpha-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-l-phosphate. GDP-mannose is required for O-mannosylation of proteins, including alpha-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced alpha-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of alpha-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of alpha-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of alpha-DG. C1 [Carss, Keren J.; Stemple, Derek L.; Hurles, Matthew E.; Lin, Yung-Yao] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. [Stevens, Elizabeth; Foley, A. Reghan; Cirak, Sebahattin; Torelli, Silvia; Quinlivan, Ros; Feng, Lucy; Sewry, Caroline; Muntoni, Francesco] UCL Inst Child Hlth, Dubowitz Neuromuscular Ctr, London WC1N 1EH, England. [Cirak, Sebahattin; Kesari, Akanchha; Punetha, Jaya; Hoffinan, Eric] Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA. [Riemersma, Moniek; Lefeber, Dirk J.] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, Dept Neurol, NL-6525 HB Nijmegen, Netherlands. [Riemersma, Moniek; van Scherpenzeel, Monique; Lefeber, Dirk J.] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, Dept Lab Med, NL-6525 HB Nijmegen, Netherlands. [Riemersma, Moniek; Hoischen, Alexander] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, Dept Human Genet,Nijmegen Ctr Mol Life Sci, NL-6500 HB Nijmegen, Netherlands. [Willer, Tobias; Campbell, Kevin P.] Univ Iowa, Carver Coll Med, Howard Hughes Med Inst, Iowa City, IA 52242 USA. [Willer, Tobias; Campbell, Kevin P.] Univ Iowa, Carver Coll Med, Dept Neurol, Iowa City, IA 52242 USA. [Willer, Tobias; Campbell, Kevin P.] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [Willer, Tobias; Campbell, Kevin P.] Univ Iowa, Carver Coll Med, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA. [Moore, Steven A.] Univ Iowa, Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA. [Messina, Sonia] Univ Messina, Azienda Osped Univ Policlin G Martino, Dept Neurosci, I-98125 Messina, Italy. [Bertini, Enrico] Bambino Gesu Childrens Res Hosp, Mol Med Lab, I-00146 Rome, Italy. [Boennemann, Carsten G.] NINDS, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Abdenur, Jose E.] Childrens Hosp Orange Cty, Div Metab Disorders, Orange, CA 92868 USA. [Abdenur, Jose E.] Univ Calif Irvine, Sch Med, Dept Pediat, Irvine, CA 92697 USA. [Grosmann, Carla M.] Univ Calif San Diego, Rady Childrens Hosp, Sch Med, Dept Neurosci, San Diego, CA 92123 USA. [Grosmann, Carla M.] Univ Calif San Diego, Rady Childrens Hosp, Sch Med, Dept Pediat, San Diego, CA 92123 USA. [Punetha, Jaya; Hoffinan, Eric] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20037 USA. [Quinlivan, Ros] Natl Hosp Neurol & Neurosurg, MRC Ctr Neuromuscular Dis, London WC1N 3BG, England. [Waddell, Leigh B.; North, Kathryn N.] Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW 2145, Australia. [Young, Helen K.] Childrens Hosp Westmead, Dept Neurogenet, Sydney, NSW 2145, Australia. [Young, Helen K.] Univ Sydney, Royal N Shore Hosp, Northern Clin Sch, St Leonards, NSW 2065, Australia. [Wraige, Elizabeth] Guys & St Thomas NHS Fdn Trust, Evelina Childrens Hosp, Dept Paediat Neurol, London SE1 7EH, England. [Yau, Shu; Brodd, Lina] GSTS Pathol, DNA Lab, London SE1 9RT, England. [Sewry, Caroline] Robert Jones & Agnes Hunt Orthopaed Hosp NHS Fdn, Wolfson Ctr Inherited Neuromuscular Dis, Oswestry SY10 7AG, Shrops, England. [MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [MacArthur, Daniel G.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [North, Kathryn N.] Univ Sydney, Sydney Med Sch, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. [North, Kathryn N.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [van Bokhoven, Hans] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands. [van Bokhoven, Hans] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, NL-6500 HB Nijmegen, Netherlands. [Lin, Yung-Yao] Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England. RP Muntoni, F (reprint author), UCL Inst Child Hlth, Dubowitz Neuromuscular Ctr, London WC1N 1EH, England. EM f.muntoni@ucl.ac.uk RI Moayyeri, Alireza/N-3332-2014; Lefeber, Dirk/A-2146-2014; Bolton, Patrick/E-8501-2010; Hoischen, Alexander/D-1282-2013; Bokhoven, J.H.L.M./H-8015-2014; Schmidts, Miriam/A-3777-2012; van Scherpenzeel, Monique/N-7008-2015; North, Kathryn/K-6476-2012; McQuillin, Andrew/C-1623-2008; Scambler, Peter/C-4998-2008 OI Messina, Sonia/0000-0001-7994-3391; Suvisaari, Jaana/0000-0001-7167-0990; Moayyeri, Alireza/0000-0002-9143-2161; Bolton, Patrick/0000-0002-5270-6262; Hoischen, Alexander/0000-0002-8072-4476; Ritchie, Graham/0000-0002-6456-9736; Punetha, Jaya/0000-0002-6774-4464; Schmidts, Miriam/0000-0002-1714-6749; van Scherpenzeel, Monique/0000-0002-9696-4562; North, Kathryn/0000-0003-0841-8009; McQuillin, Andrew/0000-0003-1567-2240; Scambler, Peter/0000-0002-1487-4628 FU Wellcome Trust [WT091310] FX This study makes use of data generated by the UK10K Consortium. A full list of the investigators who contributed to the generation of the data is available at http://www.uk10k.org/publications_and_posters.html. Funding for UK10K was provided by the Wellcome Trust under award WT091310. We are grateful to the UK10K consortium for making this study possible. Acknowledgments are continued in the Supplemental Data. NR 63 TC 60 Z9 62 U1 1 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 11 PY 2013 VL 93 IS 1 BP 29 EP 41 DI 10.1016/j.ajhg.2013.05.009 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 183HG UT WOS:000321804500003 PM 23768512 ER PT J AU Ko, WY Rajan, P Gomez, F Scheinfeldt, L An, P Winkler, CA Froment, A Nyambo, TB Omar, SA Wambebe, C Ranciaro, A Hirbo, JB Tishkoff, SA AF Ko, Wen-Ya Rajan, Prianka Gomez, Felicia Scheinfeldt, Laura An, Ping Winkler, Cheryl A. Froment, Alain Nyambo, Thomas B. Omar, Sabah A. Wambebe, Charles Ranciaro, Alessia Hirbo, Jibril B. Tishkoff, Sarah A. TI Identifying Darwinian Selection Acting on Different Human APOL1 Variants among Diverse African Populations SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HIV-ASSOCIATED NEPHROPATHY; CHRONIC KIDNEY-DISEASE; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; STAGE RENAL-DISEASE; HAPLOTYPE RECONSTRUCTION; GENOMEWIDE ASSOCIATION; TRYPANOLYTIC FACTOR; POSITIVE SELECTION; UNITED-STATES; GENOTYPE DATA AB Disease susceptibility can arise as a consequence of adaptation to infectious disease. Recent findings have suggested that higher rates of chronic kidney disease (CKD) in individuals with recent African ancestry might be attributed to two risk alleles (G1 and G2) at the serum-resistance-associated (SRA)-interacting-domain-encoding region of APOL1. These two alleles appear to have arisen adaptively, possibly as a result of their protective effects against human African trypanosomiasis (HAT), or African sleeping sickness. In order to explore the distribution of potential functional variation at APOL1, we studied nucleotide variation in 187 individuals across ten geographically and genetically diverse African ethnic groups with exposure to two Trypanosoma brucei subspecies that cause HAT. We observed unusually high levels of nonsynonymous polymorphism in the regions encoding the functional domains that are required for lysing parasites. Whereas allele frequencies of G2 were similar across all populations (3%-8%), the G1 allele was only common in the Yoruba (39%). Additionally, we identified a haplo type (termed G3) that contains a nonsynonymous change at the membrane-addressing-domain-encoding region of APOL1 and is present in all populations except for the Yoruba. Analyses of long-range patterns of linkage disequilibrium indicate evidence of recent selection acting on the G3 haplotype in Fulani from Cameroon. Our results indicate that the G1 and G2 variants in APOL1 are geographically restricted and that there might be other functional variants that could play a role in HAT resistance and CKD risk in African populations. C1 [Ko, Wen-Ya; Rajan, Prianka; Gomez, Felicia; Scheinfeldt, Laura; Ranciaro, Alessia; Hirbo, Jibril B.; Tishkoff, Sarah A.] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Ko, Wen-Ya] Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal. [Gomez, Felicia] George Washington Univ, Dept Anthropol, Ctr Adv Study Hominid Paleobiol, Washington, DC 20052 USA. [An, Ping; Winkler, Cheryl A.] NCI, Basic Res Lab, Ctr Canc Res, Frederick Natl Lab,Sci Applicat Int Corp, Frederick, MD 21702 USA. [Froment, Alain] Musee Homme Paris, Unite Mixte Rech 208, Inst Rech Dev, Museum Natl Hist Nat, F-75116 Paris, France. [Nyambo, Thomas B.] Muhimbili Univ Hlth & Allied Sci, Dept Biochem, Dar Es Salaam, Tanzania. [Omar, Sabah A.] Kenya Govt Med Res Ctr, Ctr Biotechnol Res & Dev, Nairobi 5484000200, Kenya. [Wambebe, Charles] Int Biomed Res Africa, Kampala, Uganda. [Tishkoff, Sarah A.] Univ Penn, Sch Arts & Sci, Dept Biol, Philadelphia, PA 19104 USA. RP Tishkoff, SA (reprint author), Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. EM tishkoff@mail.med.upenn.edu FU National Science Foundation [BCS-0196183, BCS-0827436]; National Institutes of Health (NIH) [5-R01-GM076637-05, 8DP1ES022577-04]; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research FX We thank Joseph Lachance and two anonymous reviewers for their valuable comments on the manuscript. We are grateful to Char la Lambert for her assistance with the analyses of extended haplotype homozygosity and integrated haplotype scores. We thank Bill Beggs for his technical assistance. This research was funded by National Science Foundation grants BCS-0196183 and BCS-0827436 and National Institutes of Health (NIH) grants 5-R01-GM076637-05 and 8DP1ES022577-04 to S.A.T. This project was funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. This research was supported (in part) by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. NR 60 TC 32 Z9 33 U1 3 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 11 PY 2013 VL 93 IS 1 BP 54 EP 66 DI 10.1016/j.ajhg.2013.05.014 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 183HG UT WOS:000321804500005 PM 23768513 ER PT J AU Ko, WY Rajan, P Gomez, F Scheinfeldt, L An, P Winkler, CA Froment, A Nyambo, TB Omar, SA Wambebe, C Ranciaro, A Hirbo, JB Tishkoff, SA AF Ko, Wen-Ya Rajan, Prianka Gomez, Felicia Scheinfeldt, Laura An, Ping Winkler, Cheryl A. Froment, Alain Nyambo, Thomas B. Omar, Sabah A. Wambebe, Charles Ranciaro, Alessia Hirbo, Jibril B. Tishkoff, Sarah A. TI Identifying Darwinian Selection Acting on Different Human APOL1 Variants among Diverse African Populations (vol 93, pg 54, 2013) SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Correction C1 [An, Ping; Winkler, Cheryl A.] NCI, Basic Res Lab, Ctr Canc Res, Frederick Natl Lab,Sci Applicat Int Corp Frederic, Frederick, MD 21702 USA. NR 1 TC 0 Z9 0 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 11 PY 2013 VL 93 IS 1 BP 191 EP 191 DI 10.1016/j.ajhg.2013.06.021 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 183HG UT WOS:000321804500020 ER PT J AU Gutierrez, E Shin, BS Woolstenhulme, CJ Kim, JR Saini, P Buskirk, AR Dever, TE AF Gutierrez, Erik Shin, Byung-Sik Woolstenhulme, Christopher J. Kim, Joo-Ran Saini, Preeti Buskirk, Allen R. Dever, Thomas E. TI elF5A Promotes Translation of Polyproline Motifs SO MOLECULAR CELL LA English DT Article ID ELONGATION-FACTOR-P; PEPTIDE-BOND FORMATION; SYNTHESIS INITIATION-FACTORS; PROTEIN-SYNTHESIS; TRANSFER-RNA; EF-P; SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURE; MESSENGER-RNA; 70S RIBOSOME AB Translation factor elF5A, containing the unique amino acid hypusine, was originally shown to stimulate Met-puromycin synthesis, a model assay for peptide bond formation. More recently, elF5A was shown to promote translation elongation; however, its precise requirement in protein synthesis remains elusive. We use in vivo assays in yeast and in vitro reconstituted translation assays to reveal a specific requirement for elF5A to promote peptide bond formation between consecutive Pro residues. Addition of elF5A relieves ribosomal stalling during translation of three consecutive Pro residues in vitro, and loss of elF5A function impairs translation of polyproline-containing proteins in vivo. Hydroxyl radical probing experiments localized elF5A near the E site of the ribosome with its hypusine residue adjacent to the acceptor stem of the P site tRNA. Thus, elF5A, like its bacterial ortholog EFP, is proposed to stimulate the peptidyl transferase activity of the ribosome and facilitate the reactivity of poor substrates like Pro. C1 [Gutierrez, Erik; Shin, Byung-Sik; Kim, Joo-Ran; Saini, Preeti; Dever, Thomas E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Gutierrez, Erik] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Woolstenhulme, Christopher J.; Buskirk, Allen R.] Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA. RP Dever, TE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM tdever@nih.gov FU Intramural Research Program of the NIH; NICHD; NIH [GM77633] FX We thank Beth Grayhack for dual-luciferase constructs; Daniel Wilson for discussing results prior to publication; Peter Backlund for mass spectrometry services; and Rachel Green, Hani Zaher, Dan Eyler, Julie Brunelle, Alan Hinnebusch, Jon Lorsch, and members of the Dever, Buskirk, Hinnebusch, Lorsch, and Green labs for helpful discussions. This work was supported in part by the Intramural Research Program of the NIH, NICHD, and NIH Grant GM77633 (A.B.). NR 51 TC 102 Z9 103 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL 11 PY 2013 VL 51 IS 1 BP 35 EP 45 DI 10.1016/j.molcel.2013.04.021 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 183DL UT WOS:000321794100005 PM 23727016 ER PT J AU Ray, D Kazan, H Cook, KB Weirauch, MT Najafabadi, HS Li, X Gueroussov, S Albu, M Zheng, H Yang, A Na, H Irimia, M Matzat, LH Dale, RK Smith, SA Yarosh, CA Kelly, SM Nabet, B Mecenas, D Li, WM Laishram, RS Qiao, M Lipshitz, HD Piano, F Corbett, AH Carstens, RP Frey, BJ Anderson, RA Lynch, KW Penalva, LOF Lei, EP Fraser, AG Blencowe, BJ Morris, QD Hughes, TR AF Ray, Debashish Kazan, Hilal Cook, Kate B. Weirauch, Matthew T. Najafabadi, Hamed S. Li, Xiao Gueroussov, Serge Albu, Mihai Zheng, Hong Yang, Ally Na, Hong Irimia, Manuel Matzat, Leah H. Dale, Ryan K. Smith, Sarah A. Yarosh, Christopher A. Kelly, Seth M. Nabet, Behnam Mecenas, Desirea Li, Weimin Laishram, Rakesh S. Qiao, Mei Lipshitz, Howard D. Piano, Fabio Corbett, Anita H. Carstens, Russ P. Frey, Brendan J. Anderson, Richard A. Lynch, Kristen W. Penalva, Luiz O. F. Lei, Elissa P. Fraser, Andrew G. Blencowe, Benjamin J. Morris, Quaid D. Hughes, Timothy R. TI A compendium of RNA-binding motifs for decoding gene regulation SO NATURE LA English DT Article ID PRE-MESSENGER-RNA; GENOME-WIDE ANALYSIS; TRANSCRIPTION FACTORS; SPLICING REGULATOR; PROTEINS; SPECIFICITIES; RECOGNITION; REVEALS; FAMILY; CODE AB RNA-binding proteins are key regulators of gene expression, yet only a small fraction have been functionally characterized. Here we report a systematic analysis of the RNA motifs recognized by RNA-binding proteins, encompassing 205 distinct genes from 24 diverse eukaryotes. The sequence specificities of RNA-binding proteins display deep evolutionary conservation, and the recognition preferences for a large fraction of metazoan RNA-binding proteins can thus be inferred from their RNA-binding domain sequence. The motifs that we identify in vitro correlate well with in vivo RNA-binding data. Moreover, we can associate them with distinct functional roles in diverse types of post-transcriptional regulation, enabling new insights into the functions of RNA-binding proteins both in normal physiology and in human disease. These data provide an unprecedented overview of RNA-binding proteins and their targets, and constitute an invaluable resource for determining post-transcriptional regulatory mechanisms in eukaryotes. C1 [Ray, Debashish; Weirauch, Matthew T.; Najafabadi, Hamed S.; Albu, Mihai; Zheng, Hong; Yang, Ally; Na, Hong; Irimia, Manuel; Fraser, Andrew G.; Blencowe, Benjamin J.; Morris, Quaid D.; Hughes, Timothy R.] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Kazan, Hilal; Morris, Quaid D.] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 2E4, Canada. [Cook, Kate B.; Li, Xiao; Gueroussov, Serge; Lipshitz, Howard D.; Fraser, Andrew G.; Blencowe, Benjamin J.; Morris, Quaid D.; Hughes, Timothy R.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Najafabadi, Hamed S.; Frey, Brendan J.; Morris, Quaid D.] Univ Toronto, Dept Elect & Comp Engn, Toronto, ON M5S 3G4, Canada. [Matzat, Leah H.; Dale, Ryan K.; Lei, Elissa P.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Smith, Sarah A.; Yarosh, Christopher A.; Nabet, Behnam; Carstens, Russ P.; Lynch, Kristen W.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Kelly, Seth M.; Corbett, Anita H.] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. [Mecenas, Desirea; Piano, Fabio] NYU, Dept Biol, New York, NY 10003 USA. [Mecenas, Desirea; Piano, Fabio] NYU, Ctr Genom & Syst Biol, New York, NY 10003 USA. [Li, Weimin; Laishram, Rakesh S.; Anderson, Richard A.] Univ Wisconsin, Sch Med & Publ Hlth, Mol & Cellular Pharmacol Program, Madison, WI 53706 USA. [Qiao, Mei; Penalva, Luiz O. F.] UTHSCSA, Childrens Canc Res Inst, San Antonio, TX 78229 USA. RP Hughes, TR (reprint author), Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. EM quaid.morris@utoronto.ca; t.hughes@utoronto.ca RI Kazan, Hilal/B-2247-2014; Irimia, Manuel/E-3040-2010; OI Laishram, Rakesh/0000-0003-4124-0468; Dale, Ryan/0000-0003-2664-3744; Irimia, Manuel/0000-0002-2179-2567; Fraser, Andrew/0000-0001-9939-6014; Anderson, Richard/0000-0001-6265-8359 FU NIH [1R01HG00570, R01GM084034]; CIHR [MOP-49451, MOP-93671, MOP-125894, MOP-67011, MOP-14409]; Intramural Program of the NIDDK [DK015602-05]; NSERC Alexander Graham Bell Canada Graduate Scholarships; CIHR; CIFAR; Charles H. Best Fellowship; HFSP LT Fellowship FX We thank H. van Bakel for computational support, A. Ramani and J. Calarco for discussions, Y. Wu, G. Rasanathan, M. Krishnamoorthy, O. Boright, A. Janska, J. Li, S. Talukder, A. Cote and S. Votruba for technical assistance, L. Sutherland for purchasing RBM5 protein and for feedback on the manuscript, S. Jain for software modified to create Fig. 2, and N. Barbosa-Morais for generating cRPKM values from autism RNA-seq data. We thank M. Kiledjian (PCBP1 and PCBP2), J. Stevenin (SRSF2 and SFRS7), S. Richard (QKI), M. Gorospe (TIA1), B. Chabot (SRSF9), A. Berglund (MBNL1), F. Pagani (DAZAP1), A. Bindereif (HNRNPL), M. Freeman (HNRNPK), E. Miska (LIN28A), K. Kohno (YBX1), M. Garcia-Blanco (PTBP1), R. Wharton (PUM-HD), C. Smibert (Vts1p) and M. Blanchette (Hrb27C, Hrb87F and Hrb98DE) for sending published constructs. This work was supported by funding from NIH (1R01HG00570 to T. R. H. and Q. D. M., R01GM084034 to K. W. L.), CIHR (MOP-49451 to T. R. H., MOP-93671 to Q. D. M., MOP-125894 to Q. D. M. and T. R. H., MOP-67011 to B. J. B., and MOP-14409 to H. D. L.), and the Intramural Program of the NIDDK (DK015602-05 to E. P. L.). K. B. C. and S. G. hold NSERC Alexander Graham Bell Canada Graduate Scholarships. M. T. W. was funded by fellowships from CIHR and CIFAR. H. S. N. holds a Charles H. Best Fellowship and was funded partially by awards from CIFAR to T. R. H. and B. J. F. M. I. is the recipient of an HFSP LT Fellowship. NR 47 TC 312 Z9 317 U1 7 U2 90 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 11 PY 2013 VL 499 IS 7457 BP 172 EP 177 DI 10.1038/nature12311 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179YA UT WOS:000321557600054 PM 23846655 ER PT J AU Lawrence, MS Stojanov, P Polak, P Kryukov, GV Cibulskis, K Sivachenko, A Carter, SL Stewart, C Mermel, CH Roberts, SA Kiezun, A Hammerman, PS McKenna, A Drier, Y Zou, LH Ramos, AH Pugh, TJ Stransky, N Helman, E Kim, J Sougnez, C Ambrogio, L Nickerson, E Shefler, E Cortes, ML Auclair, D Saksena, G Voet, D Noble, M DiCara, D Lin, P Lichtenstein, L Heiman, DI Fennell, T Imielinski, M Hernandez, B Hodis, E Baca, S Dulak, AM Lohr, J Landau, DA Wu, CJ Melendez-Zajgla, J Hidalgo-Miranda, A Koren, A McCarroll, SA Mora, J Lee, RS Crompton, B Onofrio, R Parkin, M Winckler, W Ardlie, K Gabriel, SB Roberts, CWM Biegel, JA Stegmaier, K Bass, AJ Garraway, LA Meyerson, M Golub, TR Gordenin, DA Sunyaev, S Lander, ES Getz, G AF Lawrence, Michael S. Stojanov, Petar Polak, Paz Kryukov, Gregory V. Cibulskis, Kristian Sivachenko, Andrey Carter, Scott L. Stewart, Chip Mermel, Craig H. Roberts, Steven A. Kiezun, Adam Hammerman, Peter S. McKenna, Aaron Drier, Yotam Zou, Lihua Ramos, Alex H. Pugh, Trevor J. Stransky, Nicolas Helman, Elena Kim, Jaegil Sougnez, Carrie Ambrogio, Lauren Nickerson, Elizabeth Shefler, Erica Cortes, Maria L. Auclair, Daniel Saksena, Gordon Voet, Douglas Noble, Michael DiCara, Daniel Lin, Pei Lichtenstein, Lee Heiman, David I. Fennell, Timothy Imielinski, Marcin Hernandez, Bryan Hodis, Eran Baca, Sylvan Dulak, Austin M. Lohr, Jens Landau, Dan-Avi Wu, Catherine J. Melendez-Zajgla, Jorge Hidalgo-Miranda, Alfredo Koren, Amnon McCarroll, Steven A. Mora, Jaume Lee, Ryan S. Crompton, Brian Onofrio, Robert Parkin, Melissa Winckler, Wendy Ardlie, Kristin Gabriel, Stacey B. Roberts, Charles W. M. Biegel, Jaclyn A. Stegmaier, Kimberly Bass, Adam J. Garraway, Levi A. Meyerson, Matthew Golub, Todd R. Gordenin, Dmitry A. Sunyaev, Shamil Lander, Eric S. Getz, Gad TI Mutational heterogeneity in cancer and the search for new cancer-associated genes SO NATURE LA English DT Article ID COMPREHENSIVE GENOMIC CHARACTERIZATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; SOMATIC MUTATIONS; HUMAN-PAPILLOMAVIRUS; MAMMALIAN GENOMES; DNA; LANDSCAPE; CARCINOMA; PATHWAYS; LYMPHOMA AB Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer(1-9). These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer. C1 [Lawrence, Michael S.; Stojanov, Petar; Polak, Paz; Kryukov, Gregory V.; Cibulskis, Kristian; Sivachenko, Andrey; Carter, Scott L.; Stewart, Chip; Mermel, Craig H.; Kiezun, Adam; Hammerman, Peter S.; McKenna, Aaron; Drier, Yotam; Zou, Lihua; Ramos, Alex H.; Pugh, Trevor J.; Stransky, Nicolas; Helman, Elena; Kim, Jaegil; Sougnez, Carrie; Ambrogio, Lauren; Nickerson, Elizabeth; Shefler, Erica; Cortes, Maria L.; Auclair, Daniel; Saksena, Gordon; Voet, Douglas; Noble, Michael; DiCara, Daniel; Lin, Pei; Lichtenstein, Lee; Heiman, David I.; Fennell, Timothy; Imielinski, Marcin; Hernandez, Bryan; Hodis, Eran; Baca, Sylvan; Dulak, Austin M.; Lohr, Jens; Landau, Dan-Avi; Koren, Amnon; McCarroll, Steven A.; Onofrio, Robert; Parkin, Melissa; Winckler, Wendy; Ardlie, Kristin; Gabriel, Stacey B.; Stegmaier, Kimberly; Bass, Adam J.; Garraway, Levi A.; Meyerson, Matthew; Golub, Todd R.; Sunyaev, Shamil; Lander, Eric S.; Getz, Gad] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA. [Stojanov, Petar; Hammerman, Peter S.; Pugh, Trevor J.; Hodis, Eran; Baca, Sylvan; Dulak, Austin M.; Lohr, Jens; Landau, Dan-Avi; Wu, Catherine J.; Lee, Ryan S.; Crompton, Brian; Roberts, Charles W. M.; Stegmaier, Kimberly; Bass, Adam J.; Garraway, Levi A.; Meyerson, Matthew; Golub, Todd R.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Polak, Paz; Kryukov, Gregory V.; Drier, Yotam; Pugh, Trevor J.; Wu, Catherine J.; Koren, Amnon; McCarroll, Steven A.; Lee, Ryan S.; Roberts, Charles W. M.; Bass, Adam J.; Garraway, Levi A.; Meyerson, Matthew; Golub, Todd R.; Sunyaev, Shamil; Lander, Eric S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Polak, Paz; Kryukov, Gregory V.; Sunyaev, Shamil] Brigham & Womens Hosp, Boston, MA 02115 USA. [Mermel, Craig H.; Drier, Yotam; Imielinski, Marcin; Getz, Gad] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Roberts, Steven A.; Gordenin, Dmitry A.] NIEHS, Lab Mol Genet, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [McKenna, Aaron] Univ Washington, Seattle, WA 98195 USA. [Drier, Yotam; Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Stransky, Nicolas] Blueprint Med, Cambridge, MA 02142 USA. [Helman, Elena; Lander, Eric S.] MIT, Cambridge, MA 02139 USA. [Landau, Dan-Avi] Yale Canc Ctr, Dept Hematol, New Haven, CT 06510 USA. [Melendez-Zajgla, Jorge; Hidalgo-Miranda, Alfredo] Inst Nacl Med Genom, Mexico City 14610, DF, Mexico. [Mora, Jaume] Hosp St Joan de Deu, Dept Pediat Oncol, Barcelona 08950, Spain. [Lee, Ryan S.; Crompton, Brian; Roberts, Charles W. M.; Stegmaier, Kimberly] Boston Childrens Hosp, Boston, MA 02115 USA. [Biegel, Jaclyn A.] Childrens Hosp, Philadelphia, PA 19104 USA. RP Lander, ES (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02141 USA. EM lander@broadinstitute.org; gadgetz@broadinstitute.org RI Hidalgo-Miranda, Alfredo/B-2123-2010; Kryukov, Gregory/A-9592-2008; Drier, Yotam/K-5208-2012; OI Hidalgo-Miranda, Alfredo/0000-0003-2315-3977; Drier, Yotam/0000-0003-1725-2995; Gordenin, Dmitry/0000-0002-8399-1836 FU Intramural Research Program of the National Institute of Environmental Health Sciences (National Institutes of Health, United States Department of Health and Human Services) [ES065073] FX This work was conducted as part of TCGA, a project of the National Cancer Institute and National Human Genome Research Institute. This work was conducted as part of the Slim Initiative for Genomic Medicine, a joint US-Mexico project founded by the Carlos Slim Health Institute. Support to D. A. G. and S. A. R. was through the Intramural Research Program of the National Institute of Environmental Health Sciences (National Institutes of Health, United States Department of Health and Human Services) project ES065073 (principal investigator M. Resnick). NR 30 TC 1037 Z9 1050 U1 27 U2 208 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 11 PY 2013 VL 499 IS 7457 BP 214 EP 218 DI 10.1038/nature12213 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179YA UT WOS:000321557600063 PM 23770567 ER PT J AU Jiang, LB Mu, JB Zhang, QF Ni, T Srinivasan, P Rayavara, K Yang, WJ Turner, L Lavstsen, T Theander, TG Peng, WQ Wei, GY Jing, QQ Wakabayashi, Y Bansal, A Luo, Y Ribeiro, JMC Scherf, A Aravind, L Zhu, J Zhao, KJ Miller, LH AF Jiang, Lubin Mu, Jianbing Zhang, Qingfeng Ni, Ting Srinivasan, Prakash Rayavara, Kempaiah Yang, Wenjing Turner, Louise Lavstsen, Thomas Theander, Thor G. Peng, Weiqun Wei, Guiying Jing, Qingqing Wakabayashi, Yoshiyuki Bansal, Abhisheka Luo, Yan Ribeiro, Jose M. C. Scherf, Artur Aravind, L. Zhu, Jun Zhao, Keji Miller, Louis H. TI PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum SO NATURE LA English DT Article ID ANTIGENIC VARIATION; MALARIA PARASITES; LYSINE 36; HETEROCHROMATIN; TRANSCRIPTION; RECOMBINATION; ERYTHROCYTES; INVASION; TARGETS; PROTEIN AB The variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which is expressed on the surface of P. falciparum-infected red blood cells, is a critical virulence factor for malaria(1). Each parasite has 60 antigenically distinct var genes that each code for a different PfEMP1 protein. During infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune-evasion mechanism to avoid the host antibody response(2,3). The mechanism by which 59 of the 60 var genes are silenced remains largely unknown(4-7). Here we show that knocking out the P. falciparum variant-silencing SET gene (here termed PfSETvs), which encodes an orthologue of Drosophila melanogaster ASH1 and controls histone H3 lysine 36 trimethylation (H3K36me3) on var genes, results in the transcription of virtually all var genes in the single parasite nuclei and their expression as proteins on the surface of individual infected red blood cells. PfSETvs-dependent H3K36me3 is present along the entire gene body, including the transcription start site, to silence var genes. With low occupancy of PfSETvs at both the transcription start site of var genes and the intronic promoter, expression of var genes coincides with transcription of their corresponding antisense long noncoding RNA. These results uncover a previously unknown role of PfSETvs-dependent H3K36me3 in silencing var genes in P. falciparum that might provide a general mechanism by which orthologues of PfSETvs repress gene expression in other eukaryotes. PfSETvs knockout parasites expressing all PfEMP1 proteins may also be applied to the development of a malaria vaccine. C1 [Jiang, Lubin; Jing, Qingqing] Chinese Acad Sci, Inst Pasteur Shanghai, Unit Human Parasite Mol & Cell Biol, Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China. [Jiang, Lubin; Jing, Qingqing] Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China. [Mu, Jianbing; Srinivasan, Prakash; Rayavara, Kempaiah; Bansal, Abhisheka; Ribeiro, Jose M. C.; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Zhang, Qingfeng; Wei, Guiying] Tongji Univ, Sch Med, Inst Infect Dis & Vaccine Dev, Shanghai 200092, Peoples R China. [Zhang, Qingfeng; Scherf, Artur] Inst Pasteur, Dept Parasitol & Mycol, Unite Biol Interact Hote Parasite, F-75015 Paris, France. [Zhang, Qingfeng; Scherf, Artur] CNRS, URA 2581, F-75015 Paris, France. [Ni, Ting] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Ni, Ting] Fudan Univ, Sch Life Sci, MOE Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Yang, Wenjing; Wakabayashi, Yoshiyuki; Luo, Yan; Zhu, Jun] NHLBI, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Turner, Louise; Lavstsen, Thomas; Theander, Thor G.] Univ Copenhagen, Fac Hlth Sci, Dept Int Hlth Immunol & Microbiol, Ctr Med Parasitol, DK-1014 Copenhagen, Denmark. [Turner, Louise; Lavstsen, Thomas; Theander, Thor G.] Rigshosp, Copenhagen Univ Hosp, Dept Infect Dis, DK-1014 Copenhagen, Denmark. [Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Jiang, LB (reprint author), Chinese Acad Sci, Inst Pasteur Shanghai, Unit Human Parasite Mol & Cell Biol, Key Lab Mol Virol & Immunol, 320 Yueyang Rd, Shanghai 200031, Peoples R China. EM lbjiang@ips.ac.cn; lmiller@niaid.nih.gov RI Scherf, Artur/A-9674-2014; Theander, Thor/F-6714-2015; Ribeiro, Jose/J-7011-2015; OI Turner, Louise/0000-0003-4494-2289; Theander, Thor G./0000-0002-3509-7514; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural Research Program of the National Institute of Allergy and Infectious Disease; National Heart, Lung, and Blood Institute, National Institutes of Health; National Natural Science Foundation of China [81271863]; Key Research Program of the Chinese Academy of Sciences [KSZD-EW-Z-003-1-2]; ERC [250320] FX We thank S. K. Pierce at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, for critical suggestions on the manuscript and A. F. Cowman for providing the pHTK transfection plasmid. We also thank V. Nair and E. Fisher at the NIH Research Technology Branch for assistance with electron microscopy. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Disease and the National Heart, Lung, and Blood Institute, National Institutes of Health, and also by the National Natural Science Foundation of China (81271863) and the Key Research Program of the Chinese Academy of Sciences (KSZD-EW-Z-003-1-2). A. S. was supported by an ERC grant PlasmoEscape (250320). All authors have reviewed and agreed with the content of the manuscript. NR 36 TC 64 Z9 70 U1 2 U2 50 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 11 PY 2013 VL 499 IS 7457 BP 223 EP + DI 10.1038/nature12361 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179YA UT WOS:000321557600065 PM 23823717 ER PT J AU Wing, R Bolin, P Brancati, FL Bray, GA Clark, JM Coday, M Crow, RS Curtis, JM Egan, CM Espeland, MA Evans, M Foreyt, JP Ghazarian, S Gregg, EW Harrison, B Hazuda, HP Hill, JO Horton, ES Hubbard, V Jakicic, JM Jeffery, RW Johnson, KC Kahn, SE Kitabchi, AE Knowler, WC Lewis, CE Maschak-Carey, BJ Montez, MG Murillo, A Nathan, DM Patricio, J Peters, A Pi-Sunyer, X Pownall, H Reboussin, D Regensteiner, JG Rickman, AD Ryan, DH Safford, M Wadden, TA Wagenknecht, LE West, DS Williamson, DF Yanovski, SZ AF Wing, Rena Bolin, Paula Brancati, Frederick L. Bray, George A. Clark, Jeanne M. Coday, Mace Crow, Richard S. Curtis, Jeffrey M. Egan, Caitlin M. Espeland, Mark A. Evans, Mary Foreyt, John P. Ghazarian, Siran Gregg, Edward W. Harrison, Barbara Hazuda, Helen P. Hill, James O. Horton, Edward S. Hubbard, Van S. Jakicic, John M. Jeffery, Robert W. Johnson, Karen C. Kahn, Steven E. Kitabchi, Abbas E. Knowler, William C. Lewis, Cora E. Maschak-Carey, Barbara J. Montez, Maria G. Murillo, Anne Nathan, David M. Patricio, Jennifer Peters, Anne Pi-Sunyer, Xavier Pownall, Henry Reboussin, David Regensteiner, Judith G. Rickman, Amy D. Ryan, Donna H. Safford, Monika Wadden, Thomas A. Wagenknecht, Lynne E. West, Delia S. Williamson, David F. Yanovski, Susan Z. CA Look AHEAD Res Grp TI Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LOOK-AHEAD ACTION; WEIGHT-LOSS; CLINICAL-TRIAL; OBESE ADULTS; PREVENTION; MORTALITY; HEALTH; INDIVIDUALS; MELLITUS; PROGRAM AB Background Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients. Methods In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. Results The trial was stopped early on the basis of a futility analysis when the median follow- up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P = 0.51). Conclusions An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. C1 [Wing, Rena; Curtis, Jeffrey M.] Brown Univ, Warren Alpert Med Sch, Weight Control & Diabet Res Ctr, Providence, RI 02903 USA. [Bolin, Paula; Evans, Mary; Harrison, Barbara; Hubbard, Van S.] NIDDK, NIH, Bethesda, MD 20892 USA. [Brancati, Frederick L.; Clark, Jeanne M.] Johns Hopkins Sch Med, Baltimore, MD USA. [Bray, George A.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Coday, Mace; Johnson, Karen C.; Kitabchi, Abbas E.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Crow, Richard S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Curtis, Jeffrey M.] NIDDK, NIH, Phoenix, AZ USA. [Egan, Caitlin M.] Miriam Hosp, Providence, RI 02906 USA. [Espeland, Mark A.] Wake Forest Univ, Dept Biostat Sci, Sch Med, Winston Salem, NC 27109 USA. [Foreyt, John P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Ghazarian, Siran; Peters, Anne] Roybal Comprehens Hlth Ctr, Los Angeles, CA USA. [Gregg, Edward W.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Hazuda, Helen P.; Montez, Maria G.] Univ Texas Hlth Sci Ctr San Antonio, Dept Clin Epidemiol, San Antonio, TX 78229 USA. [Hill, James O.] Univ Colorado, Hlth Sci Ctr, Ctr Human Nutr, Aurora, CO USA. [Horton, Edward S.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Jakicic, John M.] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA USA. [Jeffery, Robert W.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Kahn, Steven E.; Murillo, Anne] Univ Washington, Dept Med, Seattle, WA USA. [Knowler, William C.] NIDDK, NIH, Southwest Amer Indian Ctr, Phoenix, AZ USA. [Lewis, Cora E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Maschak-Carey, Barbara J.] Univ Penn, Weight & Eating Disorder Program, Philadelphia, PA 19104 USA. [Nathan, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Patricio, Jennifer] St Lukes Roosevelt Hosp, Dept Med, New York, NY 10025 USA. [Pi-Sunyer, Xavier] St Lukes Roosevelt Hosp, Dept Med, New York, NY 10025 USA. [Pownall, Henry] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Reboussin, David] Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC 27109 USA. [Regensteiner, Judith G.] Univ Colorado, Hlth Sci Ctr, Ctr Womens Hlth Res, Aurora, CO USA. [Rickman, Amy D.] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA USA. [Ryan, Donna H.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Safford, Monika] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Wadden, Thomas A.] Univ Penn, Weight & Eating Disorder Program, Philadelphia, PA 19104 USA. [Wagenknecht, Lynne E.] Wake Forest Univ, Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [West, Delia S.] Univ Arkansas Med Sci, Coll Publ Hlth, Dept Hlth Behav & Hlth Educ, Little Rock, AR 72205 USA. [Williamson, David F.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Yanovski, Susan Z.] NIDDK, NIH, Bethesda, MD USA. RP Wing, R (reprint author), Brown Univ, Warren Alpert Med Sch, Weight Control & Diabet Res Ctr, 196 Richmond St, Providence, RI 02903 USA. EM rwing@lifespan.org OI Kahn, Steven/0000-0001-7307-9002 FU National Institutes of Health (NIH); Department of Health and Human Services agencies; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, DK56992]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; NIH Office of Research on Women's Health; Centers for Disease Control and Prevention; Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01RR02719]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center; Massachusetts Institute of Technology General Clinical Research Center [M01RR01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01RR00051]; Clinical Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR0021140]; University of Pittsburgh General Clinical Research Center [M01RR000056]; Clinical Translational Research Center; Clinical and Translational Science Award [UL1 RR 024153]; NIH [DK 046204]; VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; Frederic C. Bartter General Clinical Research Center [M01RR01346]; FedEx; Health Management Resources; Johnson Johnson; Nestle HealthCare Nutrition; Hoffmann-La Roche; Abbott Nutrition; Unilever North America FX Supported by the National Institutes of Health (NIH) and other Department of Health and Human Services agencies through cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, and DK56992). Additional funding was provided by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; the National Heart, Lung, and Blood Institute; the National Institute of Nursing Research; the National Center on Minority Health and Health Disparities; the NIH Office of Research on Women's Health; and the Centers for Disease Control and Prevention. The Indian Health Service (IHS) provided personnel, medical oversight, and use of facilities. Additional support was provided by the Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center and the Massachusetts Institute of Technology General Clinical Research Center (M01RR01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01RR00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR0021140); the University of Pittsburgh General Clinical Research Center(M01RR000056) and Clinical Translational Research Center (funded by a Clinical and Translational Science Award [UL1 RR 024153] and an NIH grant [DK 046204]); the VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; and the Frederic C. Bartter General Clinical Research Center (M01RR01346); and by FedEx, Health Management Resources, Johnson & Johnson, Nestle HealthCare Nutrition, Hoffmann-La Roche, Abbott Nutrition, and Unilever North America. NR 28 TC 578 Z9 589 U1 10 U2 102 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 11 PY 2013 VL 369 IS 2 BP 145 EP 154 DI 10.1056/NEJMoa1212914 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 180BH UT WOS:000321567300010 ER PT J AU Al Busaidy, S Al-Gohary, A Ampofo, WK Bekshin, Z Cerkaoui, I Claes, F Cox, NJ Cracknell, W Cui, L Paiva, TM de Wit, M Diep, LDT Donabedian, A Donis, R Dormitzer, PR Eichelberger, M El Kholy, N Engelhardt, O Engelmann, HB Eropkin, MY Fasce, R Fontaine, L Ghadakchi, HF Ghedin, E Giovanni, MY Golding, H da Silva, HC Gysin, R Hamilton, K Hauge, SH Hay, A Huang, S Hungnes, O Ibrahim, SSS Immamura, T Inglis, SC Kadjo, H Katz, J Kawaoka, Y Kelso, A Khan, MI Kilander, A Klimov, A Kreij, K Kusmiaty, D Linde, A Liu, MT Lupulescu, E Mai, LQ Martinez, VR McCauley, J Meyer, Q Modi, R Mohammadi, AA Mokhtari-Azad, T Mol, E Music, T Nelson, K Neuhaus, E Neumeier, ER Niang, MN Odagiri, T Peiris, M Pohlmann, A Popow-Kraupp, T Trilar, KP Rabadan, R Rambaut, A Robertson, JS Rolls, C Sampurno, OD Savy, V Sawanpanyaltert, P Schmid, G Schweiger, B Shapira, S Shinde, V Shu, Y Siqueira, M Smith, D Spiro, D Stevens, J Takizawa, K Tashiro, M Taylor, B Thomas, Y Tsai, T Van der Werf, S Venter, M Waddell, AL Wan, XF Wang, D Webby, R Weir, JP Wentworth, D Wickramasinghe, G Ye, ZP Zambon, M Ziegler, T AF Al Busaidy, Suleiman Al-Gohary, Amany Ampofo, William K. Bekshin, Zhandarbek Cerkaoui, Imad Claes, Filip Cox, Nancy J. Cracknell, William Cui, Lin de Paiva, Terezinha Maria de Wit, Marel Lan Do Thi Diep Donabedian, Armen Donis, Ruben Dormitzer, Philip R. Eichelberger, Maryna El Kholy, Nagwa Engelhardt, Othmar Engelmann, Hans B. Eropkin, Mikhail Yurievich Fasce, Rodrigo Fontaine, Laurent Ghadakchi, Hadi Famil Ghedin, Elodie Giovanni, Maria Y. Golding, Hana da Silva, Hugo Comes Gysin, Rene Hamilton, Keith Hauge, Siri Helene Hay, Alan Huang, Sue Hungnes, Olav Ibrahim, Sally Saber Said Immamura, Tomohiko Inglis, Stephen C. Kadjo, Herve Katz, Jacqueline Kawaoka, Yoshihiro Kelso, Anne Khan, Mohammed Ilyas Kilander, Anette Klimov, Alexander Kreij, Karl Kusmiaty, Dede Linde, Annika Liu, Ming-Tsan Lupulescu, Emilia Mai, Le Quynh Martinez, Virginia Ramirez McCauley, John Meyer, Quinton Modi, Rajiv Mohammadi, Ali A. Mokhtari-Azad, Talat Mol, Els Music, Tamara Nelson, Karen Neuhaus, Elizabeth Neumeier, Elisabeth R. Niang, Mbayame Ndiaye Odagiri, Takato Peiris, Malik Pohlmann, Anne Popow-Kraupp, Therese Trilar, Katharina Prosenc Rabadan, Raul Rambaut, Andrew Robertson, James S. Rolls, Chris Sampurno, Ondri Dwi Savy, Vilma Sawanpanyaltert, Pathom Schmid, George Schweiger, Brunhilde Shapira, Sagi Shinde, Vivek Shu, Yuelong Siqueira, Marilda Smith, Derek Spiro, David Stevens, James Takizawa, Kazuyuki Tashiro, Masato Taylor, Beverly Thomas, Yves Tsai, Theodore Van der Werf, Sylvie Venter, Marietjie Waddell, Anthony L. Wan, Xiufeng Wang, Dayan Webby, Richard Weir, Jerry P. Wentworth, David Wickramasinghe, Geethani Ye, Zhiping Zambon, Maria Ziegler, Thedi TI Strengthening the influenza vaccine virus selection and development process Outcome of the 2nd WHO Informal Consultation for Improving Influenza Vaccine Virus Selection held at the Centre International de Conferences (CICG) Geneva, Switzerland, 7 to 9 December 2011 SO VACCINE LA English DT Article ID MIXED INFECTION; NEURAMINIDASE; H1N1; TRANSMISSION; EVOLUTION; ANTIBODY; A(H3N2); FERRETS C1 [Al Busaidy, Suleiman] Natl Influenza Ctr, Muscat, Oman. [Al-Gohary, Amany] Natl Influenza Ctr, Cairo, Egypt. [Ampofo, William K.] Natl Influenza Ctr, Accra, Ghana. [Bekshin, Zhandarbek] Minist Hlth, Alma Ata, Kazakhstan. [Cerkaoui, Imad] Natl Influenza Ctr, Rabat, Morocco. [Claes, Filip] OFFLU, Rome, Italy. [Cox, Nancy J.] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Cracknell, William] CSL Biotherapies, Melbourne, Vic, Australia. [Cui, Lin] Natl Influenza Ctr, Singapore, Singapore. [de Paiva, Terezinha Maria] Natl Influenza Ctr, Sao Paulo, Brazil. [de Wit, Marel] Abbott Biol, Weesp, Netherlands. [Lan Do Thi Diep] Natl Inst Control Vaccines & Biol, Hanoi, Vietnam. [Donabedian, Armen] BARDA, Washington, DC USA. [Donis, Ruben] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Dormitzer, Philip R.] Novartis Vaccines & Diagnost, Cambridge, MA USA. [Eichelberger, Maryna] US FDA, Bethesda, MD 20014 USA. [El Kholy, Nagwa] Natl Influenza Ctr, Cairo, Egypt. [Engelmann, Hans B.] GlaxoSmithKline Biol, Dresden, Germany. [Eropkin, Mikhail Yurievich] Natl Influenza Ctr, St Petersburg, Russia. [Fasce, Rodrigo] Natl Influenza Ctr, Santiago, Chile. [Fontaine, Laurent] Sanofi Pasteur, Val De Reuil, France. [Ghadakchi, Hadi Famil] Razi Vaccine & Serum Res Inst, Karaj, Iran. [Ghedin, Elodie] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Giovanni, Maria Y.] NIH, Bethesda, MD 20892 USA. [Golding, Hana] US FDA, Rockville, MD 20857 USA. [da Silva, Hugo Comes] GlaxoSmithKline Biol, Wavre, Belgium. [Gysin, Rene] Swissmedic, Bern, Switzerland. [Hamilton, Keith] OFFLU, Paris, France. [Hauge, Siri Helene] Norwegian Inst Publ Hlth, Oslo, Norway. [Hay, Alan] Natl Inst Med Res, London NW7 1AA, England. [Huang, Sue] Natl Influenza Ctr, Upper Hutt, New Zealand. [Hungnes, Olav] Natl Influenza Ctr, Oslo, Norway. [Ibrahim, Sally Saber Said] CAPA, Cairo, Egypt. [Immamura, Tomohiko] Denka Seiken Co Ltd, Tokyo, Japan. [Kadjo, Herve] Natl Influenza Ctr, Abidjan, Cote Ivoire. [Katz, Jacqueline] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Kawaoka, Yoshihiro] Univ Wisconsin, Madison, WI USA. [Kelso, Anne] VIDRL, Melbourne, Vic, Australia. [Khan, Mohammed Ilyas] Hamad Med Coorporat, Doha, Qatar. [Kilander, Anette] Natl Influenza Ctr, Oslo, Norway. [Klimov, Alexander] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Kreij, Karl] Crucell Switzerland AG, Bern, Switzerland. [Kusmiaty, Dede] NADFC, Jakarta, Pusat, Indonesia. [Linde, Annika] Swedish Inst Infect Dis Control, Solna, Sweden. [Lupulescu, Emilia] Natl Influenza Ctr, Bucharest, Romania. [Mai, Le Quynh] Natl Influenza Ctr, Hanoi, Vietnam. [Martinez, Virginia Ramirez] Fed Commiss Protect Sanit Risks, Mexico City, DF, Mexico. [McCauley, John] NIMR, London, England. [Meyer, Quinton] SA Natl Control Lab Biol Prod, Bloemfontein, South Africa. [Modi, Rajiv] Cadila Pharmaceut Ltd, Ahmadabad, Gujarat, India. [Mohammadi, Ali A.] Global Hlth & Secur Consultants, Geneva, Switzerland. [Mokhtari-Azad, Talat] Natl Influenza Ctr, Tehran, Iran. [Mol, Els] Abbott Biol, Weesp, Netherlands. [Music, Tamara] IFPMA, Geneva, Switzerland. [Nelson, Karen] Craig Venter Inst, Rockville, MD USA. [Neuhaus, Elizabeth] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Neumeier, Elisabeth R.] GlaxoSmithKline Biol, Dresden, Germany. [Niang, Mbayame Ndiaye] Natl Influenza Ctr, Dakar, Senegal. [Odagiri, Takato] NIID, Tokyo, Japan. [Peiris, Malik] Univ Hong Kong, Hong Kong Special Adm, Hong Kong, Hong Kong, Peoples R China. [Pohlmann, Anne] Fed Res Inst Anim Hlth Greifswald, Insel Riems, Germany. [Popow-Kraupp, Therese] Natl Influenza Ctr, Vienna, Austria. [Trilar, Katharina Prosenc] Natl Influenza Ctr, Ljubljana, Slovenia. [Rabadan, Raul] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Rambaut, Andrew] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Rolls, Chris] TGA, Symonston, Australia. [Sampurno, Ondri Dwi] Natl Influenza Ctr, Jakarta, Indonesia. [Savy, Vilma] Natl Influenza Ctr, Buenos Aires, DF, Argentina. [Sawanpanyaltert, Pathom] Natl Influenza Ctr, Bangkok, Thailand. [Schmid, George] Ctr Dis Control & Prevent CDC, Alma Ata, Kazakhstan. [Schweiger, Brunhilde] Natl Influenza Ctr, Berlin, Germany. [Shapira, Sagi] Joint Ctr Syst Biol, New York, NY USA. [Shapira, Sagi] Dept Microbiol & Immunol, New York, NY USA. [Shinde, Vivek] GlaxoSmithKline Biol, Wavre, Belgium. [Shu, Yuelong] Natl Inst Viral Dis Control & Prevent, Beijing, Peoples R China. [Siqueira, Marilda] Natl Influenza Ctr, Rio De Janeiro, Brazil. [Smith, Derek] Univ Cambridge, Cambridge, England. [Spiro, David] NIH, Bethesda, MD 20892 USA. [Stevens, James] Ctr Dis Control & Prevent CDC, Atlanta, GA USA. [Takizawa, Kazuyuki] Denka Seiken Co Ltd, Niigata, Japan. [Tashiro, Masato] NIID, Tokyo, Japan. [Taylor, Beverly] Novartis Pharma SA, Liverpool, Merseyside, England. [Thomas, Yves] Natl Influenza Ctr, Geneva, Switzerland. [Tsai, Theodore] Novartis Vaccines Cambridge, Cambridge, MA USA. [Van der Werf, Sylvie] Natl Influenza Ctr, Paris, France. [Venter, Marietjie] Natl Influenza Ctr, Johannesburg, South Africa. [Wan, Xiufeng] Mississippi State Univ, Mississippi State, MS 39762 USA. [Wang, Dayan] Natl Inst Viral Dis Control & Prevent, Beijing, Peoples R China. [Webby, Richard] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Weir, Jerry P.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Wentworth, David] J Craig Venter Inst, Rockville, MD USA. [Wickramasinghe, Geethani] Natl Influenza Ctr, Colombo, Sri Lanka. [Ye, Zhiping] CBER, Bethesda, MD USA. [Zambon, Maria] Natl Influenza Ctr, London, England. [Ziegler, Thedi] Natl Influenza Ctr, Helsinki, Finland. RP Al Busaidy, S (reprint author), Natl Influenza Ctr, Muscat, Oman. RI Venter, Marietjie/P-9604-2016; Vaccine & Serum Research Institute, Razi /A-3892-2017 OI Venter, Marietjie/0000-0003-2696-824X; NR 31 TC 10 Z9 10 U1 0 U2 18 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JUL 11 PY 2013 VL 31 IS 32 BP 3209 EP 3221 DI 10.1016/j.vaccine.2013.05.049 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 179RE UT WOS:000321538200002 ER PT J AU Setiawan, VW Yang, HP Pike, MC McCann, SE Yu, H Xiang, YB Wolk, A Wentzensen, N Weiss, NS Webb, PM van den Brandt, PA van de Vijver, K Thompson, PJ Strom, BL Spurdle, AB Soslow, RA Shu, XO Schairer, C Sacerdote, C Rohan, TE Robien, K Risch, HA Ricceri, F Rebbeck, TR Rastogi, R Prescott, J Polidoro, S Park, Y Olson, SH Moysich, KB Miller, AB McCullough, ML Matsuno, RK Magliocco, AM Lurie, G Lu, LG Lissowska, J Liang, XL Lacey, JV Kolonel, LN Henderson, BE Hankinson, SE Hakansson, N Goodman, MT Gaudet, MM Garcia-Closas, M Friedenreich, CM Freudenheim, JL Doherty, J De Vivo, I Courneya, KS Cook, LS Chen, C Cerhan, JR Cai, H Brinton, LA Bernstein, L Anderson, KE Anton-Culver, H Schouten, LJ Horn-Ross, PL AF Setiawan, Veronica Wendy Yang, Hannah P. Pike, Malcolm C. McCann, Susan E. Yu, Herbert Xiang, Yong-Bing Wolk, Alicja Wentzensen, Nicolas Weiss, Noel S. Webb, Penelope M. van den Brandt, Piet A. van de Vijver, Koen Thompson, Pamela J. Strom, Brian L. Spurdle, Amanda B. Soslow, Robert A. Shu, Xiao-ou Schairer, Catherine Sacerdote, Carlotta Rohan, Thomas E. Robien, Kim Risch, Harvey A. Ricceri, Fulvio Rebbeck, Timothy R. Rastogi, Radhai Prescott, Jennifer Polidoro, Silvia Park, Yikyung Olson, Sara H. Moysich, Kirsten B. Miller, Anthony B. McCullough, Marjorie L. Matsuno, Rayna K. Magliocco, Anthony M. Lurie, Galina Lu, Lingeng Lissowska, Jolanta Liang, Xiaolin Lacey, James V., Jr. Kolonel, Laurence N. Henderson, Brian E. Hankinson, Susan E. Hakansson, Niclas Goodman, Marc T. Gaudet, Mia M. Garcia-Closas, Montserrat Friedenreich, Christine M. Freudenheim, Jo L. Doherty, Jennifer De Vivo, Immaculata Courneya, Kerry S. Cook, Linda S. Chen, Chu Cerhan, James R. Cai, Hui Brinton, Louise A. Bernstein, Leslie Anderson, Kristin E. Anton-Culver, Hoda Schouten, Leo J. Horn-Ross, Pamela L. CA Australian Natl Endometrial Canc S TI Type I and II Endometrial Cancers: Have They Different Risk Factors? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CARCINOMA; OBESITY; WOMEN; CARCINOGENESIS; METAANALYSIS; SMOKING; HEALTH AB Purpose Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. Patients and Methods Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. Results Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P-heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. Conclusion The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed. (C) 2013 by American Society of Clinical Oncology C1 [Setiawan, Veronica Wendy; Pike, Malcolm C.; Henderson, Brian E.] Univ So Calif, Los Angeles, CA 90033 USA. [Lacey, James V., Jr.; Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Anton-Culver, Hoda] Univ Calif Irvine, Irvine, CA USA. [Horn-Ross, Pamela L.] Canc Prevent Inst Calif, Fremont, CA USA. [Yang, Hannah P.; Wentzensen, Nicolas; Schairer, Catherine; Park, Yikyung; Brinton, Louise A.] NCI, Bethesda, MD 20892 USA. [Pike, Malcolm C.; Soslow, Robert A.; Rastogi, Radhai; Olson, Sara H.; Liang, Xiaolin] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [McCann, Susan E.; Moysich, Kirsten B.] Roswell Pk Canc Inst, Buffalo, NY USA. [Freudenheim, Jo L.] SUNY Buffalo, Buffalo, NY 14260 USA. [Rohan, Thomas E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Yu, Herbert; Thompson, Pamela J.; Matsuno, Rayna K.; Lurie, Galina; Kolonel, Laurence N.; Goodman, Marc T.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Xiang, Yong-Bing] Shanghai Canc Inst, Shanghai, Peoples R China. [Wolk, Alicja; Hakansson, Niclas] Karolinska Inst, Stockholm, Sweden. [Weiss, Noel S.] Univ Washington, Seattle, WA 98195 USA. [Chen, Chu] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Webb, Penelope M.; Spurdle, Amanda B.; Australian Natl Endometrial Canc S] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [van den Brandt, Piet A.; van de Vijver, Koen; Schouten, Leo J.] Maastricht Univ, Maastricht, Netherlands. [Strom, Brian L.; Rebbeck, Timothy R.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Shu, Xiao-ou; Cai, Hui] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Sacerdote, Carlotta; Ricceri, Fulvio; Polidoro, Silvia] Human Genet Fdn, Turin, Italy. [Robien, Kim; Anderson, Kristin E.] Univ Minnesota, Minneapolis, MN USA. [Risch, Harvey A.; Lu, Lingeng] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Prescott, Jennifer; Hankinson, Susan E.; De Vivo, Immaculata] Brigham & Womens Hosp, Boston, MA 02115 USA. [Prescott, Jennifer; Hankinson, Susan E.; De Vivo, Immaculata] Harvard Univ, Med Sch, Cambridge, MA 02138 USA. [De Vivo, Immaculata] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Amherst, MA 01003 USA. [Miller, Anthony B.] Univ Toronto, Toronto, ON, Canada. [Friedenreich, Christine M.] Alberta Hlth Serv Canc Care, Calgary, AB, Canada. [Courneya, Kerry S.] Univ Alberta, Edmonton, AB, Canada. [McCullough, Marjorie L.; Gaudet, Mia M.] Amer Canc Soc, Atlanta, GA 30329 USA. [Magliocco, Anthony M.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Garcia-Closas, Montserrat] Inst Canc Res, Sutton, Surrey, England. [Doherty, Jennifer] Dartmouth Coll, Hanover, NH 03755 USA. [Cook, Linda S.] Univ New Mexico, Albuquerque, NM 87131 USA. [Cerhan, James R.] Mayo Clin, Rochester, MN USA. RP Setiawan, VW (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, 1450 Biggy St,Rm 1517G, Los Angeles, CA 90033 USA. EM vsetiawa@usc.edu RI Schouten, Leo/G-3713-2012; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Spurdle, Amanda/A-4978-2011 OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Lissowska, Jolanta/0000-0003-2695-5799; Sacerdote, Carlotta/0000-0002-8008-5096; Robien, Kim/0000-0002-2120-2280; Park, Yikyung/0000-0002-6281-489X; Brinton, Louise/0000-0003-3853-8562; Cerhan, James/0000-0002-7482-178X; Soslow, Robert/0000-0002-7269-5898; Webb, Penelope/0000-0003-0733-5930; Spurdle, Amanda/0000-0003-1337-7897 FU National Institutes of Health (NIH) National Cancer Institute (NCI) [CA135632]; NCI K07 Career Development Award [CA116543]; ANECS (National Health and Medical Research Council [NHMRC] of Australia [339435]; Cancer Council of Queensland; Cancer Council of Tasmania; NHMRC; BAWHS (NIH) [R01 CA74877]; NIH [R01 63446, DAMD 17-96-607]; NIH (California Breast Cancer Research Program) [4JB-1106]; BCDDP (Intramural Research Programs of the NCI, NIH, Department of Health and Human Services, United States); CECS (NIH) [R01 CA098346]; CPS-II (the American Cancer Society); CTS (NIH) [R01CA77398]; California Breast Cancer Research Fund; NCI's Surveillance, Epidemiology and End Results Program; EDGE (NIH) [R01 CA83918]; FHCRC (NIH) [R35 CA39779, R01 CA75977, N01 HD23166, K05 CA92002, R01 CA105212, R01 CA87538]; HAW (NIH) [P01 CA33619, R01 CA58598, N01 CN67001, N01 PC35137]; IWHS (NIH) [R01 CA39742]; MEC (NIH) [CA54281]; NLCS (the Dutch Cancer Society); NHS (NIH) [P01 CA87262, R01 CA082838]; PECS (Intramural Research Funds of the NCI, NIH, Department of Health and Human Services, United States); SECS (NIH) [R01CA092585]; SMC (the Swedish Cancer Registry); Swedish Research Council; Karolinska Institutet's Research Funds; US (Intramural Research Funds of the NCI, NIH, Department of Health and Human Services, USA); USCLA (NIH) [R01 CA48774, P30 CA14089]; WISE (NIH) [P01 CA77596] FX Supported by a grant from the National Institutes of Health (NIH) National Cancer Institute (NCI; Grant No. CA135632 to V. W. S). V. W. S. is supported in part by NCI K07 Career Development Award (Grant No. CA116543). The individual studies were funded by the following grants: ANECS (National Health and Medical Research Council [NHMRC, Grant No. 339435] of Australia and the Cancer Councils of Queensland and Tasmania; P. M. W. and A. B. S. are supported by Fellowships from the NHMRC); BAWHS (NIH Grant No. R01 CA74877; controls were collected under: NIH Grants No. R01 63446, DAMD 17-96-607, and California Breast Cancer Research Program 4JB-1106); BCDDP (Intramural Research Programs of the NCI, NIH, Department of Health and Human Services, United States); CECS (NIH Grant No. R01 CA098346); CPS-II (the American Cancer Society); CTS (NIH Grant No. R01CA77398 and the California Breast Cancer Research Fund; the collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the NCI's Surveillance, Epidemiology and End Results Program awarded to the Cancer Prevention Institute of California, University of Southern California, the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries); EDGE (NIH Grant No. R01 CA83918); FHCRC (NIH Grants No. R35 CA39779, R01 CA75977, N01 HD23166, K05 CA92002, R01 CA105212, R01 CA87538); HAW (NIH Grants No. P01 CA33619, R01 CA58598, N01 CN67001, N01 PC35137); IWHS (NIH Grant No. R01 CA39742); MEC (NIH Grant No. CA54281); NLCS (the Dutch Cancer Society); NHS (NIH Grants No. P01 CA87262 and R01 CA082838); PECS (Intramural Research Funds of the NCI, NIH, Department of Health and Human Services, United States); SECS (NIH Grant No. R01CA092585); SMC (the Swedish Cancer Registry, the Swedish Research Council, and the Karolinska Institutet's Research Funds); US (Intramural Research Funds of the NCI, NIH, Department of Health and Human Services, USA); USCLA (NIH Grants No. R01 CA48774 and P30 CA14089); and WISE (NIH Grant No. P01 CA77596). NR 29 TC 120 Z9 126 U1 3 U2 23 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2013 VL 31 IS 20 BP 2607 EP + DI 10.1200/JCO.2012.48.2596 PG 14 WC Oncology SC Oncology GA 301NA UT WOS:000330537800031 PM 23733771 ER PT J AU Hershman, DL Unger, JM Crew, KD Minasian, LM Awad, D Moinpour, CM Hansen, L Lew, DL Greenlee, H Fehrenbacher, L Wade, JL Wong, SF Hortobagyi, GN Meyskens, FL Albain, KS AF Hershman, Dawn L. Unger, Joseph M. Crew, Katherine D. Minasian, Lori M. Awad, Danielle Moinpour, Carol M. Hansen, Lisa Lew, Danika L. Greenlee, Heather Fehrenbacher, Louis Wade, James L., III Wong, Siu-Fun Hortobagyi, Gabriel N. Meyskens, Frank L. Albain, Kathy S. TI Randomized Double-Blind Placebo-Controlled Trial of Acetyl-L-Carnitine for the Prevention of Taxane-Induced Neuropathy in Women Undergoing Adjuvant Breast Cancer Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INDUCED PERIPHERAL NEUROPATHY; FUNCTIONAL ASSESSMENT; INDUCED NEUROTOXICITY; VITAMIN-E; PACLITAXEL; NERVE; MITOCHONDRIA; PREVALENCE; DEFICIENCY; MANAGEMENT AB Purpose Chemotherapy-induced peripheral neuropathy (CIPN) is common and leads to suboptimal treatment. Acetyl-L-carnitine (ALC) is a natural compound involved in neuronal protection. Studies have suggested ALC may be effective for the prevention and treatment of CIPN. Patients and Methods A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) -Taxane scale at 12 weeks. Secondary objectives included changes in 24-week end points, functional status (FACT-Trial Outcome Index [TOI]), fatigue (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue), and NTX grade. Results A total of 409 patients were evaluable (208 received ALC; 201, placebo). In a multivariate linear regression, week-12 scores were 0.9 points lower (more CIPN) with ALC than placebo (95% CI, -2.2 to 0.4; P=.17), whereas week-24 scores were 1.8 points lower with ALC (95% CI, -3.2 to -0.4; P=.01). Patients receiving ALC were more likely to have a > 5-point decrease in FACT-NTX scores (38% v 28%; P=.05), and FACT-TOI scores were 3.5 points lower with ALC (P=.03). Grade 3 to 4 neurotoxicity was more frequent in the ALC arm (eight v one). No differences between arms were observed for FACIT-Fatigue or other toxicities. Serum carnitine level increased with ALC but remained stable with placebo. Conclusion There was no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks. This is the first study to our knowledge showing that a nutritional supplement increased CIPN. Patients should be discouraged from using supplements without proven efficacy. (C) 2013 by American Society of Clinical Oncology C1 [Hershman, Dawn L.; Crew, Katherine D.; Awad, Danielle; Greenlee, Heather] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Unger, Joseph M.; Lew, Danika L.] Southwest Oncol Grp, Stat Ctr, Seattle, WA USA. [Moinpour, Carol M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Minasian, Lori M.] NCI, Bethesda, MD 20892 USA. [Hansen, Lisa] Legacy Good Samaritan Hosp, Portland, OR USA. [Fehrenbacher, Louis] Kaiser Permanente No Calif, Vallejo, CA USA. [Wong, Siu-Fun] Loma Linda Univ, Sch Pharm, Loma Linda, CA 92350 USA. [Meyskens, Frank L.] Univ Calif Irvine, Orange, CA 92668 USA. [Wade, James L., III] Canc Care Specialists Cent Illinois, Cent Illinois Community Clin Oncol Program, Decatur, IL USA. [Hortobagyi, Gabriel N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Albain, Kathy S.] Loyola Univ, Chicago Stritch Sch Med, Maywood, IL 60153 USA. RP Hershman, DL (reprint author), Columbia Univ, 161 Ft Washington Ave,10-1068, New York, NY 10032 USA. EM dlh23@columbia.edu FU Advanced Clinical Research Award from the American Society of Clinical Oncology Conquer Cancer Foundation; Avon Foundation; National Cancer Institute Division of Cancer Prevention [CA037429]; Clinical and Translational Science Awards [ULR000040] FX Supported by an Advanced Clinical Research Award from the American Society of Clinical Oncology Conquer Cancer Foundation, by the Avon Foundation, by Grant No. CA037429 from the National Cancer Institute Division of Cancer Prevention, and by Clinical and Translational Science Awards Grant No. ULR000040. NR 36 TC 44 Z9 47 U1 0 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2013 VL 31 IS 20 BP 2627 EP + DI 10.1200/JCO.2012.44.8738 PG 8 WC Oncology SC Oncology GA 301NA UT WOS:000330537800033 PM 23733756 ER PT J AU Dasari, S Abramowitz, J Birnbaumer, L Gulledge, AT AF Dasari, Sameera Abramowitz, Joel Birnbaumer, Lutz Gulledge, Allan T. TI Do canonical transient receptor potential channels mediate cholinergic excitation of cortical pyramidal neurons? SO NEUROREPORT LA English DT Article DE acetylcholine; afterdepolarization; canonical transient receptor potential channel; mouse; muscarinic receptor; neocortex; pyramidal neuron; TRPC1 channel; TRPC5 channel; TRPC6 channel ID RAT-ASSOCIATION CORTEX; OPERATED CA2+ ENTRY; CATION CHANNEL; TRPC5 CHANNELS; EXCITABILITY; CELLS; INHIBITION; MODULATION; MECHANISMS; EXPRESSION AB Activation of M1-type muscarinic acetylcholine receptors excites neocortical pyramidal neurons, in part by gating a nonselective cation conductance that produces calcium-dependent afterdepolarizing potentials' (ADPs) following short trains of action potentials. Although the identity of the cation conductance mediating the ADP is not known, previous work has implicated canonical transient receptor potential (TRPC) channels, specifically the TRPC5 and TRPC6 subtypes. Using pharmacological and genetic approaches, we tested the role of TRPC channels in generating cholinergic ADPs in layer 5 pyramidal neurons in the mouse medial prefrontal cortex (mPFC). A variety of compounds that block TRPC channels, including 2-aminoethoxydiphenyl borate, flufenamic acid, lanthanum, SKF-96365, and Pyr-3, had little, if any, impact on cholinergic ADPs. Similarly, genetic deletion of several TRPC subunits, including TPRC1, TRPC5, and TRPC6 (single knockouts), or both TRPC5 and TRPC6 together (double knockout), failed to reduce the amplitude of cholinergic ADPs. These data suggest that TRPC5 and TRPC6 subunits are not required for cholinergic excitation of layer 5 pyramidal neurons in the mouse mPFC and that the focus of future work should be expanded to test the involvement of other potential ionic effectors. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Dasari, Sameera; Gulledge, Allan T.] Geisel Sch Med Dartmouth, Dept Physiol & Neurobiol, Lebanon, NH 03756 USA. [Abramowitz, Joel; Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. RP Gulledge, AT (reprint author), Geisel Sch Med Dartmouth, Dept Physiol & Neurobiol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM allan.gulledge@dartmouth.edu RI Gulledge, Allan/C-2733-2008; Abramowitz, Joel/A-2620-2015 OI Gulledge, Allan/0000-0002-5721-374X; FU National Institute for Mental Health [R01 MH83806]; Intramural Research Program of the NIH [Z01-ES-101684] FX The study was funded by the National Institute for Mental Health grant R01 MH83806 (A.T.G.) and the Intramural Research Program of the NIH, project Z01-ES-101684 (L.B.). NR 25 TC 10 Z9 10 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUL 10 PY 2013 VL 24 IS 10 BP 550 EP 554 DI 10.1097/WNR.0b013e3283621344 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 202KT UT WOS:000323215200009 PM 23652155 ER PT J AU Li, JH Loukili, N Rosenblatt-Velin, N Pacher, P Feihl, F Waeber, B Liaudet, L AF Li, Jianhui Loukili, Noureddine Rosenblatt-Velin, Nathalie Pacher, Pal Feihl, Francois Waeber, Bernard Liaudet, Lucas TI Peroxynitrite Is a Key Mediator of the Cardioprotection Afforded by Ischemic Postconditioning In Vivo SO PLOS ONE LA English DT Article ID MYOCARDIAL REPERFUSION INJURY; RAT ISOLATED HEARTS; NITRIC-OXIDE; REACTIVE OXYGEN; H9C2 CARDIOMYOCYTES; INFARCT SIZE; CELL-DEATH; ACTIVATION; MECHANISM; VITRO AB Myocardial ischemic postconditioning (PosC) describes an acquired resistance to lethal ischemia-reperfusion (I/R) injury afforded by brief episodes of I/R applied immediately after the ischemic insult. Cardioprotection is conveyed by parallel signaling pathways converging to prevent mitochondria permeability transition. Recent observations indicated that PostC is associated with free radicals generation, including nitric oxide (NO.) and superoxide (O-2.(-)), and that cardioprotection is abrogated by antioxidants. Since NO. And O-2.(-) react to form peroxynitrite, we hypothesized that postC might trigger the formation of peroxyntrite to promote cardioprotection in vivo. Rats were exposed to 45 min of myocardial ischemia followed by 3h reperfusion. PostC (3 cycles of 30 seconds ischemia/30 seconds reperfusion) was applied at the end of index ischemia. In a subgroup of rats, the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrinato iron (FeTPPS) was given intravenously (10 mg/kg(-1)) 5 minutes before PostC. Myocardial nitrotyrosine was determined as an index of peroxynitrite formation. Infarct size (colorimetric technique and plasma creatine kinase-CK-levels) and left ventricle (LV) function (micro-tip pressure transducer), were determined. A significant generation of 3-nitrotyrosine was detected just after the PostC manoeuvre. PostC resulted in a marked reduction of infarct size, CK release and LV systolic dysfunction. Treatment with FeTPPS before PostC abrogated the beneficial effects of PostC on myocardial infarct size and LV function. Thus, peroxynitrite formed in the myocardium during PostC induces cardioprotective mechanisms improving both structural and functional integrity of the left ventricle exposed to ischemia and reperfusion in vivo. C1 [Li, Jianhui] Zhejiang Univ, Coll Med, Affiliated Hosp 1, Dept Hepatobiliary Surg, Hangzhou 310003, Zhejiang, Peoples R China. [Li, Jianhui; Loukili, Noureddine; Liaudet, Lucas] Univ Lausanne Hosp, Med Ctr, Dept Intens Care Med, Lausanne, Switzerland. [Li, Jianhui; Loukili, Noureddine; Liaudet, Lucas] Univ Lausanne Hosp, Med Ctr, Burn Ctr, Lausanne, Switzerland. [Rosenblatt-Velin, Nathalie; Feihl, Francois; Waeber, Bernard; Liaudet, Lucas] Univ Lausanne Hosp, Med Ctr, Dept Internal Med, Div Clin Pathophysiol, Lausanne, Switzerland. [Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. RP Liaudet, L (reprint author), Univ Lausanne Hosp, Med Ctr, Dept Intens Care Med, Lausanne, Switzerland. EM lucas.liaudet@chuv.ch RI Pacher, Pal/B-6378-2008; Liaudet, Lucas/E-1322-2017 OI Pacher, Pal/0000-0001-7036-8108; Liaudet, Lucas/0000-0003-2670-4930 FU Swiss National Fund for Scientific Research [320000/118174]; National Natural Science Foundation of China [81000137]; Qianjiang Talent Program of Zhejiang Province, China [2012R10045]; Scientific Research program for the Returned Overseas Chinese Scholars, Ministry of Health, Zhejiang Province, China [491010-G51104] FX This work was supported, in part, by a grant from the Swiss National Fund for Scientific Research (Nr 320000/118174) to Lucas Liaudet and grants from the National Natural Science Foundation of China (Nr 81000137), the Qianjiang Talent Program of Zhejiang Province, China (Nr2012R10045), and the Scientific Research program for the Returned Overseas Chinese Scholars, Ministry of Health, Zhejiang Province, China (Nr 491010-G51104) to Jianhui Li. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 11 Z9 11 U1 1 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 10 PY 2013 VL 8 IS 7 AR UNSP e70331 DI 10.1371/journal.pone.0070331 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182SU UT WOS:000321765300085 PM 23875026 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Rigorous science as the road to better public health SO POPULATION HEALTH METRICS LA English DT Article DE Public health; Population science; Obesity; Physical activity; Life-expectancy; Randomized trials ID DISEASE AB In the current issue of Population Health Metrics, two reports paint a bleak picture of American public health. Both physical inactivity and obesity remain highly prevalent; yet, it is not clear that increased physical activity will reduce the burden of obesity. There continue to be widespread disparities in life expectancy across United States counties. These reports appear against a backdrop of debate regarding how we should allocate our scarce resources for improving health: should we focus more on improving access to high-quality medical care, or should we instead focus on more and better public health interventions? While optimal solutions remain obscure, a look at prior successes suggests that ultimately they will come from the conduct and implementation of rigorous science, and in particular event-driven trials. C1 NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8128, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 18 TC 1 Z9 1 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-7954 J9 POPUL HEALTH METR JI Popul. Health Metr. PD JUL 10 PY 2013 VL 11 AR 10 DI 10.1186/1478-7954-11-10 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 182ZZ UT WOS:000321784700001 PM 23842137 ER PT J AU Schoenbaum, G Stalnaker, TA Niv, Y AF Schoenbaum, Geoffrey Stalnaker, Thomas A. Niv, Yael TI How Did the Chicken Cross the Road? With Her Striatal Cholinergic Interneurons, Of Course SO NEURON LA English DT Editorial Material ID TONICALLY ACTIVE NEURONS; CONTEXT AB Recognizing when the world changes is fundamental for normal learning. In this issue of Neuron, Bradfield et al. (2013) show that cholinergic interneurons in dorsomedial striatum are critical to the process whereby new states of the world are appropriately registered and retrieved during associative learning. C1 [Schoenbaum, Geoffrey; Stalnaker, Thomas A.] NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Johns Hopkins Univ, Solomon Snyder Dept Neurosci, Baltimore, MD 21218 USA. [Niv, Yael] Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. [Niv, Yael] Princeton Univ, Princeton Neurosci Inst, Princeton, NJ 08544 USA. RP Schoenbaum, G (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. EM geoffrey.schoenbaum@nih.gov; yael@princeton.edu FU Intramural NIH HHS [Z99 DA999999] NR 9 TC 7 Z9 7 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 10 PY 2013 VL 79 IS 1 BP 3 EP 6 DI 10.1016/j.neuron.2013.06.033 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 183GH UT WOS:000321802000002 PM 23849192 ER PT J AU Wan, SG Lai, YZ Myers, RE Li, BS Palazzo, JP Burkart, AL Chen, GK Xing, JL Yang, HS AF Wan, Shaogui Lai, Yinzhi Myers, Ronald E. Li, Bingshan Palazzo, Juan P. Burkart, Ashlie L. Chen, Guokai Xing, Jinliang Yang, Hushan TI Post-diagnosis hemoglobin change associates with overall survival of multiple malignancies - results from a 14-year hospital-based cohort of lung, breast, colorectal, and liver cancers SO BMC CANCER LA English DT Article DE Hemoglobin; Survival; Prognosis ID CHEMOTHERAPY-INDUCED ANEMIA; ERYTHROPOIESIS-STIMULATING AGENTS; DARBEPOETIN ALPHA; METAANALYSIS; MANAGEMENT; MORTALITY; OUTCOMES; PREVALENCE; GUIDELINES; ONCOLOGY AB Background: Anemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level. Methods: We identified 6675 patients with a diagnosis of primary lung, breast, colorectal, or liver cancer who visited the Kimmel Cancer Center at the Thomas Jefferson University from 1998 to 2011. All patients had at least two Hb measurements within the first six months after diagnosis. We analyzed the main, dose-dependent, and time-dependent effects of Hb changes on patient survival. Results: Compared to patients with a low Hb change (vertical bar Delta Hb vertical bar <= 2.6), those having a vertical bar Delta Hb vertical bar>2.6 exhibited a significantly shorter survival (hazard ratio=1.40, 95% confidence interval 1.31-1.50, P=4.5 x 10(-22), P-log rank=1.6 x 10(-39)). This association remained significant across the four cancer types. Bootstrap resampling validated these findings 100% of the time with P<0.01 in all patients and in patients of individual cancers. The association exhibited an apparent U-shape dose-dependent pattern. Time-dependent modeling demonstrated that the effect of Hb change on the survival of the overall patient population persisted for approximately 4.5 years after diagnosis. Conclusion: Post-diagnosis Hb change associates with the survival of multiple cancers and may have clinical values in tailoring anti-anemia treatments. Because Hb level is frequently measured during cancer treatment, Hb changes may be a potentially important variable in building cancer prognosis models. C1 [Wan, Shaogui; Lai, Yinzhi; Myers, Ronald E.; Yang, Hushan] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Med Oncol, Div Populat Sci, Philadelphia, PA 19107 USA. [Palazzo, Juan P.; Burkart, Ashlie L.] Thomas Jefferson Univ, Dept Pathol, Philadelphia, PA 19107 USA. [Li, Bingshan] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Human Genet Res, Nashville, TN 37232 USA. [Chen, Guokai] Natl Heart Blood Lung Inst, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Xing, Jinliang] Fourth Mil Med Univ, Cell Engn Res Ctr, State Key Lab Canc Biol, Xian 710032, Peoples R China. [Xing, Jinliang] Fourth Mil Med Univ, Dept Cell Biol, Xian 710032, Peoples R China. RP Yang, HS (reprint author), Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Med Oncol, Div Populat Sci, Philadelphia, PA 19107 USA. EM hushan.yang@jefferson.edu RI Wan, Shaogui/I-5047-2013; OI Myers, Ronald E./0000-0002-8059-7390 FU Thomas Jefferson University; National Cancer Institute [CA153099, CA152703]; V Foundation for Cancer Research FX The work was supported by a start-up fund from Thomas Jefferson University, National Cancer Institute Grants CA153099 and CA152703, and a Research Scholar Award from the V Foundation for Cancer Research. NR 33 TC 3 Z9 4 U1 2 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 10 PY 2013 VL 13 AR 340 DI 10.1186/1471-2407-13-340 PG 11 WC Oncology SC Oncology GA 182WB UT WOS:000321774400002 PM 23841898 ER PT J AU Liu, N Kriegeskorte, N Mur, M Hadj-Bouziane, F Luh, WM Tootell, RBH Ungerleider, LG AF Liu, Ning Kriegeskorte, Nikolaus Mur, Marieke Hadj-Bouziane, Fadila Luh, Wen-Ming Tootell, Roger B. H. Ungerleider, Leslie G. TI Intrinsic Structure of Visual Exemplar and Category Representations in Macaque Brain SO JOURNAL OF NEUROSCIENCE LA English DT Article ID INFERIOR TEMPORAL CORTEX; INFEROTEMPORAL CORTEX; OBJECT REPRESENTATIONS; RESPONSE PATTERNS; CEREBRAL-CORTEX; CONTRAST AGENT; FMRI; MONKEY; FACE; REGIONS AB One of the most remarkable properties of the visual system is the ability to identify and categorize a wide variety of objects effortlessly. However, the underlying neural mechanisms remain elusive. Specifically, the question of how individual object information is represented and intrinsically organized is still poorly understood. To address this question, we presented images of isolated real-world objects spanning a wide range of categories to awake monkeys using a rapid event-related functional magnetic resonance imaging (fMRI) design and analyzed the responses of multiple areas involved in object processing. We found that the multivoxel response patterns to individual exemplars in the inferior temporal (IT) cortex, especially area TE, encoded the animate-inanimate categorical division, with a subordinate cluster of faces within the animate category. In contrast, the individual exemplar representations in V4, the amygdala, and prefrontal cortex showed either no categorical structure, or a categorical structure different from that in IT cortex. Moreover, in the IT face-selective regions ("face patches"), especially the anterior face patches, (1) the multivoxel response patterns to individual exemplars showed a categorical distinction between faces and nonface objects (i.e., body parts and inanimate objects), and (2) the regionally averaged activations to individual exemplars showed face-selectivity and within-face exemplar-selectivity. Our findings demonstrate that, at both the single-exemplar and the population level, intrinsic object representation and categorization are organized hierarchically as one moves anteriorly along the ventral pathway, reflecting both modular and distributed processing. C1 [Liu, Ning; Hadj-Bouziane, Fadila; Tootell, Roger B. H.; Ungerleider, Leslie G.] NIMH, Sect Neurocircuitry, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Kriegeskorte, Nikolaus; Mur, Marieke] MRC, Cognit & Brain Sci Unit, Cambridge CB2 7EF, England. [Kriegeskorte, Nikolaus; Mur, Marieke] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Mur, Marieke] Maastricht Univ, Dept Cognit Neurosci, Fac Psychol & Neurosci, NL-6200 Maastricht, Netherlands. [Luh, Wen-Ming] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. [Tootell, Roger B. H.] MGH, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Liu, N (reprint author), NIMH, Sect Neurocircuitry, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM lning@mail.nih.gov OI Kriegeskorte, Nikolaus/0000-0001-7433-9005 FU National Institute of Mental Health Intramural Research Program; European Research Council [ERC-2010-StG 261352] FX This work was supported by the National Institute of Mental Health Intramural Research Program (N.L., N.K., M. M., F. H-B., W-M. L., and L. G. U.) and European Research Council Starting Grant (ERC-2010-StG 261352) to N.K. We thank Ziad S. Saad for his invaluable assistance with the analyses and James A. Ellis for help with animal training and collection of the imaging data. NR 36 TC 9 Z9 9 U1 0 U2 10 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 10 PY 2013 VL 33 IS 28 BP 11346 EP + DI 10.1523/JNEUROSCI.4180-12.2013 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 180TX UT WOS:000321622600004 PM 23843508 ER PT J AU Hutchins, BI Klenke, U Wray, S AF Hutchins, B. Ian Klenke, Ulrike Wray, Susan TI Calcium Release-Dependent Actin Flow in the Leading Process Mediates Axophilic Migration SO JOURNAL OF NEUROSCIENCE LA English DT Article ID NEURONAL MIGRATION; OLFACTORY SYSTEM; AXON GUIDANCE; SIGNALING MECHANISMS; HORMONE-1 NEURONS; RADIAL MIGRATION; GNRH-1 NEURONS; CELL-MIGRATION; BRAIN-STEM; GROWTH AB Proper assembly of neural circuits requires newly born neurons to migrate from their place of origin to their final location. Little is known about the mechanisms of axophilic neuronal migration, whereby neurons travel along axon pathways to navigate to their destinations. Gonadotropin-releasing hormone (GnRH)-expressing neurons migrate along olfactory axons from the nose into the forebrain during development, and were used as a model of axophilic migration. After migrating, GnRH neurons are located in the hypothalamus and are essential for puberty and maintenance of reproductive function. To gain a better understanding of the mechanisms underlying axophilic migration, we investigated in mice the regulation of movement from calcium signals to cytoskeletal dynamics. Live imaging revealed robust calcium activity during axophilic migration, and calcium release through IP3 receptors was found to stimulate migration. This occurred through a signaling pathway involving the calcium sensor calcium/calmodulin protein kinase kinase, AMP-activated kinase, and RhoA/ROCK. By imaging GnRH neurons expressing actin-GFP or Lifeact-RFP, calcium release was found to stimulate leading process actin flow away from the cell body. In contrast, actin contractions at the cell rear were unaffected by this calcium signaling pathway. These findings are the first to test the regulation of cytoskeletal dynamics in axophilic migration, and reveal mechanisms of movement that have broad implications for the migration of other CNS populations. C1 [Hutchins, B. Ian; Klenke, Ulrike; Wray, Susan] NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Hutchins, B. Ian] NIGMS, Postdoctoral Res Associate Program, NIH, Bethesda, MD 20892 USA. RP Wray, S (reprint author), 35 Convent Dr,Bldg 35,Room 3A1212, Bethesda, MD 20892 USA. EM wrays@ninds.nih.gov RI Hutchins, Ian/A-5713-2009; OI Hutchins, Ian/0000-0001-7657-552X; wray, susan/0000-0001-7670-3915 FU Intramural Research Program of National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH) [ZIA NS002824-21]; Postdoctoral Research Associate Program of National Institute of General Medical Sciences, NIH FX This work was supported by the Intramural Research Program of National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH) (Grant ZIA NS002824-21 to S. W.), and a postdoctoral fellowship from the Postdoctoral Research Associate Program of National Institute of General Medical Sciences, NIH (B. I. H.). We thank Drs. M. Sixt and R. Wedlich-Soldner for generously providing the Lifeact-RFP mice used in this study. NR 57 TC 8 Z9 8 U1 0 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 10 PY 2013 VL 33 IS 28 BP 11361 EP 11371 DI 10.1523/JNEUROSCI.3758-12.2013 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 180TX UT WOS:000321622600005 PM 23843509 ER PT J AU Lukacs, V Yudin, Y Hammond, GR Sharma, E Fukami, K Rohacs, T AF Lukacs, Viktor Yudin, Yevgen Hammond, Gerald R. Sharma, Esseim Fukami, Kiyoko Rohacs, Tibor TI Distinctive Changes in Plasma Membrane Phosphoinositides Underlie Differential Regulation of TRPV1 in Nociceptive Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID POTENTIAL VANILLOID-1 TRPV1; ROOT GANGLION NEURONS; COLD SENSOR TRPM8; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; CAPSAICIN RECEPTOR; CA2+-DEPENDENT DESENSITIZATION; PHOSPHOLIPASE-C; PROTEIN-KINASE; ION-CHANNEL; VOLTAGE SENSOR AB Transient Receptor Potential Vanilloid 1 (TRPV1) is a polymodal, Ca2+-permeable cation channel crucial to regulation of nociceptor responsiveness. Sensitization of TRPV1 by G-protein coupled receptor (GPCR) agonists to its endogenous activators, such as low pH and noxious heat, is a key factor in hyperalgesia during tissue injury as well as pathological pain syndromes. Conversely, chronic pharmacological activation of TRPV1 by capsaicin leads to calcium influx-induced adaptation of the channel. Paradoxically, both conditions entail activation of phospholipase C (PLC) enzymes, which hydrolyze phosphoinositides. We found that in sensory neurons PLC beta activation by bradykinin led to a moderate decrease in phosphatidylinositol-4,5-bisphosphate (PI(4,5)P-2), but no sustained change in the levels of its precursor PI(4)P. Preventing this selective decrease in PI(4,5)P-2 inhibited TRPV1 sensitization, while selectively decreasing PI(4,5)P-2 independently of PLC potentiated the sensitizing effect of protein kinase C (PKC) on the channel, thereby inducing increased TRPV1 responsiveness. Maximal pharmacological TRPV1 stimulation led to a robust decrease of both PI(4,5)P-2 and its precursor PI(4)P in sensory neurons. Attenuating the decrease of either lipid significantly reduced desensitization, and simultaneous reduction of PI(4,5)P-2 and PI(4)P independently of PLC inhibited TRPV1. We found that, on the mRNA level, the dominant highly Ca2+-sensitive PLC isoform in dorsal root ganglia is PLC delta 4. Capsaicin-induced desensitization of TRPV1 currents was significantly reduced, whereas capsaicin-induced nerve impulses in the skin-nerve preparation increased in mice lacking this isoform. We propose a comprehensive model in which differential changes in phosphoinositide levels mediated by distinct PLC isoforms result in opposing changes in TRPV1 activity. C1 [Lukacs, Viktor; Yudin, Yevgen; Sharma, Esseim; Rohacs, Tibor] Rutgers New Jersey Med Sch, Dept Physiol & Pharmacol, Newark, NJ 07103 USA. [Hammond, Gerald R.] NICHHD, Sect Mol Signal Transduct, Bethesda, MD 20892 USA. [Fukami, Kiyoko] Tokyo Univ Pharm & Life Sci, Lab Genome & Biosignal, Tokyo, Japan. RP Rohacs, T (reprint author), Rutgers New Jersey Med Sch, Dept Physiol & Pharmacol, 185 S Orange Ave, Newark, NJ 07103 USA. EM rohacsti@njms.rutgers.edu RI Hammond, Gerald/A-5759-2016; OI Hammond, Gerald/0000-0002-6660-3272; Lukacs, Viktor/0000-0003-3652-5469 FU National Institutes of Health [R01NS055159, R01GM093290] FX T.R. was supported by National Institutes of Health Grants R01NS055159 and R01GM093290. The authors thank Dr. Tamas Balla (National Institutes of Health) for insightful comments and for providing the Osh2-PH-GFP clone, Dr. David Julius for providing the TRPV1 clone, Dr. Yasushi Okamura (Osaka University, Japan) for providing the ci-VSP and dr-VSP clones, Drs. Nikita Gamper (University of Leeds) and Andrew Tinker (University College London) for providing the tubby-R33 2H-YFP clone, and Linda Zabelka for maintaining the mouse colony. NR 57 TC 26 Z9 28 U1 0 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 10 PY 2013 VL 33 IS 28 BP 11451 EP 11463 DI 10.1523/JNEUROSCI.5637-12.2013 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 180TX UT WOS:000321622600013 PM 23843517 ER PT J AU Ferguson, SM Phillips, PEM Roth, BL Wess, J Neumaier, JF AF Ferguson, Susan M. Phillips, Paul E. M. Roth, Bryan L. Wess, Juergen Neumaier, John F. TI Direct-Pathway Striatal Neurons Regulate the Retention of Decision-Making Strategies SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DORSAL STRIATUM; STRIATOPALLIDAL NEURONS; SYNAPTIC PLASTICITY; MEMORY-SYSTEMS; NUCLEUS; DOPAMINE; MODULATION; LESIONS; HIPPOCAMPUS; INVOLVEMENT AB The dorsal striatum has been implicated in reward-based decision making, but the role played by specific striatal circuits in these processes is essentially unknown. Using cell phenotype-specific viral vectors to express engineered G-protein-coupled DREADD (designer receptors exclusively activated by designer drugs) receptors, we enhanced G(i/o) - or G(s)-protein-mediated signaling selectively in direct-pathway (striatonigral) neurons of the dorsomedial striatum in Long-Evans rats during discrete periods of training of a high versus low reward-discrimination task. Surprisingly, these perturbations had no impact on reward preference, task performance, or improvement of performance during training. However, we found that transiently increasing G(i/o) signaling during training significantly impaired the retention of task strategies used to maximize reward obtainment during subsequent preference testing, whereas increasing G(s) signaling produced the opposite effect and significantly enhanced the encoding of a high-reward preference in this decision-making task. Thus, the fact that the endurance of this improved performance was significantly altered over time-long after these neurons were manipulated-indicates that it is under bidirectional control of canonical G-protein-mediated signaling in striatonigral neurons during training. These data demonstrate that cAMP-dependent signaling in direct-pathway neurons play a well-defined role in reward-related behavior; that is, they modulate the plasticity required for the retention of task-specific information that is used to improve performance on future renditions of the task. C1 [Ferguson, Susan M.] Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA 98101 USA. [Ferguson, Susan M.; Phillips, Paul E. M.; Neumaier, John F.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Phillips, Paul E. M.; Neumaier, John F.] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Div Chem Biol, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH, Drug Screening Program, Chapel Hill, NC 27599 USA. [Wess, Juergen] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Neumaier, JF (reprint author), Univ Washington, Harborview Med Ctr, 325 9th Ave, Seattle, WA 98104 USA. EM neumaier@uw.edu RI Ferguson, Susan/J-5427-2013; Phillips, Paul/E-7813-2013; Phillips, Paul/A-4463-2008; Roth, Bryan/F-3928-2010 OI Ferguson, Susan/0000-0002-2840-757X; Phillips, Paul/0000-0002-8749-7026; Phillips, Paul/0000-0002-8749-7026; FU National Institutes of Health [K99 DA024762, R01 MH079292, U19MH82441, R21 DA021273, R01 DA030807]; National Institute of Mental Health Psychoactive Drug Screening Program FX This work was supported by National Institutes of Health Grants K99 DA024762 (S.M.F.), R01 MH079292 (P.E.M.P.), U19MH82441 (B.L.R.), and R21 DA021273 and R01 DA030807 (J.F.N.) and National Institute of Mental Health Psychoactive Drug Screening Program (B.L.R.). We thank Dr. Michele Kelly and Hannah DeMeritt for packaging the viral vectors and Dr. Jerylin Gan for technical assistance. NR 37 TC 33 Z9 33 U1 2 U2 18 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 10 PY 2013 VL 33 IS 28 BP 11668 EP 11676 DI 10.1523/JNEUROSCI.4783-12.2013 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 180TX UT WOS:000321622600030 PM 23843534 ER PT J AU Chan, AWY AF Chan, Annie W-Y TI Functional organization and visual representations of human ventral lateral prefrontal cortex SO FRONTIERS IN PSYCHOLOGY LA English DT Review DE fMRI; prefrontal cortex; faces; eyes; functional organization ID INFERIOR FRONTAL JUNCTION; HUMAN FACE PERCEPTION; DISTRIBUTED NEURAL SYSTEM; HUMAN EXTRASTRIATE CORTEX; SUPERIOR TEMPORAL SULCUS; SPATIAL WORKING-MEMORY; FUSIFORM BODY AREAS; WORD FORM AREA; COGNITIVE CONTROL; OCCIPITOTEMPORAL CORTEX AB Recent neuroimaging studies in both human and non-human primates have identified face selective activation in the ventral lateral prefrontal cortex (VLPFC) even in the absence of working memory (WM) demands. Further, research has suggested that this face-selective response is largely driven by the presence of the eyes. However, the nature and origin of visual category responses in the VLPFC remain unclear. In a broader sense, how do these findings relate to our current understandings of lateral prefrontal cortex? What do these findings tell us about the underlying function and organization principles of the VLPFC? What is the future direction for investigating visual representations in this cortex? This review focuses on the function, topography, and circuitry of the VLPFC to enhance our understanding of the evolution and development of this cortex. C1 NIMH, Unit Learning & Plast, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Chan, AWY (reprint author), NIMH, Unit Learning & Plast, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM chanannie@mail.nih.gov NR 153 TC 8 Z9 8 U1 3 U2 6 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD JUL 9 PY 2013 VL 4 AR 371 DI 10.3389/fpsyg.2013.00371 PG 15 WC Psychology, Multidisciplinary SC Psychology GA AA5AN UT WOS:000331108000001 PM 23847558 ER PT J AU Dlugos, D Shinnar, S Cnaan, A Hu, FM Moshe, S Mizrahi, E Masur, D Sogawa, Y Le Pichon, JB Levine, C Hirtz, D Clark, P Adamson, PC Glauser, T AF Dlugos, Dennis Shinnar, Shlomo Cnaan, Avital Hu, Fengming Moshe, Solomon Mizrahi, Eli Masur, David Sogawa, Yoshi Le Pichon, J. B. Levine, Calley Hirtz, Deborah Clark, Peggy Adamson, Peter C. Glauser, Tracy CA Childhood Absence Epilepsy Study TI Pretreatment EEG in childhood absence epilepsy Associations with attention and treatment outcome SO NEUROLOGY LA English DT Article ID VALPROIC ACID; LAMOTRIGINE MONOTHERAPY; SEIZURES; ETHOSUXIMIDE; CHILDREN; DIAGNOSIS AB Objective: In children with newly diagnosed childhood absence epilepsy (CAE), determine pretreatment EEG features and their associations with baseline neuropsychological function and short-term treatment outcome. Methods: In a multicenter, randomized clinical trial, patients with CAE underwent a pretreatment, 1-hour video-EEG and neuropsychological testing with freedom-from-failure and seizure-freedom (SF) outcome assessed at the 16- to 20-week visit. Results: Detailed evaluation of the pretreatment EEG was possible for 99.8% of participants (445/446). Median time to first seizure was 6.0 minutes (range 0-59 minutes), median number of seizures was 5 (range 1-60), and median seizure duration was 10.8 seconds (range 3.3-77.6 seconds). Median duration of shortest seizure per EEG was 7.5 seconds (range 3.0-77.6 seconds). Seizure frequency was not associated with baseline measures of attention, executive function, or treatment outcome. Presence of a seizure lasting >= 20 seconds was noted in 29% of subjects (129/440); these children had higher median omissions T score on the Conners Continuous Performance Test (56.3 vs 51.6, p = 0.01). Patients with a shortest seizure of longer duration were more likely to demonstrate treatment success by both freedom-from-failure (p = 0.02) and SF (p = 0.005) criteria, even after controlling for age, treatment group, and number of seizures, with good predictive value (area under the curve 78% for SF). Conclusions: CAE is reliably and quickly confirmed by EEG. Occurrence of a seizure >= 20 seconds, but not overall seizure frequency, was associated with differential baseline measures of attention. Patients whose shortest pretreatment EEG seizure was longer in duration were more likely to achieve SF, regardless of treatment. C1 [Dlugos, Dennis; Levine, Calley; Adamson, Peter C.] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. [Shinnar, Shlomo; Moshe, Solomon; Masur, David; Sogawa, Yoshi] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Cnaan, Avital; Hu, Fengming] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Mizrahi, Eli; Le Pichon, J. B.] Baylor Coll Med, Houston, TX 77030 USA. [Hirtz, Deborah] NINDS, Bethesda, MD 20892 USA. [Clark, Peggy; Glauser, Tracy] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Clark, Peggy; Glauser, Tracy] Univ Cincinnati, Coll Med, Cincinnati, OH USA. RP Dlugos, D (reprint author), Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. EM dlugos@email.chop.edu FU NIH [U01-NS045911, U01-NS045803] FX Supported by the NIH (grants U01-NS045911and U01-NS045803). NR 18 TC 18 Z9 18 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 9 PY 2013 VL 81 IS 2 BP 150 EP 156 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 304JJ UT WOS:000330742600012 PM 23719147 ER PT J AU Ditiatkovski, M D'Souza, W Kesani, R Chin-Dusting, J de Haan, JB Remaley, A Sviridov, D AF Ditiatkovski, Michael D'Souza, Wilissa Kesani, Rajitha Chin-Dusting, Jaye de Haan, Judy B. Remaley, Alan Sviridov, Dmitri TI An Apolipoprotein A-I Mimetic Peptide Designed with a Reductionist Approach Stimulates Reverse Cholesterol Transport and Reduces Atherosclerosis in Mice SO PLOS ONE LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; APOE-NULL MICE; LESION FORMATION; HDL; BINDING; EFFLUX; VIVO; 4F; INFLAMMATION; MACROPHAGES AB Apolipoprotein A-I (apoA-I) mimetic peptides are considered a promising novel therapeutic approach to prevent and/or treat atherosclerosis. An apoA-I mimetic peptide ELK-2A2K2E was designed with a reductionist approach and has shown exceptional activity in supporting cholesterol efflux but modest anti-inflammatory and anti-oxidant properties in vitro. In this study we compared these in vitro properties with the capacity of this peptide to modify rates of reverse cholesterol transport and development of atherosclerosis in mouse models. The peptide enhanced the rate of reverse cholesterol transport in C57BL/6 mice and reduced atherosclerosis in Apoe(-/-) mice receiving a high fat diet. The peptide modestly reduced the size of the plaques in aortic arch, but was highly active in reducing vascular inflammation and oxidation. Administration of the peptide to Apoe(-/-) mice on a high fat diet reduced the levels of total, high density lipoprotein and non-high density lipoprotein cholesterol and triglycerides. It increased the proportion of smaller HDL particles in plasma at the expense of larger HDL particles, and increased the capacity of the plasma to support cholesterol efflux. Thus, ELK-2A2K2E peptide reduced atherosclerosis in Apoe(-/-) mice, however, the functional activity profile after chronic in vivo administration was different from that found in acute in vitro studies. C1 [Ditiatkovski, Michael; D'Souza, Wilissa; Kesani, Rajitha; Chin-Dusting, Jaye; de Haan, Judy B.; Sviridov, Dmitri] Baker Heart & Diabet Inst, Melbourne, Vic, Australia. [Remaley, Alan] NHLBI, Lipoprot Sect, NIH, Bethesda, MD 20892 USA. RP Sviridov, D (reprint author), Baker Heart & Diabet Inst, Melbourne, Vic, Australia. EM Dmitri.Sviridov@Bakeridi.edu.au RI Sviridov, Dmitri/E-7943-2010 FU National Health and Medical Research Council of Australia [GNT1003106]; Victorian Government's OIS Program; Intramural Research Program of the National Institutes of Health; National Heart, Lung and Blood Institute FX This work was supported by the National Health and Medical Research Council of Australia (GNT1003106) and in part by the Victorian Government's OIS Program. DS is a Fellow of the National Health and Medical Research Council of Australia. This research was supported in part by the Intramural Research Program of the National Institutes of Health, and National Heart, Lung and Blood Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 16 Z9 16 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 9 PY 2013 VL 8 IS 7 AR e68802 DI 10.1371/journal.pone.0068802 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JD UT WOS:000321736900114 PM 23874769 ER PT J AU Huser, V Cimino, JJ AF Huser, Vojtech Cimino, James J. TI Linking ClinicalTrials.gov and PubMed to Track Results of Interventional Human Clinical Trials SO PLOS ONE LA English DT Article ID PUBLICATION BIAS; REGISTRATION; UPDATE AB Objective: In an effort to understand how results of human clinical trials are made public, we analyze a large set of clinical trials registered at ClinicalTrials.gov, the world's largest clinical trial registry. Materials and Methods: We considered two trial result artifacts: (1) existence of a trial result journal article that is formally linked to a registered trial or (2) the deposition of a trial's basic summary results within the registry. Results: The study sample consisted of 8907 completed, interventional, phase 2-or-higher clinical trials that were completed in 2006-2009. The majority of trials (72.2%) had no structured trial-article link present. A total of 2367 trials (26.6%) deposited basic summary results within the registry. Of those, 969 trials (10.9%) were classified as trials with extended results and 1398 trials (15.7%) were classified as trials with only required basic results. The majority of the trials (54.8%) had no evidence of results, based on either linked result articles or basic summary results (silent trials), while a minimal number (9.2%) report results through both registry deposition and publication. Discussion: Our study analyzes the body of linked knowledge around clinical trials (which we refer to as the "trialome"). Our results show that most trials do not report results and, for those that do, there is minimal overlap in the types of reporting. We identify several mechanisms by which the linkages between trials and their published results can be increased. Conclusion: Our study shows that even when combining publications and registry results, and despite availability of several information channels, trial sponsors do not sufficiently meet the mandate to inform the public either via a linked result publication or basic results submission. C1 [Huser, Vojtech; Cimino, James J.] NIH, Ctr Clin, Lab Informat Dev, Bethesda, MD 20892 USA. RP Huser, V (reprint author), NIH, Ctr Clin, Lab Informat Dev, Bethesda, MD 20892 USA. EM vojtech.huser@nih.gov OI Cimino, James/0000-0003-4101-1622 FU Intramural Research Program of the National Institutes of Health Clinical Center; National Library of Medicine FX This research was supported by the Intramural Research Program of the National Institutes of Health Clinical Center and the National Library of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 11 Z9 11 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 9 PY 2013 VL 8 IS 7 AR UNSP e68409 DI 10.1371/journal.pone.0068409 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JD UT WOS:000321736900085 PM 23874614 ER PT J AU Lin, YJ Lan, YC Hung, CH Lin, TH Huang, SM Liao, CC Lin, CW Lai, CH Tien, N Liu, X Ho, MW Chien, WK Chen, JH Wang, JH Tsai, FJ AF Lin, Ying-Ju Lan, Yu-Ching Hung, Chien-Hui Lin, Ting-Hsu Huang, Shao-Mei Liao, Chiu-Chu Lin, Cheng-Wen Lai, Chih-Ho Tien, Ni Liu, Xiang Ho, Mao-Wang Chien, Wen-Kuei Chen, Jin-Hua Wang, Jen-Hsien Tsai, Fuu-Jen TI Variants in ZNRD1 Gene Predict HIV-1/AIDS Disease Progression in a Han Chinese Population in Taiwan SO PLOS ONE LA English DT Article ID MAJOR DETERMINANTS; HIV-INFECTION; HOST CONTROL; HLA-C; ASSOCIATION; REPLICATION; EXPRESSION; GENOME; RNA; DATABASE AB Patients demonstrate notable variations in disease progression following human immunodeficiency virus (HIV) infection. We aimed to identify ZNRD1 and RNF39 genetic variants linked to AIDS progression. We conducted a genetic association study in HIV-1-infected Han Chinese patients residing in Taiwan. The clinical characteristics of 143 HIV-1-infected patients were measured, and patients were split into 2 groups: AIDS progression and AIDS non-progression. Genotyping of ZNRD1 and RNF39 was performed in all participants. We found that patients in the AIDS progression group had higher HIV-1 viral loads and lower CD4 cell counts than did patients in the AIDS non-progression group. The frequency of the AA genotype of ZNRD1 (rs16896970) was lower in the AIDS progression group than in the AIDS non-progression group. Patients with AA genotypes had lower levels of HIV-1 viral loads and higher levels of CD4 cell counts than did patients with AG+GG genotypes. AIDS progression in patients with the AA group is significantly different from that in patients with the AG and GG groups by using Kaplan-Meier survival analysis. The hazard ratio for progression was lower in the AA group than in the AG and GG groups. We identified a SNP that contributes to AIDS progression in HIV-1-infected patients in this population. This SNP had a significant protective influence on AIDS progression, and polymorphisms of the ZNRD1 gene may play a role in the pathogenesis of HIV-1 infection. C1 [Lin, Ying-Ju; Lin, Ting-Hsu; Huang, Shao-Mei; Liao, Chiu-Chu; Tsai, Fuu-Jen] China Med Univ Hosp, Dept Med Res, Taichung, Taiwan. [Lin, Ying-Ju; Tsai, Fuu-Jen] China Med Univ, Sch Chinese Med, Taichung, Taiwan. [Lan, Yu-Ching] China Med Univ, Dept Hlth Risk Management, Taichung, Taiwan. [Hung, Chien-Hui] Chang Gung Univ, Grad Inst Clin Med Sci, Chiayi, Taiwan. [Lin, Cheng-Wen; Tien, Ni] China Med Univ, Dept Med Lab Sci & Biotechnol, Taichung, Taiwan. [Lai, Chih-Ho] China Med Univ, Sch Med, Dept Microbiol, Taichung, Taiwan. [Liu, Xiang] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Ho, Mao-Wang; Wang, Jen-Hsien] China Med Univ Hosp, Dept Internal Med, Infect Dis Sect, Taichung, Taiwan. [Chien, Wen-Kuei; Chen, Jin-Hua] China Med Univ, Biostat Ctr, Taichung, Taiwan. [Tsai, Fuu-Jen] Asia Univ, Dept Biotechnol, Taichung, Taiwan. RP Wang, JH (reprint author), China Med Univ Hosp, Dept Internal Med, Infect Dis Sect, Taichung, Taiwan. EM jenhsien@mail.cmuh.org.tw; d0704@mail.cmuh.org.tw RI Liu, Xiang/F-5731-2014; Tsai, Fuu-Jen/J-4140-2015; Lai, Chih-Ho/M-2433-2013; Lan, Yu-Ching/F-2449-2017 OI Lai, Chih-Ho/0000-0001-9229-818X; Lan, Yu-Ching/0000-0003-4781-6405 FU China Medical University [CMU100-S-01]; China Medical University Hospital [DMR-100-060]; Republic of China National Science Council [NSC 99-2628-B-039-001-MY3, NSC100-2320-B-039-012-MY3] FX Support for this research was provided by China Medical University (CMU100-S-01), China Medical University Hospital (DMR-100-060), and the Republic of China National Science Council (NSC 99-2628-B-039-001-MY3; NSC100-2320-B-039-012-MY3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 3 Z9 3 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 9 PY 2013 VL 8 IS 7 AR e67572 DI 10.1371/journal.pone.0067572 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JD UT WOS:000321736900013 ER PT J AU Coady, SA Wagner, E AF Coady, Sean A. Wagner, Elizabeth TI Sharing individual level data from observational studies and clinical trials: a perspective from NHLBI SO TRIALS LA English DT Editorial Material DE Data sharing; Clinical trials; Cohort studies; HIPAA ID OPEN SCIENCE; RAW DATA; PRIVACY; ACCESS AB There are numerous benefits to the research community from data sharing, and yet the open sharing of participant level data is not without potential pitfalls. In addition to the scientific community, the interests of study participants who volunteered their data must be considered, along with the interests of study investigators who expend a substantial amount of effort into the design, conduct, and analytical plans for the study. The National Heart, Lung, and Blood Institute (NHLBI) has developed a data-sharing protocol focused on balancing the interests of study participants, study investigators, and the research community with independent oversight by the NHLBI IRB. The data repository presently includes individual level data on more than 560,000 participants from 100 Institute-supported clinical trials and observational studies. C1 [Coady, Sean A.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Wagner, Elizabeth] Div Blood Dis & Resources, Bethesda, MD USA. RP Coady, SA (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 10200, Bethesda, MD 20892 USA. EM coadys@nhlbi.nih.gov NR 14 TC 14 Z9 14 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD JUL 9 PY 2013 VL 14 AR 201 DI 10.1186/1745-6215-14-201 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 198JP UT WOS:000322919300001 PM 23837497 ER PT J AU Murtas, D Maric, D De Giorgi, V Reinboth, J Worschech, A Fetsch, P Filie, A Ascierto, ML Bedognetti, D Liu, Q Uccellini, L Chouchane, L Wang, E Marincola, FM Tomei, S AF Murtas, D. Maric, D. De Giorgi, V. Reinboth, J. Worschech, A. Fetsch, P. Filie, A. Ascierto, M. L. Bedognetti, D. Liu, Q. Uccellini, L. Chouchane, L. Wang, E. Marincola, F. M. Tomei, S. TI IRF-1 responsiveness to IFN-gamma predicts different cancer immune phenotypes SO BRITISH JOURNAL OF CANCER LA English DT Article DE IRF-1; IFN-gamma; immune phenotype; NF-kappa B; TNF-alpha; nuclear translocation ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; TRANSCRIPTION FACTORS; SIGNALING PATHWAYS; INTERFERON-GAMMA; GENE-EXPRESSION; TNF-ALPHA; ACTIVATION; MELANOMA; PROMOTER AB Background: Several lines of evidence suggest a dichotomy between immune active and quiescent cancers, with the former associated with a good prognostic phenotype and better responsiveness to immunotherapy. Central to such dichotomy is the master regulator of the acute inflammatory process interferon regulatory factor (IRF)-1. However, it remains unknown whether the responsiveness of IRF-1 to cytokines is able to differentiate cancer immune phenotypes. Methods: IRF-1 activation was measured in 15 melanoma cell lines at basal level and after treatment with IFN-gamma, TNF-alpha and a combination of both. Microarray analysis was used to compare transcriptional patterns between cell lines characterised by high or low IRF-1 activation. Results: We observed a strong positive correlation between IRF-1 activation at basal level and after IFN-gamma and TNF-alpha treatment. Microarray demonstrated that three cell lines with low and three with high IRF-1 inducible translocation scores differed in the expression of 597 transcripts. Functional interpretation analysis showed mTOR and Wnt/beta-cathenin as the top downregulated pathways in the cell lines with low inducible IRF-1 activation, suggesting that a low IRF-1 inducibility recapitulates a cancer phenotype already described in literature characterised by poor prognosis. Conclusion: Our findings support the central role of IRF-1 in influencing different tumour phenotypes. C1 [Murtas, D.; De Giorgi, V.; Reinboth, J.; Ascierto, M. L.; Bedognetti, D.; Liu, Q.; Uccellini, L.; Wang, E.; Marincola, F. M.; Tomei, S.] NIH, IDIS, Dept Transfus Med, Clin Ctr & Trans NIH,CHI, Bethesda, MD 20892 USA. [Murtas, D.] Univ Cagliari, Dept Biomed Sci, Sect Cytomorphol, I-09123 Cagliari, Italy. [Maric, D.] NINDS, Flow Cytometry Core Facil, Bethesda, MD 20892 USA. [Reinboth, J.] Univ Wurzburg, Dept Biochem, Bioctr, D-97070 Wurzburg, Germany. [Reinboth, J.] San Diego Sci Ctr, Genelux Corp, San Diego, CA 92109 USA. [Worschech, A.; Chouchane, L.; Tomei, S.] Weill Cornell Med Coll Qatar, Dept Med Genet, Doha, Qatar. [Fetsch, P.; Filie, A.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Ascierto, M. L.] Univ Genoa, CEBR, I-16126 Genoa, Italy. [Ascierto, M. L.] Natl Canc Inst Fdn G Pascale, I-80131 Naples, Italy. [Uccellini, L.] Univ Milan, L Sacco Hosp, Inst Infect & Trop Dis, I-20122 Milan, Italy. [Marincola, F. M.] Sidra Med & Res Ctr, Doha, Qatar. RP Tomei, S (reprint author), NIH, IDIS, Dept Transfus Med, Clin Ctr & Trans NIH,CHI, Bldg 10, Bethesda, MD 20892 USA. EM sat2024@qatar-med.cornell.edu RI De Giorgi, Valeria/D-4582-2017; OI Bedognetti, Davide/0000-0002-5857-773X FU National Institutes of Health; Conquer Cancer Foundation of the American Society of Clinical Oncology; Regione Autonoma della Sardegna, Italy FX This study was financed by the National Institutes of Health; all NIH affiliated authors performed this work as part of their official duties. DB's scholarship was supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology (2011 Young Investigator Award). DM's scholarship was supported by the Master and Back Program of Regione Autonoma della Sardegna, Italy. NR 32 TC 16 Z9 16 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 9 PY 2013 VL 109 IS 1 BP 76 EP 82 DI 10.1038/bjc.2013.335 PG 7 WC Oncology SC Oncology GA 181XB UT WOS:000321702400011 PM 23807161 ER PT J AU Crocetti, E De Angelis, R Buzzoni, C Mariotto, A Storm, H Colonna, M Zanetti, R Serraino, D Michiara, M Cirilli, C Iannelli, A Mazzoleni, G Sechi, O Gonzalez, MES Guzzinati, S Capocaccia, R Dal Maso, L AF Crocetti, E. De Angelis, R. Buzzoni, C. Mariotto, A. Storm, H. Colonna, M. Zanetti, R. Serraino, D. Michiara, M. Cirilli, C. Iannelli, A. Mazzoleni, G. Sechi, O. Gonzalez, M. E. Sanoja Guzzinati, S. Capocaccia, R. Dal Maso, L. CA AIRTUM Working Grp TI Cancer prevalence in United States, Nordic Countries, Italy, Australia, and France: an analysis of geographic variability SO BRITISH JOURNAL OF CANCER LA English DT Article DE cancer prevalence; incidence; survival; ageing ID PROSTATE-CANCER; REGISTRY AREAS; SURVIVAL; POPULATION; TIME AB Background: The objectives of this study were to quantitatively assess the geographic heterogeneity of cancer prevalence in selected Western Countries and to explore the associations between its determinants. Methods: For 20 cancer sites, 5-year cancer prevalence, incidence, and survival were observed and age standardised for the mid 2000s in the United States, Nordic European Countries, Italy, Australia, and France. Results: In Italy, 5-year crude prevalence for all cancers was 1.9% in men and 1.7% in women, while it was similar to 1.5% in all other countries and sexes. After adjustment for the different age distribution of the populations, cancer prevalence in the United States was higher (20% in men and 10% in women) than elsewhere. For all cancers combined, the geographic heterogeneities were limited, though relevant for specific cancers (e. g., prostate, showing >30% higher prevalence in the United States, or lung, showing >50% higher prevalence in USA women than in other countries). For all countries, the correlations between differences of prevalence and differences of incidence were >0.9, while prevalence and survival were less consistently correlated. Conclusion: Geographic differences and magnitude of crude cancer prevalence were more strongly associated with incidence rates, influenced by population ageing, than with survival rates. These estimates will be helpful in allocating appropriate resources. C1 [Crocetti, E.; Buzzoni, C.] ISPO, UO Epidemiol Clin & Descrittiva, Tuscany Canc Registry, I-50141 Florence, Italy. [De Angelis, R.; Capocaccia, R.] ISS, CNESPS, Rome, Italy. [Buzzoni, C.] AIRTUM Database, Florence, Italy. [Mariotto, A.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Storm, H.] Kraeftens Bekaempelse, Danish Canc Soc, DK-2100 Copenhagen O, Denmark. [Colonna, M.] CHU Grenoble, Isere Canc Registry, F-38043 Grenoble 9, France. [Zanetti, R.] CPO, Registro Tumori Piemonte, Turin, Italy. [Serraino, D.] Cent Hlth Direct, Friuli Venezia Giulia Canc Registry, Udine, Italy. [Michiara, M.] Univ Hosp Parma, Parma Prov Canc Registry, Parma, Italy. [Cirilli, C.] Univ Modena & Reggio Emilia, Dept Oncol Hematol & Resp Dis, Modena Canc Registry, Modena, Italy. [Iannelli, A.] Salerno Canc Registry, Salerno, Italy. [Mazzoleni, G.] Alto Adige Sudtirol Canc Registry, Bolzano, Italy. [Sechi, O.] Canc Registry Sassari, Sassari, Italy. [Gonzalez, M. E. Sanoja] Local Hlth Agcy, Sondrio Canc Registry, Sondrio, Italy. [Guzzinati, S.] Ist Oncol Veneto IRCCS, Registro Tumori Veneto, Padua, Italy. [Dal Maso, L.] Ctr Riferimento Oncol IRCCS, Epidemiol & Biostat Unit, Sci Directorate, I-33081 Aviano, Pordenone, Italy. RP Crocetti, E (reprint author), ISPO, UO Epidemiol Clin & Descrittiva, Tuscany Canc Registry, Via Oblate 2, I-50141 Florence, Italy. EM e.crocetti@ispo.toscana.it; epidemiology@cro.it RI Guzzinati, Stefano/K-4987-2012; OI Storm, Hans/0000-0001-7223-8198; PIRO, SARA/0000-0003-4198-7035; dal maso, luigino/0000-0001-6163-200X; Serraino, Diego/0000-0003-0565-8920; guzzinati, stefano/0000-0002-4908-5506 FU Italian Association for Cancer Research; Italian Ministry of Health (Programma Integrato Oncologia) FX We thank the Cancer and Screening Unit of the Australian Institute of Health and Welfare for providing data for Australia and helpful comments. We also thank Mrs Luigina Mei for editorial assistance. This work was supported by the Italian Association for Cancer Research and by the Italian Ministry of Health (Programma Integrato Oncologia). NR 40 TC 12 Z9 12 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 9 PY 2013 VL 109 IS 1 BP 219 EP 228 DI 10.1038/bjc.2013.311 PG 10 WC Oncology SC Oncology GA 181XB UT WOS:000321702400028 PM 23799856 ER PT J AU Clarke, CA Morton, LM Lynch, C Pfeiffer, RM Hall, EC Gibson, TM Weisenburger, DD Martinez-Maza, O Hussain, SK Yang, J Chang, ET Engels, EA AF Clarke, C. A. Morton, L. M. Lynch, C. Pfeiffer, R. M. Hall, E. C. Gibson, T. M. Weisenburger, D. D. Martinez-Maza, O. Hussain, S. K. Yang, J. Chang, E. T. Engels, E. A. TI Risk of lymphoma subtypes after solid organ transplantation in the United States SO BRITISH JOURNAL OF CANCER LA English DT Article ID NON-HODGKIN-LYMPHOMA; POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISORDERS; HIV-POSITIVE INDIVIDUALS; KIDNEY-TRANSPLANTATION; CANCER-RISK; HEPATITIS-C; RECIPIENTS; IMMUNOSUPPRESSION; REGISTRY; PEOPLE AB Background: Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes. Methods: We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987-2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation. Results: The risk varied widely across subtypes, with strong elevations (SIRs 10-100) for hepatosplenic T-cell lymphoma, Burkitt's lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2-4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (<20 years) and those receiving organs other than kidneys. Conclusion: Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma. C1 [Clarke, C. A.; Yang, J.] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [Clarke, C. A.; Chang, E. T.] Stanford Univ, Sch Med, Dept Hlth Res & Policy & Med, Div Epidemiol, Stanford, CA 94305 USA. [Morton, L. M.; Pfeiffer, R. M.; Hall, E. C.; Gibson, T. M.; Engels, E. A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Lynch, C.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Weisenburger, D. D.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Martinez-Maza, O.; Hussain, S. K.] Univ Calif Los Angeles, Dept Epidemiol, Los Angeles, CA USA. RP Clarke, CA (reprint author), Canc Prevent Inst Calif, 2201 Walnut Ave,Suite 300, Fremont, CA 94538 USA. EM tina@cpic.org RI Martinez-Maza, Otoniel/B-2667-2009; Morton, Lindsay/B-5234-2015 OI Martinez-Maza, Otoniel/0000-0003-1364-0675; Morton, Lindsay/0000-0001-9767-2310 FU National Cancer Institute's Intramural Research Program; Surveillance, Epidemiology and End Results (SEER) program [HHSN 261201000040C]; Arbor Research Collaborative for Health in Ann Arbor, MI [HHSH234200537009C]; National Program of Cancer Registries of the Centers for Disease Control and Prevention: California [1U58 DP000807-01]; National Program of Cancer Registries of the Centers for Disease Control and Prevention, Colorado [U58 DP000848-04]; National Program of Cancer Registries of the Centers for Disease Control and Prevention, Georgia [5U58DP000817-05]; National Program of Cancer Registries of the Centers for Disease Control and Prevention, Illinois [5658DP 000805-04]; National Program of Cancer Registries of the Centers for Disease Control and Prevention, Michigan [5U58DP000812-03]; National Program of Cancer Registries of the Centers for Disease Control and Prevention, New Jersey [5U58/DP000808-05]; National Program of Cancer Registries of the Centers for Disease Control and Prevention, New York [15-0351]; National Program of Cancer Registries of the Centers for Disease Control and Prevention, North Carolina [U58DP 000832]; National Program of Cancer Registries of the Centers for Disease Control and Prevention, Texas [5U58DP000824-04]; SEER Program of the National Cancer Institute: California [HHSN261201000040C, 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 [HHSN261201000032C, N01-PC-35143]; SEER Program of the National Cancer Institute, New Jersey [HHSN261201000027C N01-PC-54405]; 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 state of California [14-2491]; Cancer Surveillance Improvement Initiative state of Colorado [14-2491]; Cancer Surveillance Improvement Initiative state of Connecticut [14-2491]; Cancer Surveillance Improvement Initiative state of Illinois [14-2491]; Cancer Surveillance Improvement Initiative state of Iowa [14-2491]; Cancer Surveillance Improvement Initiative state of New Jersey [14-2491]; Cancer Surveillance Improvement Initiative state of New York [14-2491]; Cancer Surveillance Improvement Initiative state of Texas [14-2491]; Cancer Surveillance Improvement Initiative state of Washington [14-2491]; Fred Hutchinson Cancer Research Center in Seattle, WA FX This research was supported by the National Cancer Institute's Intramural Research Program and the Surveillance, Epidemiology and End Results (SEER) program under contract HHSN 261201000040C awarded to the Cancer Prevention Institute of California (CPIC). During the initial period when registry linkages were performed, the SRTR was managed by Arbor Research Collaborative for Health in Ann Arbor, MI (contract HHSH234200537009C); beginning in September 2010, the SRTR was managed by Minneapolis Medical Research Foundation in Minneapolis, MN (HHSH250201000018C). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP000817-05), Illinois (5658DP 000805-04), Michigan (5U58DP000812-03), New Jersey (5U58/DP000808-05), New York (15-0351), North Carolina (U58DP 000832), and Texas (5U58DP000824-04). The following cancer registries were supported by the SEER Program of the National Cancer Institute: California (contracts HHSN261201000040C, HHSN261201000035C, and HHSN261201000034C), Connecticut (HHSN261201000024C), Hawaii (HHSN261201000037C, N01-PC-35137, and N01-PC-35139), Iowa (HHSN261201000032C, N01-PC-35143), New Jersey (HHSN261201000027C N01-PC-54405), Seattle-Puget Sound (N01-PC-35142), and Utah (HHSN261201000026C). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, New Jersey, New York (Cancer Surveillance Improvement Initiative 14-2491), Texas, and Washington, as well as the Fred Hutchinson Cancer Research Center in Seattle, WA. We gratefully acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration (including Monica Lin), the SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, Jon Snyder), and the following cancer registries: the states of California (Christina Clarke), Colorado (Jack Finch), Connecticut (Lou Gonsalves), Florida (Brad Wohler), Georgia (Rana Bayakly), Hawaii (Marc Goodman), Iowa (Charles Lynch), Illinois (Lori Koch), Michigan (Glenn Copeland), New Jersey (Karen Pawlish, Xiaoling Niu), New York (Amy Kahn), North Carolina (Chandrika Rao), Texas (Melanie Williams), and Utah (Janna Harrell), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). We also thank analysts at Information Management Services for programming support (David Castenson, Ruth Parsons). NR 44 TC 24 Z9 27 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 9 PY 2013 VL 109 IS 1 BP 280 EP 288 DI 10.1038/bjc.2013.294 PG 9 WC Oncology SC Oncology GA 181XB UT WOS:000321702400036 PM 23756857 ER PT J AU Jay, SM Murthy, AC Hawkins, JF Wortzel, JR Steinhauser, ML Alvarez, LM Gannon, J Macrae, CA Griffith, LG Lee, RT AF Jay, Steven M. Murthy, Ashwin C. Hawkins, Jessica F. Wortzel, Joshua R. Steinhauser, Matthew L. Alvarez, Luis M. Gannon, Joseph Macrae, Calum A. Griffith, Linda G. Lee, Richard T. TI An Engineered Bivalent Neuregulin Protects Against Doxorubicin-Induced Cardiotoxicity With Reduced Proneoplastic Potential SO CIRCULATION LA English DT Article DE anthracyclines; translational cancer chemotherapy protocols; protein engineering ID PROGENITOR-CELL FUNCTION; BREAST-CANCER; VENTRICULAR MYOCYTES; CARDIAC MYOCYTES; HEART-FAILURE; CARDIOMYOPATHY; INJURY; HER2; ANTHRACYCLINES; PROLIFERATION AB Background Doxorubicin (DOXO) is an effective anthracycline chemotherapeutic, but its use is limited by cumulative dose-dependent cardiotoxicity. Neuregulin-1 is an ErbB receptor family ligand that is effective against DOXO-induced cardiomyopathy in experimental models but is also proneoplastic. We previously showed that an engineered bivalent neuregulin-1 (NN) has reduced proneoplastic potential in comparison with the epidermal growth factor-like domain of neuregulin-1 (NRG), an effect mediated by receptor biasing toward ErbB3 homotypic interactions uncommonly formed by native neuregulin-1. Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced proneoplastic effects in comparison with NRG. Methods and Results NN was expressed as a maltose-binding protein fusion in Escherichia coli. As established previously, NN stimulated antineoplastic or cytostatic signaling and phenotype in cancer cells, whereas NRG stimulated proneoplastic signaling and phenotype. In neonatal rat cardiomyocytes, NN and NRG induced similar downstream signaling. NN, like NRG, attenuated the double-stranded DNA breaks associated with DOXO exposure in neonatal rat cardiomyocytes and human cardiomyocytes derived from induced pluripotent stem cells. NN treatment significantly attenuated DOXO-induced decrease in fractional shortening as measured by blinded echocardiography in mice in a chronic cardiomyopathy model (57.7 +/- 0.6% versus 50.9 +/- 2.6%, P=0.004), whereas native NRG had no significant effect (49.4 +/- 3.7% versus 50.9 +/- 2.6%, P=0.813). Conclusions NN is a cardioprotective agent that promotes cardiomyocyte survival and improves cardiac function in DOXO-induced cardiotoxicity. Given the reduced proneoplastic potential of NN versus NRG, NN has translational potential for cardioprotection in patients with cancer receiving anthracyclines. C1 [Jay, Steven M.; Murthy, Ashwin C.; Hawkins, Jessica F.; Wortzel, Joshua R.; Steinhauser, Matthew L.; Gannon, Joseph; Macrae, Calum A.; Lee, Richard T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Cardiovasc, Boston, MA 02115 USA. [Jay, Steven M.; Wortzel, Joshua R.; Steinhauser, Matthew L.; Macrae, Calum A.; Lee, Richard T.] MIT, Harvard Stem Cell Inst, Cambridge, MA 02139 USA. [Jay, Steven M.; Alvarez, Luis M.; Griffith, Linda G.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Jay, Steven M.; Alvarez, Luis M.; Griffith, Linda G.] MIT, Ctr Gynepathol Res, Cambridge, MA 02139 USA. [Alvarez, Luis M.] NCI, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. RP Lee, RT (reprint author), Partners Res Facil, 65 Landsdowne St,Room 280, Cambridge, MA 02139 USA. EM rlee@partners.org OI Jay, Steven/0000-0002-3827-5988 FU US Department of Defense CDMRP Breast Cancer Research Program Postdoctoral Fellowship [W81XWH-11-1-0035]; National Institutes of Health [HL112905, DK090147, AG032977, DE019523, U54-CA112967, EB003805]; US Department of Defense CDMRP Orthopedic Research Program Career Development Award [W81XWH-11-1-0821]; Sarnoff Fellowship; Hertz Fellowship; Harvard Stem Cell Institute FX Funding was provided by a US Department of Defense CDMRP Breast Cancer Research Program Postdoctoral Fellowship (W81XWH-11-1-0035) to Dr Jay, by National Institutes of Health grants HL112905 (to Dr Jay), DK090147 (to Dr Steinhauser), AG032977 (to Dr Lee), DE019523 and U54-CA112967 (to Dr Griffith), EB003805 (to Drs Griffith and Lee), by a US Department of Defense CDMRP Orthopedic Research Program Career Development Award (W81XWH-11-1-0821) to Dr Alvarez, by a Sarnoff Fellowship to Dr Murthy, by a Hertz Fellowship to Dr Alvarez, and by the Harvard Stem Cell Institute to J.R. Wortzel and Drs Macrae, and Lee. NR 36 TC 23 Z9 23 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 9 PY 2013 VL 128 IS 2 BP 152 EP 161 DI 10.1161/CIRCULATIONAHA.113.002203 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 178ZZ UT WOS:000321487200016 PM 23757312 ER PT J AU Pang, LJ Tian, HY Chang, N Yi, J Xue, LX Jiang, B Gorospe, M Zhang, XW Wang, WG AF Pang, Lijun Tian, Haiyan Chang, Na Yi, Jie Xue, Lixiang Jiang, Bin Gorospe, Myriam Zhang, Xiaowei Wang, Wengong TI Loss of CARM1 is linked to reduced HuR function in replicative senescence SO BMC MOLECULAR BIOLOGY LA English DT Article DE CARM1; HuR methylation; mRNA turnover; Replicative senescence ID RNA-BINDING PROTEIN; ELAV-LIKE PROTEIN; MESSENGER-RNA; CYCLOOXYGENASE-2 EXPRESSION; ARGININE METHYLATION; CYTOPLASMIC HUR; NUCLEAR EXPORT; IN-VIVO; METHYLTRANSFERASE; DIFFERENTIATION AB Background: The co-activator-associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of HuR. However, the functional impact of this modification is not fully understood. Here, we investigated the influence of HuR methylation by CARM1 upon the turnover of HuR target mRNAs encoding senescence-regulatory proteins. Results: Changing the methylation status of HuR in HeLa cells by either silencing CARM1 or mutating the major methylation site (R217K) greatly diminished the effect of HuR in regulating the turnover of mRNAs encoding cyclin A, cyclin B1, c-fos, SIRT1, and p16. Although knockdown of CARM1 or HuR individually influenced the expression of cyclin A, cyclin B1, c-fos, SIRT1, and p16, joint knockdown of both CARM1 and HuR did not show further effect. Methylation by CARM1 enhanced the association of HuR with the 3'UTR of p16 mRNA, but not with the 3'UTR of cyclin A, cyclin B1, c-fos, or SIRT1 mRNAs. In senescent human diploid fibroblasts (HDFs), reduced CARM1 was accompanied by reduced HuR methylation. In addition, knockdown of CARM1 or mutation of the major methylation site of HuR in HDF markedly impaired the ability of HuR to regulate the expression of cyclin A, cyclin B1, c-fos, SIRT1, and p16 as well to maintain a proliferative phenotype. Conclusion: CARM1 represses replicative senescence by methylating HuR and thereby enhancing HuR's ability to regulate the turnover of cyclin A, cyclin B1, c-fos, SIRT1, and p16 mRNAs. C1 [Pang, Lijun; Tian, Haiyan; Chang, Na; Yi, Jie; Xue, Lixiang; Jiang, Bin; Zhang, Xiaowei; Wang, Wengong] Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Beijing 100191, Peoples R China. [Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. RP Zhang, XW (reprint author), Peking Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, 38 Xueyuan Rd, Beijing 100191, Peoples R China. EM xiaoweizhang@bjmu.edu.cn; wwg@bjmu.edu.cn FU National Science Foundation of China [8123008, 81070274, 30973147, 81170320]; Ministry of Education of People's Republic of China [B07001]; Research Fund for the Doctoral Program of higher Education of China [20090001110059]; National Institute on Aging-IRP, National Institutes of health FX This work was supported by the grants 8123008, 81070274, 30973147, and 81170320 from National Science Foundation of China; Grant B07001 from the Ministry of Education of People's Republic of China (111 project); Grant 20090001110059 from the Research Fund for the Doctoral Program of higher Education of China. MG was supported by the National Institute on Aging-IRP, National Institutes of health. We thank J. Shay for generously providing us the IDH4 cells. NR 36 TC 13 Z9 13 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2199 J9 BMC MOL BIOL JI BMC Mol. Biol. PD JUL 9 PY 2013 VL 14 AR 15 DI 10.1186/1471-2199-14-15 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 186KU UT WOS:000322043600001 PM 23837869 ER PT J AU Libich, DS Fawzi, NL Ying, JF Clore, GM AF Libich, David S. Fawzi, Nicolas L. Ying, Jinfa Clore, G. Marius TI Probing the transient dark state of substrate binding to GroEL by relaxation-based solution NMR SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE w supramolecular machine; protein-protein interactions; conformational sampling ID NUCLEAR-MAGNETIC-RESONANCE; ATOMIC-RESOLUTION DYNAMICS; CHAPERONIN GROEL; SECONDARY STRUCTURE; STRUCTURAL MODEL; DISPERSION NMR; SPECTROSCOPY; PROTEINS; MECHANISM; KINETICS AB The mechanism whereby the prototypical chaperonin GroEL performs work on substrate proteins has not yet been fully elucidated, hindered by lack of detailed structural and dynamic information on the bound substrate. Previous investigations have produced conflicting reports on the state of GroEL-bound polypeptides, largely due to the transient and dynamic nature of these complexes. Here, we present a unique approach, based on combined analysis of four complementary relaxation-based NMR experiments, to probe directly the "dark" NMR-invisible state of the model, intrinsically disordered, polypeptide amyloid beta (A beta 40) bound to GroEL. The four NMR experiments, lifetime line-broadening, dark-state exchange saturation transfer, relaxation dispersion, and small exchange-induced chemical shifts, are dependent in different ways on the overall exchange rates and populations of the free and bound states of the substrate, as well as on residue-specific dynamics and structure within the bound state as reported by transverse magnetization relaxation rates and backbone chemical shifts, respectively. Global fitting of all the NMR data shows that the complex is transient with a lifetime of <1 ms, that binding involves two predominantly hydrophobic segments corresponding to predicted GroEL consensus binding sequences, and that the structure of the bound polypeptide remains intrinsically and dynamically disordered with minimal changes in secondary structure propensity relative to the free state. Our results establish a unique method to observe NMR-invisible dynamic states of GroEL-bound substrates and to describe at atomic resolution the events between substrate binding and encapsulation that are crucial for understanding the normal and stress-related metabolic function of chaperonins. C1 [Libich, David S.; Fawzi, Nicolas L.; Ying, Jinfa; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Fawzi, Nicolas L.] Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Providence, RI 02912 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU National Institute of Diabetes and Digestive and Kidney Diseases; NIH; AIDS Targeted Antiviral Program; NIH Director FX We thank Dusty Baber and Dan Garrett for NMR technical assistance, Dennis Torchia and George Lorimer for valuable discussions, and George Lorimer and Dong Yang for their generous gift of GroEL and Rubisco. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (NIH). This work was supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, and by the AIDS Targeted Antiviral Program of the NIH Director (G. M. C.). NR 38 TC 24 Z9 24 U1 1 U2 50 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 9 PY 2013 VL 110 IS 28 BP 11361 EP 11366 DI 10.1073/pnas.1305715110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 183OT UT WOS:000321827000046 PM 23798407 ER PT J AU Li, YL Wang, Q Chen, S Brown, PH Mariuzza, RA AF Li, Yili Wang, Qian Chen, Sharon Brown, Patrick H. Mariuzza, Roy A. TI Structure of NKp65 bound to its keratinocyte ligand reveals basis for genetically linked recognition in natural killer gene complex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MISSING-SELF-RECOGNITION; LECTIN-LIKE DOMAIN; CRYSTAL-STRUCTURE; CELL RECEPTORS; CUTTING EDGE; MOLECULAR ARCHITECTURE; HUMAN NKR-P1A; T-CELLS; MHC; ACTIVATION AB The natural killer (NK) gene complex (NKC) encodes numerous C-type lectin-like receptors that govern the activity of NK cells. Although some of these receptors (Ly49s, NKG2D, CD94/NKG2A) recognize MHC or MHC-like molecules, others (Nkrp1, NKRP1A, NKp80, NKp65) instead bind C-type lectin-like ligands to which they are genetically linked in the NKC. To understand the basis for this recognition, we determined the structure of human NKp65, an activating receptor implicated in the immunosurveillance of skin, bound to its NKC-encoded ligand keratinocyte-associated C-type lectin (KACL). Whereas KACL forms a homodimer resembling other C-type lectin-like dimers, NKp65 is monomeric. The binding mode in the NKp65-KACL complex, in which a monomeric receptor engages a dimeric ligand, is completely distinct from those used by Ly49s, NKG2D, or CD94/NKG2A. The structure explains the exceptionally high affinity of the NKp65-KACL interaction compared with other cell-cell interaction pairs (K-D = 6.7 x 10(-10)M), which may compensate for the monomeric nature of NKp65 to achieve cell activation. This previously unreported structure of an NKC-encoded receptor-ligand complex, coupled with mutational analysis of the interface, establishes a docking template that is directly applicable to other genetically linked pairs in the NKC, including Nkrp1-Clr, NKRP1A-LLT1, and NKp80-AICL. C1 [Li, Yili; Wang, Qian; Chen, Sharon; Mariuzza, Roy A.] Univ Maryland, Inst Biosci & Biotechnol Res, WM Keck Lab Struct Biol, Rockville, MD 20850 USA. [Li, Yili; Wang, Qian; Mariuzza, Roy A.] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. [Brown, Patrick H.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. RP Mariuzza, RA (reprint author), Univ Maryland, Inst Biosci & Biotechnol Res, WM Keck Lab Struct Biol, Rockville, MD 20850 USA. EM rmariuzz@umd.edu FU Offices of Biological and Environmental Research; Basic Energy Sciences of the Department of Energy; National Center for Research Resources of the National Institutes of Health; National Institutes of Health [AI047990] FX We thank H. Robinson (Brookhaven National Synchrotron Light Source) for X-ray data collection. Support for beamline X29 comes from the Offices of Biological and Environmental Research and of Basic Energy Sciences of the Department of Energy, and from the National Center for Research Resources of the National Institutes of Health. This study was supported by National Institutes of Health Grant AI047990 (to R.A.M.). NR 45 TC 11 Z9 13 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 9 PY 2013 VL 110 IS 28 BP 11505 EP 11510 DI 10.1073/pnas.1303300110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 183OT UT WOS:000321827000070 PM 23803857 ER PT J AU Chen, P Price, C Li, ZJ Li, YY Cao, DL Wiley, A He, CJ Gurbuxani, S Kunjamma, RB Huang, H Jiang, X Arnovitz, S Xu, MY Hong, GM Elkahloun, AG Neilly, MB Wunderlich, M Larson, RA Le Beau, MM Mulloy, JC Liu, PP Rowley, JD Chen, JJ AF Chen, Ping Price, Colles Li, Zejuan Li, Yuanyuan Cao, Donglin Wiley, Anissa He, Chunjiang Gurbuxani, Sandeep Kunjamma, Rejani B. Huang, Hao Jiang, Xi Arnovitz, Stephen Xu, Mengyi Hong, Gia-Ming Elkahloun, Abdel G. Neilly, Mary Beth Wunderlich, Mark Larson, Richard A. Le Beau, Michelle M. Mulloy, James C. Liu, Paul P. Rowley, Janet D. Chen, Jianjun TI miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACUTE MYELOID-LEUKEMIA; TUMOR-SUPPRESSOR; DEREGULATED EXPRESSION; GENE-EXPRESSION; MLL; CELL; LEUKEMOGENESIS; CANCER; IMMORTALIZATION; TRANSLOCATIONS AB MicroRNAs (miRNAs), small noncoding RNAs that regulate target gene mRNAs, are known to contribute to pathogenesis of cancers. Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies with various chromosomal and/or molecular abnormalities. AML with chromosomal translocations involving the mixed lineage leukemia (MLL) gene are usually associated with poor survival. In the present study, through a large-scale, genome-wide miRNA expression assay, we show that microRNA-9 (miR-9) is the most specifically up-regulated miRNA in MLL-rearranged AML compared with both normal control and non-MLL-rearranged AML. We demonstrate that miR-9 is a direct target of MLL fusion proteins and can be significantly up-regulated in expression by the latter in human and mouse hematopoietic stem/progenitor cells. Depletion of endogenous miR-9 expression by an appropriate antagomiR can significantly inhibit cell growth/viability and promote apoptosis in human MLL-rearranged AML cells, and the opposite is true when expression of miR-9 is forced. Blocking endogenous miR-9 function by anti-miRNA sponge can significantly inhibit, whereas forced expression of miR-9 can significantly promote, MLL fusion-induced immortalization/transformation of normalmouse bone marrowprogenitor cells in vitro. Furthermore, forced expression of miR-9 can significantly promote MLL fusion-mediated leukemogenesis in vivo. In addition, a group of putative target genes of miR-9 exhibited a significant inverse correlation of expression with miR-9 in a series of leukemia sample sets, suggesting that they are potential targets of miR-9 in MLL-rearranged AML. Collectively, our data demonstrate that miR-9 is a critical oncomiR in MLL-rearranged AML and can serve as a potential therapeutic target to treat this dismal disease. C1 [Chen, Ping; Price, Colles; Li, Zejuan; Li, Yuanyuan; Cao, Donglin; Wiley, Anissa; He, Chunjiang; Kunjamma, Rejani B.; Huang, Hao; Jiang, Xi; Arnovitz, Stephen; Xu, Mengyi; Hong, Gia-Ming; Neilly, Mary Beth; Larson, Richard A.; Le Beau, Michelle M.; Rowley, Janet D.; Chen, Jianjun] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Gurbuxani, Sandeep] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Cao, Donglin] Guangdong 2 Prov Peoples Hosp, Dept Lab Med, Guangzhou 510317, Guangdong, Peoples R China. [Elkahloun, Abdel G.; Liu, Paul P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Wunderlich, Mark; Mulloy, James C.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. RP Rowley, JD (reprint author), Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. EM jrowley@bsd.uchicago.edu; jchen@bsd.uchicago.edu OI He, Chunjiang/0000-0002-4868-331X; Larson, Richard/0000-0001-9168-3203 FU National Institutes of Health [R01 CA127277, F31 CA171702, R01 CA118319, P01 CA40046, P30 CA014599]; Intramural Program of National Human Genome Research Institute; American Cancer Society Research Scholar grant; Leukemia and Lymphoma Society; University of Chicago Committee on Cancer Biology fellowship program; Gabrielle's Angel Foundation for Cancer Research FX We thank Drs. Gregory Hannon, Scott Hammond, Lin He, and Scott Armstrong for providing retroviral constructs and Dr. Robert K. Slany for the MLL-ENL-ERtm cell line. This work was supported in part by National Institutes of Health Grants R01 CA127277 (to J.C.), F31 CA171702 (to C.P.), R01 CA118319 (to J.C.M.), and P01 CA40046 and P30 CA014599 (to M.M.L.B.), the Intramural Program of National Human Genome Research Institute (A.E. and P.P.L.), an American Cancer Society Research Scholar grant (to J.C.), the Leukemia and Lymphoma Society (translational research grant to J.D.R. and J.C., special fellowship to Z.L., and scholar award to J.C.M.), the University of Chicago Committee on Cancer Biology fellowship program(X.J.), and Gabrielle's Angel Foundation for Cancer Research (J.C., X.J., Z.L., H.H., and G.M.H.). NR 42 TC 36 Z9 37 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 9 PY 2013 VL 110 IS 28 BP 11511 EP 11516 DI 10.1073/pnas.1310144110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 183OT UT WOS:000321827000071 PM 23798388 ER PT J AU Xu, WQ Stadler, CK Gorman, K Jensen, N Kim, D Zheng, HQ Tang, SH Switzer, WM Pye, GW Eiden, MV AF Xu, Wenqin Stadler, Cynthia K. Gorman, Kristen Jensen, Nathaniel Kim, David Zheng, HaoQiang Tang, Shaohua Switzer, William M. Pye, Geoffrey W. Eiden, Maribeth V. TI An exogenous retrovirus isolated from koalas with malignant neoplasias in a US zoo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID APE LEUKEMIA-VIRUS; NUCLEOTIDE-SEQUENCE; CELL-LINE; IDENTIFICATION; RECEPTOR; TRANSMISSION; EVOLUTION; ELEMENTS; PROTEIN AB Leukemia and lymphoma account for more than 60% of deaths in captive koalas (Phascolarctos cinereus) in northeastern Australia. Although the endogenizing gammaretrovirus koala endogenous retrovirus (KoRV) was isolated from these koalas, KoRV has not been definitively associated with leukemogenesis. We performed KoRV screening in koalas from the San Diego Zoo, maintained for more than 45 y with very limited outbreeding, and the Los Angeles Zoo, maintained by continuously assimilating captive-born Australian koalas. San Diego Zoo koalas are currently free of malignant neoplasias and were infected with only endogenous KoRV, which we now term subtype "KoRV-A," whereas Los Angeles Zoo koalas with lymphomas/leukemias are infected in addition to KoRV-A by a unique KoRV we term subtype "KoRV-B." KoRV-B is most divergent in the envelope protein and uses a host receptor distinct from KoRV-A. KoRV-B also has duplicated enhancer regions in the LTR associated with increased pathology in gammaretroviruses. Whereas KoRV-A uses the sodium-dependent phosphate transporter 1 (PiT1) as a receptor, KoRV-B employs a different receptor, the thiamine transporter 1 (THTR1), to infect cells. KoRV-B is transmitted from dam to offspring through de novo infection, rather than via genetic inheritance like KoRV-A. Detection of KoRV-B in native Australian koalas should provide a history, and a mode for remediation, of leukemia/lymphoma currently endemic in this population. C1 [Xu, Wenqin; Gorman, Kristen; Jensen, Nathaniel; Kim, David; Eiden, Maribeth V.] Natl Inst Mental Hlth, Natl Inst Hlth, Lab Cellular & Mol Regulat, Sect Directed Gene Transfer, Bethesda, MD 20892 USA. [Stadler, Cynthia K.] Los Angeles Zoo, Los Angeles, CA 90027 USA. [Zheng, HaoQiang; Tang, Shaohua; Switzer, William M.] Ctr Dis Control & Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Div HIV AIDS, Branch Lab, Atlanta, GA 30333 USA. RP Eiden, MV (reprint author), Natl Inst Mental Hlth, Natl Inst Hlth, Lab Cellular & Mol Regulat, Sect Directed Gene Transfer, Bethesda, MD 20892 USA. EM eidenm@mail.nih.gov FU National Institute of Mental Health FX We thank Dr. Robin Weiss and Dr. Laura Levy for helpful comments; James Nagle and Deborah Kauffman (National Institute of Neurological Disorders and Stroke sequencing facility, National Institutes of Health) for sequencing; Jill Russ, Mickeyas Alemayehu, Joseph Tran, and Laura Li for expert technical assistance; and Dr. Michael M. Garner (Northwest ZooPath) for providing tissue samples. This work was supported by National Institute of Mental Health intramural funding. NR 21 TC 33 Z9 33 U1 3 U2 47 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 9 PY 2013 VL 110 IS 28 BP 11547 EP 11552 DI 10.1073/pnas.1304704110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 183OT UT WOS:000321827000077 PM 23798387 ER PT J AU Wang, JB Abnet, CC Fan, JH Qiao, YL Taylor, PR AF Wang, Jian-Bing Abnet, Christian C. Fan, Jin-Hu Qiao, You-Lin Taylor, Philip R. TI The Randomized Linxian Dysplasia Nutrition Intervention Trial After 26 Years of Follow-up: No Effect of Multivitamin Supplementation on Mortality SO JAMA INTERNAL MEDICINE LA English DT Letter ID CARDIOVASCULAR-DISEASE; PHYSICIANS HEALTH; PREVENTION; VITAMINS; CANCER; MINERALS; EVENTS; WOMEN; MEN C1 [Wang, Jian-Bing; Fan, Jin-Hu; Qiao, You-Lin] Chinese Acad Med Sci, Peking Union Med Coll, Canc Inst & Hosp, Dept Canc Epidemiol, Beijing 100730, Peoples R China. [Wang, Jian-Bing; Abnet, Christian C.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Taylor, PR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 7006, Rockville, MD 20852 USA. EM ptaylor@mail.nih.gov RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 FU CCR NIH HHS [N01RC47701]; Intramural NIH HHS [Z99 CA999999, ZIA CP000112-9]; NCI NIH HHS [N01-SC-91030] NR 8 TC 7 Z9 9 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL 8 PY 2013 VL 173 IS 13 BP 1259 EP 1261 DI 10.1001/jamainternmed.2013.6066 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 207LU UT WOS:000323602100024 PM 23712839 ER PT J AU Lee, YT Kim, KS Byrnes, C de Vasconcellos, JF Noh, SJ Rabel, A Meier, ER Miller, JL AF Lee, Y. Terry Kim, Ki Soon Byrnes, Colleen de Vasconcellos, Jaira F. Noh, Seung-Jae Rabel, Antoinette Meier, Emily R. Miller, Jeffery L. TI A Synthetic Model of Human Beta-Thalassemia Erythropoiesis Using CD34+Cells from Healthy Adult Donors SO PLOS ONE LA English DT Article ID INEFFECTIVE ERYTHROPOIESIS; ERYTHROID-CELLS; MOUSE MODEL; HEMOGLOBIN; EXPRESSION; MURINE; GLOBIN; APOPTOSIS; HEPCIDIN; BLOOD AB Based upon the lack of clinical samples available for research in many laboratories worldwide, a significant gap exists between basic and clinical studies of beta-thalassemia major. To bridge this gap, we developed an artificially engineered model for human beta thalassemia by knocking down beta-globin gene and protein expression in cultured CD34+ cells obtained from healthy adults. Lentiviral-mediated transduction of beta-globin shRNA (beta-KD) caused imbalanced globin chain production. Beta-globin mRNA was reduced by 90% compared to controls, while alpha-globin mRNA levels were maintained. HPLC analyses revealed a 96% reduction in HbA with only a minor increase in HbF. During the terminal phases of differentiation (culture days 14-21), beta-KD cells demonstrated increased levels of insoluble alpha-globin, as well as activated caspase-3. The majority of the beta-KD cells underwent apoptosis around the polychromatophilic stage of maturation. GDF15, a marker of ineffective erythropoiesis in humans with thalassemia, was significantly increased in the culture supernatants from the beta-KD cells. Knockdown of beta-globin expression in cultured primary human erythroblasts provides a robust ex vivo model for beta-thalassemia. C1 [Lee, Y. Terry; Kim, Ki Soon; Byrnes, Colleen; de Vasconcellos, Jaira F.; Noh, Seung-Jae; Rabel, Antoinette; Meier, Emily R.; Miller, Jeffery L.] NIDDK, Mol Genom & Therapeut Sect, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDK, Mol Genom & Therapeut Sect, Mol Med Branch, NIH, Bethesda, MD 20892 USA. EM jm7f@nih.gov FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (Bethesda, MD) FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (Bethesda, MD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 1 Z9 1 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 8 PY 2013 VL 8 IS 7 AR e68307 DI 10.1371/journal.pone.0068307 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 181TS UT WOS:000321692000021 PM 23861885 ER PT J AU Rommel, PC Bosque, D Gitlin, AD Croft, GF Heintz, N Casellas, R Nussenzweig, MC Kriaucionis, S Robbiani, DF AF Rommel, Philipp C. Bosque, David Gitlin, Alexander D. Croft, Gist F. Heintz, Nathaniel Casellas, Rafael Nussenzweig, Michel C. Kriaucionis, Skirmantas Robbiani, Davide F. TI Fate Mapping for Activation-Induced Cytidine Deaminase (AID) Marks Non-Lymphoid Cells During Mouse Development SO PLOS ONE LA English DT Article ID CLASS SWITCH RECOMBINATION; DNA-LIGASE-IV; SOMATIC HYPERMUTATION; B-CELL; EMBRYONIC LETHALITY; REPAIR DEFICIENCY; TRANSLOCATIONS; MICE; PATHWAY; MEDULLOBLASTOMAS AB The Aicda gene encodes Activation-Induced cytidine Deaminase (AID), an enzyme essential for remodeling antibody genes in mature B lymphocytes. AID is also responsible for DNA damage at oncogenes, leading to their mutation and cancer-associated chromosome translocation in lymphoma. We used fate mapping and AID(GFP) reporter mice to determine if AID expression in the mouse extends beyond lymphocytes. We discovered that AID(cre) tags a small fraction of non-lymphoid cells starting at 10.5 days post conception (dpc), and that AID(GFP+) cells are detectable at dpc 11.5 and 12.5. Embryonic cells are tagged by AID(cre) in the submandibular region, where conditional deletion of the tumor suppressor PTEN causes squamous papillomas. AID(cre) also tags non-lymphoid cells in the embryonic central nervous system. Finally, in the adult mouse brain, AID(cre) marks a small fraction of diverse neurons and distinct neuronal populations, including pyramidal cells in cortical layer IV. C1 [Rommel, Philipp C.; Bosque, David; Gitlin, Alexander D.; Nussenzweig, Michel C.; Robbiani, Davide F.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. [Croft, Gist F.] Rockefeller Univ, Lab Mol Vertebrate Embryol, New York, NY 10021 USA. [Heintz, Nathaniel; Kriaucionis, Skirmantas] Rockefeller Univ, Mol Biol Lab, New York, NY 10021 USA. [Heintz, Nathaniel; Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. [Casellas, Rafael] NIAMS, Bethesda, MD USA. [Casellas, Rafael] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kriaucionis, Skirmantas] Ludwig Inst Canc Res, Oxford, England. [Kriaucionis, Skirmantas] Univ Oxford, Oxford, England. RP Robbiani, DF (reprint author), Rockefeller Univ, Lab Mol Immunol, 1230 York Ave, New York, NY 10021 USA. EM drobbiani@rockefeller.edu RI Kriaucionis, Skirmantas/A-2986-2015; OI Kriaucionis, Skirmantas/0000-0002-2273-5994; Rommel, Philipp/0000-0002-9790-4086 FU Ludwig Institute for Cancer Research; National Institutes of Health (NIH) [AI037526]; NIH Medical Scientist Training Program grant [GM007739] FX This research was supported by institutional funds to DFR, the Ludwig Institute for Cancer Research to SK, and in part by National Institutes of Health (NIH) AI037526 to MCN. ADG was supported by NIH Medical Scientist Training Program grant GM007739. NH and MCN are HHMI Investigators. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 8 Z9 8 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 8 PY 2013 VL 8 IS 7 AR UNSP e69208 DI 10.1371/journal.pone.0069208 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 181TS UT WOS:000321692000038 PM 23861962 ER PT J AU Clarke, M Schiffman, M Wacholder, S Rodriguez, AC Hildesheim, A Quint, W AF Clarke, Megan Schiffman, Mark Wacholder, Sholom Cecilia Rodriguez, Ana Hildesheim, Allan Quint, Wim CA Costa Rican Vaccine Trial Grp TI A prospective study of absolute risk and determinants of human papillomavirus incidence among young women in Costa Rica SO BMC INFECTIOUS DISEASES LA English DT Article DE Human papillomavirus; Absolute risk; Risk factors; Sexual behavior ID FEMALE PARTNERS; CERVICAL-CANCER; HPV INFECTION; COHORT; ACQUISITION; CLEARANCE; EPIDEMIOLOGY; POPULATION; PREVALENCE; TRANSMISSION AB Background: High risk human papillomaviruses (HR-HPV) are known to be extremely common, sexually transmitted infections, but more information is needed regarding the absolute risks of type-specific HR-HPV infections in the years following sexual debut. Methods: We conducted a survival analysis of 3,737 women aged 18-25 from the control group of the Costa Rican Vaccine trial to determine the absolute risks of HR-HPV infections at 12 months, 24 months, and end of follow-up (average of 50.7 months). To corroborate determinants of infection, we used Cox proportional hazards methods to assess associations between demographics and sexual risk behaviors and incident HR-HPV. Results: Cumulative incidence for HR-HPV infections was 51.3% at the end of the study period. The most common incident types were HPV52 (15.4%), HPV51 (13.6%), and HPV16 (12.4%). Type-specific cumulative incidence corresponded closely with type-specific prevalences, except that HPV16 was more prevalent than predicted by incidence, suggesting greater persistence. The strongest predictors of incident HR-HPV infections as a group in a multivariate analysis were the expected correlates of sexual behavior of the woman and her partner, such as being single (HR 1.6, 95% CI 1.4-1.8) or divorced/widowed (HR: 2.1, 95% CI: 1.7-2.7), having multiple HPV infections at enrollment (HR: 1.5, 95% CI: 1.3-1.7), and current smoking (HR: 1.2, 95% CI: 1.0-1.3). In women who reported being having only one lifetime sexual partner (being in a monogamous relationship), the strongest predictors of HR-HPV included not living with sex partner (HR: 2.1, 95% CI 1.7-2.5) and age of sex partner (HR: 1.4, 95% CI: 1.0-1.8). Conclusion: We confirm the extremely high incidence of HR-HPV in young women, emphasizing the importance of vaccinating young girls before sexual debut. C1 [Clarke, Megan; Schiffman, Mark; Wacholder, Sholom; Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Cecilia Rodriguez, Ana] Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Quint, Wim] Delft Diagnost Labs, Rijswijk, Netherlands. RP Clarke, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. EM clarkma2@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NCI; NIH Office of Research on Women's Health FX The funding agency did not have any involvement in the design of the study; the collection, analysis, and interpretation of the data; the writing of the article; or the decision to submit the article for publication. The Costa Rica HPV16/18 Vaccine Trial (NCT00128661) is a long-standing collaboration between investigators in Costa Rica and the National Cancer Institute (NCI). The trial is funded by intramural NCI and the NIH Office of Research on Women's Health and is conducted in agreement with the Ministry of Health of Costa Rica. Vaccine was provided for our trial by GLAXOSMITHKLINE Biologicals, under a clinical trials agreement with NCI. The affiliations of the members of the Costa Rica HPV16/18 Vaccine Trial group are as follows. At the Proyecto Epidemiologico Guanacaste, Fundacion INCIENSA, San Jose, Costa Rica: Mario Alfaro (Cytologist), Manuel Barrantes (Field Supervisor), M. Concepcion Bratti (Coinvestigator), Fernando Cardenas (General Field Supervisor), Bernal Cortes (Specimen and Repository Manager), Albert Espinoza (Head, coding, and data entry), Yenory Estrada (Pharmacist), Paula Gonzalez (Coinvestigator), Diego Guillen (Pathologist), Rolando Herrero (Coprincipal Investigator), Silvia E. Jimenez (Trial Coordinator), Jorge Morales (Colposcopist), Lidia Ana Morera (Head Study Nurse), Elmer Perez (Field Supervisor), Carolina Porras (Coinvestigator), Ana Cecilia Rodriguez (Coinvestigator), and Maricela Villegas (Clinic Physician); at the University of Costa Rica, San Jose, Costa Rica: Enrique Freer (Director, HPV Diagnostics Laboratory), Jose Bonilla (Head, HPV Immunology Laboratory), Sandra Silva (Head Technician, HPV Diagnostics Laboratory), Ivannia Atmella (Immunology Technician), and Margarita Ramirez (Immunology Technician); at the National Cancer Institute, Bethesda, MD: Nora Macklin (Trial Coordinator), Allan Hildesheim (Coprincipal Investigator and NCI Co-project Officer), Douglas R. Lowy (HPV Virologist), Mark Schiffman (Medical Monitor and NCI Co-project Officer), John T. Schiller (HPV Virologist), Mark Sherman (Quality Control Pathologist), Diane Solomon (Medical Monitor and Quality Control Pathologist), and Sholom Wacholder (Statistician); at SAIC, NCI-Frederick, Frederick, MD: Ligia Pinto (Head, HPV Immunology Laboratory) and Alfonso Garcia-Pineres (Scientist, HPV Immunology Laboratory); at Womens and Infants' Hospital, Providence, RI: Claire Eklund (Quality Control, cytology) and Martha Hutchinson (Quality Control, cytology); and DDL Diagnostics Laboratory, Voorburg, the Netherlands, Wim Quint (HPV DNA testing), and Leen-Jan van Doorn (HPV DNA testing), GLAXOSMITHKLINE Biologicals, Rixensart, Belgium Catherine Bougelet (HPV16/18 ELISA testing). NR 29 TC 3 Z9 3 U1 0 U2 7 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 8 PY 2013 VL 13 AR 308 DI 10.1186/1471-2334-13-308 PG 9 WC Infectious Diseases SC Infectious Diseases GA 189OA UT WOS:000322275300001 PM 23834901 ER PT J AU Rhyasen, GW Bolanos, L Fang, J Jerez, A Wunderlich, M Rigolino, C Mathews, L Ferrer, M Southall, N Guha, R Keller, J Thomas, C Beverly, LJ Cortelezzi, A Oliva, EN Cuzzola, M Maciejewski, JP Mulloy, JC Starczynowski, DT AF Rhyasen, Garrett W. Bolanos, Lyndsey Fang, Jing Jerez, Andres Wunderlich, Mark Rigolino, Carmela Mathews, Lesley Ferrer, Marc Southall, Noel Guha, Rajarshi Keller, Jonathan Thomas, Craig Beverly, Levi J. Cortelezzi, Agostino Oliva, Esther N. Cuzzola, Maria Maciejewski, Jaroslaw P. Mulloy, James C. Starczynowski, Daniel T. TI Targeting IRAK1 as a Therapeutic Approach for Myelodysplastic Syndrome SO CANCER CELL LA English DT Article ID NF-KAPPA-B; ACUTE MYELOID-LEUKEMIA; GENE-EXPRESSION; ENRICHMENT ANALYSIS; STEM-CELLS; MDS; IDENTIFICATION; MICE; AML; INHIBITION AB Myelodysplastic syndromes (MDSs) arise from a defective hematopoietic stem/progenitor cell. Consequently, there is an urgent need to develop targeted therapies capable of eliminating the MDS-initiating clones. We identified that IRAK1, an immune-modulating kinase, is overexpressed and hyperactivated in MDSs. MDS clones treated with a small molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF-kappa B inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is detrimental to MDS cells, while sparing normal CD34(+) cells. Based on an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that cotreatment more effectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDSs. C1 [Rhyasen, Garrett W.; Bolanos, Lyndsey; Fang, Jing; Wunderlich, Mark; Mulloy, James C.; Starczynowski, Daniel T.] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Rhyasen, Garrett W.; Bolanos, Lyndsey; Starczynowski, Daniel T.] Univ Cincinnati, Dept Canc Biol, Cincinnati, OH 45267 USA. [Jerez, Andres; Maciejewski, Jaroslaw P.] Cleveland Clin, Taussig Canc Inst, Dept Translat Hematol & Oncol Res, Cleveland, OH 44195 USA. [Rigolino, Carmela; Cuzzola, Maria] Azienda Osped Bianchi Melacrino Morelli, Bone Marrow Transplant Unit, I-89100 Reggio Di Calabria, Italy. [Oliva, Esther N.] Azienda Osped Bianchi Melacrino Morelli, Hematol Unit, I-89100 Reggio Di Calabria, Italy. [Mathews, Lesley; Ferrer, Marc; Southall, Noel; Guha, Rajarshi; Keller, Jonathan; Thomas, Craig] NHGRI, NIH Chem Genom Ctr, NIH, Rockville, MD 20850 USA. [Beverly, Levi J.] Univ Louisville, Div Hematol & Oncol, Dept Med, James Graham Brown Canc Ctr, Louisville, KY 40202 USA. [Cortelezzi, Agostino] Univ Milan, Fdn IRCCS Ca Granda Osped Maggiore Policlin, Dept Hematol, I-20122 Milan, Italy. RP Starczynowski, DT (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. EM daniel.starczynowski@cchmc.org RI Southall, Noel/H-8991-2012; cortelezzi, agostino/L-2633-2016; OI Southall, Noel/0000-0003-4500-880X; Maria, Cuzzola/0000-0001-8749-5402; CORTELEZZI, AGOSTINO/0000-0001-9283-4800 FU Cincinnati Children's Hospital Research Foundation, American Society of Hematology, National Institutes of Health [RO1HL111103]; Department of Defense; NIDDK Centers of Excellence in Experimental Hematology [P30DK090971] FX This work was supported by the Cincinnati Children's Hospital Research Foundation, American Society of Hematology, National Institutes of Health (RO1HL111103), and Department of Defense grants (to D.T.S.). Umbilical cord blood samples were received through the Normal Donor Repository in the Translational Core Laboratory at the Cincinnati Children's Hospital, which is supported through the NIDDK Centers of Excellence in Experimental Hematology (P30DK090971). We thank Mt. Auburn and Christ Hospital (Cincinnati) for collecting cord blood (CD34+) samples. We thank Drs. Ashish Kumar (Cincinnati Children's Hospital), Martin Carroll (University of Pennsylvania), and Yogen Saunthararajah (Cleveland Clinic) for AML samples. We thank Jeff Bailey and Victoria Summey for assistance with mice (Comprehensive Mouse and Cancer Core) and Nicholas Brown for technical assistance. MDSL cells were kindly provided by Dr. Kaoru Tohyama. NR 45 TC 48 Z9 48 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUL 8 PY 2013 VL 24 IS 1 BP 90 EP 104 DI 10.1016/j.ccr.2013.05.006 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 180OH UT WOS:000321604000012 PM 23845443 ER PT J AU Toulmay, A Prinz, WA AF Toulmay, Alexandre Prinz, William A. TI Direct imaging reveals stable, micrometer-scale lipid domains that segregate proteins in live cells SO JOURNAL OF CELL BIOLOGY LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; PLASMA-MEMBRANE; VACUOLAR; MICROSCOPY; FUSION; ORDER; RAFTS; MODEL; CHOLESTEROL; SEPARATION AB It has been proposed that membrane rafts, which are sterol- and sphingolipid-enriched liquid-ordered (L-o) domains, segregate proteins in membranes and play critical roles in numerous processes in cells. However, rafts remain controversial because they are difficult to observe in cells without invasive methods and seem to be very small (nanoscale) and short lived, leading many to question whether they exist or are physiologically relevant. In this paper, we show that micrometer-scale, stable lipid domains formed in the yeast vacuole membrane in response to nutrient deprivation, changes in the pH of the growth medium, and other stresses. All vacuolar membrane proteins tested segregated to one of two domains. These domains formed quasi-symmetrical patterns strikingly similar to those found in liposomes containing coexisting L-o and liquid-disordered regions. Indeed, we found that one of these domains is probably sterol enriched and Lo. Domain formation was shown to be regulated by the pH-responsive Rim101 signaling pathway and may also require vesicular trafficking to vacuoles. C1 [Toulmay, Alexandre; Prinz, William A.] Natl Inst Diabet & Digest & Kidney Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Prinz, WA (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM prinzw@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 34 TC 46 Z9 47 U1 1 U2 25 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JUL 8 PY 2013 VL 202 IS 1 BP 35 EP 44 DI 10.1083/jcb.201301039 PG 10 WC Cell Biology SC Cell Biology GA 179MT UT WOS:000321525100007 PM 23836928 ER PT J AU Jha, A Ahuja, M Maleth, J Moreno, CM Yuan, JP Kim, MS Muallem, S AF Jha, Archana Ahuja, Malini Maleth, Jozsef Moreno, Claudia M. Yuan, Joseph P. Kim, Min Seuk Muallem, Shmuel TI The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function SO JOURNAL OF CELL BIOLOGY LA English DT Article ID ACTIVATED CALCIUM CURRENT; FAST CA2+-DEPENDENT INACTIVATION; CRAC CHANNELS; MECHANISTIC INSIGHTS; CA2+ INFLUX; ENTRY; PERMEATION; TERMINUS AB Ca2+ influx by store-operated Ca2+ channels (SOCs) mediates all Ca2+-dependent cell functions, but excess Ca2+ influx is highly toxic. The molecular components of SOC are the pore-forming Orai1 channel and the endoplasmic reticulum Ca2+ sensor STIM1. Slow Ca2+-dependent inactivation (SCDI) of Orai1 guards against cell damage, but its molecular mechanism is unknown. Here, we used homology modeling to identify a conserved STIM1(448-530) C-terminal inhibitory domain (CTID), whose deletion resulted in spontaneous clustering of STIM1 and full activation of Orai1 in the absence of store depletion. CTID regulated SCDI by determining access to and interaction of the STIM1 inhibitor SARAF with STIM1 Orai1 activation region (SOAR), the STIM1 domain that activates Orai1. CTID had two lobes, STIM1(448-490) and STIM1(490-530), with distinct roles in mediating access of SARAF to SOAR. The STIM1 (448-490) lobe restricted, whereas the STIM1(490-530) lobe directed, SARAF to SOAR. The two lobes cooperated to determine the features of SCDI. These findings highlight the central role of STIM1 in SCDI and provide a molecular mechanism for SCDI of Orai1. C1 [Jha, Archana; Ahuja, Malini; Maleth, Jozsef; Moreno, Claudia M.; Muallem, Shmuel] Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Yuan, Joseph P.] Univ N Texas, Hlth Sci Ctr, Dept Integrat Physiol, Ft Worth, TX 76107 USA. [Kim, Min Seuk] Wonkwang Univ, Sch Dent, Dept Oral Physiol, Iksan 570749, Jeonbuk, South Korea. RP Muallem, S (reprint author), Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM shmuel.muallem@nih.gov FU National Institutes of Health; National Institute of Dental and Craniofacial Research [Z1A-DE000735] FX This work was funded by the Intramural Research Program of the National Institutes of Health and National Institute of Dental and Craniofacial Research grant Z1A-DE000735. NR 28 TC 26 Z9 26 U1 1 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JUL 8 PY 2013 VL 202 IS 1 BP 71 EP 79 DI 10.1083/jcb.201301148 PG 9 WC Cell Biology SC Cell Biology GA 179MT UT WOS:000321525100010 PM 23816623 ER PT J AU Thievessen, I Thompson, PM Berlemont, S Plevock, KM Plotnikov, SV Zemljic-Harpf, A Ross, RS Davidson, MW Danuser, G Campbell, SL Waterman, CM AF Thievessen, Ingo Thompson, Peter M. Berlemont, Sylvain Plevock, Karen M. Plotnikov, Sergey V. Zemljic-Harpf, Alice Ross, Robert S. Davidson, Michael W. Danuser, Gaudenz Campbell, Sharon L. Waterman, Clare M. TI Vinculin-actin interaction couples actin retrograde flow to focal adhesions, but is dispensable for focal adhesion growth SO JOURNAL OF CELL BIOLOGY LA English DT Article ID NASCENT ADHESIONS; ARP2/3 COMPLEX; DYNAMICS; RECRUITMENT; FORCE; ACTIVATION; MATURATION; TRACTION; REVEALS; BINDING AB In migrating cells, integrin-based focal adhesions (FAs) assemble in protruding lamellipodia in association with rapid filamentous actin (F-actin) assembly and retrograde flow. How dynamic F-actin is coupled to FA is not known. We analyzed the role of vinculin in integrating F-actin and FA dynamics by vinculin gene disruption in primary fibroblasts. Vinculin slowed F-actin flow in maturing FA to establish a lamellipodium-lamellum border and generate high extracellular matrix (ECM) traction forces. In addition, vinculin promoted nascent FA formation and turnover in lamellipodia and inhibited the frequency and rate of FA maturation. Characterization of a vinculin point mutant that specifically disrupts F-actin binding showed that vinculin-F-actin interaction is critical for these functions. However, FA growth rate correlated with F-actin flow speed independently of vinculin. Thus, vinculin functions as a molecular clutch, organizing leading edge F-actin, generating ECM traction, and promoting FA formation and turnover, but vinculin is dispensible for FA growth. C1 [Thievessen, Ingo; Plotnikov, Sergey V.; Waterman, Clare M.] NHLBI, Lab Cell & Tissue Morphodynam, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Thompson, Peter M.; Plevock, Karen M.; Campbell, Sharon L.] Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Thompson, Peter M.; Plevock, Karen M.] Univ N Carolina, Sch Med, Program Mol & Cellular Biophys, Chapel Hill, NC 27599 USA. [Berlemont, Sylvain; Danuser, Gaudenz] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Zemljic-Harpf, Alice; Ross, Robert S.] Univ Calif San Diego, Dept Med, Div Cardiol, Sch Med, San Diego, CA 92161 USA. [Zemljic-Harpf, Alice; Ross, Robert S.] Vet Affairs San Diego Healthcare Syst, San Diego, CA 92161 USA. [Davidson, Michael W.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32310 USA. RP Waterman, CM (reprint author), NHLBI, Lab Cell & Tissue Morphodynam, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov OI Thompson, Peter/0000-0001-7562-6049; Waterman, Clare/0000-0001-6142-6775 FU NHLBI Division of Intramural Research; NHLBI [PO1 HL 46345]; National Institutes of Health [T32GM008570]; National Institute of General Medical Sciences (NIGMS) [RO1GM080568]; NIGMS [U01 GM067230] FX This work was supported by NHLBI Division of Intramural Research (C. M. Waterman, I. Thievessen, and S. V. Plotnikov), NHLBI grant PO1 HL 46345, project 3 (R. S. Ross and A. Zemljic-Harpf), National Institutes of Health grant T32GM008570 (K. M. Plevock and P. M. Thompson), National Institute of General Medical Sciences (NIGMS) grant RO1GM080568 (S. L. Campbell) and NIGMS grant U01 GM067230 (G. Danuser and S. Berlemont). NR 43 TC 71 Z9 71 U1 1 U2 27 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JUL 8 PY 2013 VL 202 IS 1 BP 163 EP 177 DI 10.1083/jcb.201303129 PG 15 WC Cell Biology SC Cell Biology GA 179MT UT WOS:000321525100016 PM 23836933 ER PT J AU Strelioff, CC Vijaykrishna, D Riley, S Guan, Y Peiris, JSM Lloyd-Smith, JO AF Strelioff, Christopher C. Vijaykrishna, Dhanasekaran Riley, Steven Guan, Yi Peiris, J. S. Malik Lloyd-Smith, James O. TI Inferring patterns of influenza transmission in swine from multiple streams of surveillance data SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE influenza; swine; disease ecology; infectious disease surveillance; zoonosis; state-space model ID GENETIC-CHARACTERISTICS; CLINICAL SIGNS; UNITED-STATES; A VIRUSES; PIGS; H1N1; POPULATION; INFECTIONS; EMERGENCE; CHINA AB Swine populations are known to be an important source of new human strains of influenza A, including those responsible for global pandemics. Yet our knowledge of the epidemiology of influenza in swine is dismayingly poor, as highlighted by the emergence of the 2009 pandemic strain and the paucity of data describing its origins. Here, we analyse a unique dataset arising from surveillance of swine influenza at a Hong Kong abattoir from 1998 to 2010. We introduce a state-space model that estimates disease exposure histories by joint inference from multiple modes of surveillance, integrating both virological and serological data. We find that an observed decrease in virus isolation rates is not due to a reduction in the regional prevalence of influenza. Instead, a more likely explanation is increased infection of swine in production farms, creating greater immunity to disease early in life. Consistent with this, we find that the weekly risk of exposure on farms equals or exceeds the exposure risk during transport to slaughter. We discuss potential causes for these patterns, including competition between influenza strains and shifts in the Chinese pork industry, and suggest opportunities to improve knowledge and reduce prevalence of influenza in the region. C1 [Strelioff, Christopher C.; Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Vijaykrishna, Dhanasekaran] Duke NUS Grad Med Sch, Program Emerging Infect Dis, Lab Virus Evolut, Singapore 169857, Singapore. [Vijaykrishna, Dhanasekaran] Univ Hong Kong, Li Ka Shing Fac Med, State Key Lab Emerging Infect Dis, Pokfulam, Hong Kong, Peoples R China. [Vijaykrishna, Dhanasekaran] Univ Hong Kong, Li Ka Shing Fac Med, Dept Microbiol, Pokfulam, Hong Kong, Peoples R China. [Riley, Steven] Univ Hong Kong, Li Ka Shing Fac Med, Dept Community Med, Pokfulam, Hong Kong, Peoples R China. [Riley, Steven; Guan, Yi; Peiris, J. S. Malik] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, Pokfulam, Hong Kong, Peoples R China. [Guan, Yi; Peiris, J. S. Malik] Univ Hong Kong, Li Ka Shing Fac Med, State Key Lab Emerging Infect Dis, Pokfulam, Hong Kong, Peoples R China. [Riley, Steven] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Infect Dis Epidemiol, MRC Ctr Outbreak Anal & Modelling, London, England. [Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Lloyd-Smith, JO (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. EM jlloydsmith@ucla.edu RI Vijaykrishna, Dhanasekaran/D-1011-2010; Lloyd-Smith, James/K-4080-2012 OI Vijaykrishna, Dhanasekaran/0000-0003-3293-6279; Lloyd-Smith, James/0000-0001-7941-502X FU National Center for Foreign Animal and Zoonotic Disease Defense, a Department of Homeland Security Science and Technology Center of Excellence; National Institute of Allergy and Infectious Diseases [HHSN266200700005C]; RAPIDD programme of the Science and Technology Directorate of the Department of Homeland Security; NIH Fogarty International Center; De Logi Chair in Biological Sciences FX This work was funded by a grant from the National Center for Foreign Animal and Zoonotic Disease Defense, a Department of Homeland Security Science and Technology Center of Excellence. Data collection was supported by the National Institute of Allergy and Infectious Diseases (contract no. HHSN266200700005C). J.O.L.-S. and S. R. are supported by the RAPIDD programme of the Science and Technology Directorate of the Department of Homeland Security and NIH Fogarty International Center; J.O.L.-S. is grateful for support from the De Logi Chair in Biological Sciences. We thank the Institute for Digital Research and Education at UCLA for use of the hoffman2 cluster. NR 34 TC 4 Z9 4 U1 1 U2 25 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD JUL 7 PY 2013 VL 280 IS 1762 AR 20130872 DI 10.1098/rspb.2013.0872 PG 8 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 150IZ UT WOS:000319385100020 PM 23658205 ER PT J AU Howard, MT Carlson, BA Anderson, CB Hatfield, DL AF Howard, Michael T. Carlson, Bradley A. Anderson, Christine B. Hatfield, Dolph L. TI Translational Redefinition of UGA Codons Is Regulated by Selenium Availability SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HYDROPEROXIDE GLUTATHIONE-PEROXIDASE; SELENOCYSTEINE TRANSFER-RNA; 3 UNTRANSLATED REGION; MESSENGER-RNA; DIETARY SELENIUM; RAT-LIVER; MEDIATED DECAY; SELENOPROTEIN; SEQUENCES; METHYLATION AB Incorporation of selenium into similar to 25 mammalian selenoproteins occurs by translational recoding whereby in-frame UGA codons are redefined to encode the selenium containing amino acid, selenocysteine (Sec). Here we applied ribosome profiling to examine the effect of dietary selenium levels on the translational mechanisms controlling selenoprotein synthesis in mouse liver. Dietary selenium levels were shown to control gene-specific selenoprotein expression primarily at the translation level by differential regulation of UGA redefinition and Sec incorporation efficiency, although effects on translation initiation and mRNA abundance were also observed. Direct evidence is presented that increasing dietary selenium causes a vast increase in ribosome density downstream of UGA-Sec codons for a subset of selenoprotein mRNAs and that the selenium-dependent effects on Sec incorporation efficiency are mediated in part by the degree of Sec-tRNA([Ser]Sec) Um34 methylation. Furthermore, we find evidence for translation in the 5'-UTRs for a subset of selenoproteins and for ribosome pausing near the UGA-Sec codon in those mRNAs encoding the selenoproteins most affected by selenium availability. These data illustrate how dietary levels of the trace element selenium can alter the readout of the genetic code to affect the expression of an entire class of proteins. C1 [Howard, Michael T.; Anderson, Christine B.] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. [Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Howard, MT (reprint author), Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. EM mhoward@genetics.utah.edu FU National Institutes of Health (NIH) [21ES022716]; Intramural Research Program of the NIH, NCI, Center for Cancer Research; University of Utah FX This work was supported, in whole or in part, by the National Institutes of Health (NIH Grant R21ES022716; to M. T. H.) and the Intramural Research Program of the NIH, NCI, Center for Cancer Research (to D. L. H.). This work was also supported by a University of Utah Seed grant (to M. T. H.). NR 48 TC 27 Z9 27 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 5 PY 2013 VL 288 IS 27 BP 19401 EP 19413 DI 10.1074/jbc.M113.481051 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 179JG UT WOS:000321515800009 PM 23696641 ER PT J AU Sharma, P Wollenberg, K Sellers, M Zainabadi, K Galinsky, K Moss, E Nguitragool, W Neafsey, D Desai, SA AF Sharma, Paresh Wollenberg, Kurt Sellers, Morgan Zainabadi, Kayvan Galinsky, Kevin Moss, Eli Nguitragool, Wang Neafsey, Daniel Desai, Sanjay A. TI An Epigenetic Antimalarial Resistance Mechanism Involving Parasite Genes Linked to Nutrient Uptake SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SURFACE ANION CHANNEL; FALCIPARUM-INFECTED ERYTHROCYTES; PLASMODIUM-FALCIPARUM; MALARIA PARASITES; HIGH-THROUGHPUT; CHLOROQUINE RESISTANCE; ANTIGENIC VARIATION; FUNCTIONAL-ANALYSIS; MAXIMUM-LIKELIHOOD; MULTIGENE FAMILY AB Acquired antimalarial drug resistance produces treatment failures and has led to periods of global disease resurgence. In Plasmodium falciparum, resistance is known to arise through genome-level changes such as mutations and gene duplications. We now report an epigenetic resistance mechanism involving genes responsible for the plasmodial surface anion channel, a nutrient channel that also transports ions and antimalarial compounds at the host erythrocyte membrane. Two blasticidin S-resistant lines exhibited markedly reduced expression of clag genes linked to channel activity, but had no genome-level changes. Silencing aborted production of the channel protein and was directly responsible for reduced uptake. Silencing affected clag paralogs on two chromosomes and was mediated by specific histone modifications, allowing a rapidly reversible drug resistance phenotype advantageous to the parasite. These findings implicate a novel epigenetic resistance mechanism that involves reduced host cell uptake and is a worrisome liability for water-soluble antimalarial drugs. C1 [Sharma, Paresh; Sellers, Morgan; Zainabadi, Kayvan; Nguitragool, Wang; Desai, Sanjay A.] NIAID, Lab Malaria & Vector Res, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20852 USA. [Wollenberg, Kurt] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20852 USA. [Galinsky, Kevin; Moss, Eli; Neafsey, Daniel] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20852 USA. EM sdesai@niaid.nih.gov OI Galinsky, Kevin/0000-0003-0311-4938 FU National Institutes of Health Intramural Research Program; Bill and Melinda Gates Foundation; NIAID FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program, NIAID, and by a Global Health Program grant from the Bill and Melinda Gates Foundation. NR 58 TC 25 Z9 25 U1 0 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 5 PY 2013 VL 288 IS 27 BP 19429 EP 19440 DI 10.1074/jbc.M113.468371 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 179JG UT WOS:000321515800011 PM 23720749 ER PT J AU Gerken, TA Revoredo, L Thome, JJC Tabak, LA Vester-Christensen, MB Clausen, H Gahlay, GK Jarvis, DL Johnson, RW Moniz, HA Moremen, K AF Gerken, Thomas A. Revoredo, Leslie Thome, Joseph J. C. Tabak, Lawrence A. Vester-Christensen, Malene Bech Clausen, Henrik Gahlay, Gagandeep K. Jarvis, Donald L. Johnson, Roy W. Moniz, Heather A. Moremen, Kelley TI Family of Glycosyltransferases (ppGalNAc Ts) Acts as a Switch Directing Glycopeptide Substrate Glycosylation in an N- or C-terminal Direction, Further Controlling Mucin Type O-Glycosylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CARBOHYDRATE-BINDING MODULES; ACETYL-D-GALACTOSAMINE; NEIGHBORING RESIDUE GLYCOSYLATION; TRANSFERASE GENE FAMILY; UDP-GALNAC; LECTIN DOMAINS; POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE-1; ACETYLGALACTOSAMINYLTRANSFERASES T1; TUMORAL CALCINOSIS; SUGAR RECOGNITION AB Mucin type O-glycosylation is initiated by a large family of polypeptide GalNAc transferases (ppGalNAc Ts) that add alpha-GalNAc to the Ser and Thr residues of peptides. Of the 20 human isoforms, all but one are composed of two globular domains linked by a short flexible linker: a catalytic domain and a ricin-like lectin carbohydrate binding domain. Presently, the roles of the catalytic and lectin domains in peptide and glycopeptide recognition and specificity remain unclear. To systematically study the role of the lectin domain in ppGalNAc T glycopeptide substrate utilization, we have developed a series of novel random glycopeptide substrates containing a single GalNAc-O-Thr residue placed near either the N or C terminus of the glycopeptide substrate. Our results reveal that the presence and N- or C-terminal placement of the GalNAc-O-Thr can be important determinants of overall catalytic activity and specificity that differ between transferase isoforms. For example, ppGalNAc T1, T2, and T14 prefer C-terminally placed GalNAc-O-Thr, whereas ppGalNAc T3 and T6 prefer N-terminally placed GalNAc-O-Thr. Several transferase isoforms, ppGalNAc T5, T13, and T16, display equally enhanced N- or C-terminal activities relative to the nonglycosylated control peptides. This N-and/or C-terminal selectivity is presumably due to weak glycopeptide binding to the lectin domain, whose orientation relative to the catalytic domain is dynamic and isoform-dependent. Such N-or C-terminal glycopeptide selectivity provides an additional level of control or fidelity for the O-glycosylation of biologically significant sites and suggests that O-glycosylation may in some instances be exquisitely controlled. C1 [Gerken, Thomas A.; Thome, Joseph J. C.] Case Western Reserve Univ, Dept Pediat, WA Bernbaum Ctr Cyst Fibrosis Res, Cleveland, OH 44106 USA. [Gerken, Thomas A.] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. [Gerken, Thomas A.; Revoredo, Leslie] Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA. [Tabak, Lawrence A.] NIDCR, Sect Biol Chem, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Vester-Christensen, Malene Bech; Clausen, Henrik] Univ Copenhagen, Fac Hlth Sci, CCG, Dept Cellular & Mol Med, DK-2200 Copenhagen N, Denmark. [Vester-Christensen, Malene Bech; Clausen, Henrik] Univ Copenhagen, Fac Hlth Sci, CCG, Dept Dent, DK-2200 Copenhagen N, Denmark. [Gahlay, Gagandeep K.; Jarvis, Donald L.] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. [Johnson, Roy W.; Moniz, Heather A.; Moremen, Kelley] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. RP Gerken, TA (reprint author), Case Western Reserve Univ, Sch Med, Dept Pediat, BRB 823,2109 Adelbert Rd, Cleveland, OH 44104 USA. EM txg2@cwru.edu FU National Institutes of Health [R01-CA78834, P41-GM103390, P41-RR005351]; National Institutes of Health; NIDCR; Danish National Research Foundation Grant [DNRF107] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01-CA78834 (to T. A. G.) and P41-GM103390 and P41-RR005351 (to James Prestegard (Complex Carbohydrate Center, University of Georgia) and K. M. and D. L. J.) and a National Institutes of Health, NIDCR, intramural program grant (to L. A. T.). This work was also supported by Danish National Research Foundation Grant DNRF107 (to H. C.). NR 75 TC 25 Z9 25 U1 1 U2 24 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 5 PY 2013 VL 288 IS 27 BP 19900 EP 19914 DI 10.1074/jbc.M113.477877 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 179JG UT WOS:000321515800056 PM 23689369 ER PT J AU Yoo, SH Abdelmegeed, MA Song, BJ AF Yoo, Seong Ho Abdelmegeed, Mohamed A. Song, Byoung-Joon TI Activation of PPAR alpha by Wy-14643 ameliorates systemic lipopolysaccharide-induced acute lung injury SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Peroxisome proliferator-activated receptor-alpha; Lipopolysaccharide; Acute lung injury; Cytokines; Nitroxidative stress ID INFLAMMATION; EXPRESSION; AGONIST AB Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-alpha (PPAR alpha) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPAR alpha activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPAR alpha by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPAR alpha might have a therapeutic effect on LPS-induced ALI. (C) 2013 Elsevier Inc. All rights reserved. C1 [Yoo, Seong Ho] Seoul Natl Univ, Coll Med, Seoul Natl Univ Hosp, Biomed Res Inst, Seoul 110744, South Korea. [Yoo, Seong Ho] Seoul Natl Univ, Coll Med, Inst Forens Med, Seoul 110744, South Korea. [Abdelmegeed, Mohamed A.; Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD USA. RP Yoo, SH (reprint author), Seoul Natl Univ, Coll Med, Seoul Natl Univ Hosp, Biomed Res Inst, 101 Daehak Ro, Seoul 110744, South Korea. EM yoosh@snu.ac.kr; bj.song@nih.gov FU National Research Foundation; Korean Government [800-20120365]; Intramural Program of National Institute on Alcohol Abuse and Alcoholism FX This study was supported by a National Research Foundation grant funded by the Korean Government (800-20120365) and the Intramural Program of National Institute on Alcohol Abuse and Alcoholism. NR 18 TC 9 Z9 10 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 5 PY 2013 VL 436 IS 3 BP 366 EP 371 DI 10.1016/j.bbrc.2013.05.073 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 185UN UT WOS:000321995900003 PM 23727576 ER PT J AU Nakashima, R Hayashi, Y Md, K Jia, XF Wang, D Naito, H Ito, Y Kamijima, M Gonzalez, FJ Nakajima, T AF Nakashima, Ryosuke Hayashi, Yumi Md, Khalequzzaman Jia, Xiaofang Wang, Dong Naito, Hisao Ito, Yuki Kamijima, Michihiro Gonzalez, Frank J. Nakajima, Tamie TI Exposure to DEHP decreased four fatty acid levels in plasma of prepartum mice SO TOXICOLOGY LA English DT Article DE Di(2-ethylhexyl) phthalate; Fatty acids; Postpartum; Pregnancy; Pups ID ACTIVATED RECEPTOR-ALPHA; PPAR-ALPHA; LATE PREGNANCY; EXPRESSION; PHTHALATE; ENZYMES; RATS; DI-(2-ETHYLHEXYL)-PHTHALATE; PROLIFERATION; TRIGLYCERIDES AB Maternal exposure to di(2-ethylhexyl) phthalate (DEHP) decreased the plasma triglyceride in prepartum mice. To identify the fatty acid (FA) species involved and to understand the underlying mechanisms, pregnant Sv/129 wild-type (mPPAR alpha), peroxisome proliferator-activated receptor alpha-null (Ppar alpha-null) and humanized PPAR alpha (hPPAR alpha) mice were treated with diets containing 0%, 0.01%, 0.05% or 0.1% DEHP. Dams were dissected on gestational day 18 together with fetuses, and on postnatal day 2 together with newborns. n-3/n-6 polyunsaturated, saturated, and monounsaturated FAs in maternal plasma and in liver of wild-type offspring, and representative enzymes for FA desaturation and elongation in maternal liver, were measured. The plasma levels of linoleic acid, alpha-linolenic acid, palmitic acid and oleic acid were higher in the pregnant control mPPAR alpha mice than in Ppara-null and hPPAR alpha mice. DEHP exposure significantly decreased the levels of these four FAs only in pregnant mPPAR alpha mice. Plasma levels of many FAs were higher in pregnant mice than in postpartum ones in a genotype-independent manner, while it was lower in the livers of fetuses than pups. DEHP exposure slightly increased hepatic arachidonic acid, alpha-linolenic acid, palmitoleic acid and oleic acid in fetuses, but not in pups. However, DEHP exposure did not clearly influence FA desaturase 1 and 2 nor elongase 2 and 5 expressions in the liver of all maternal mice. Taken together, the levels of plasma four FAs with shorter carbon chains were higher in pregnant mPPAR alpha mice than in other genotypes, and DEHP exposure decreased these specific FA concentrations only in mPPAR alpha mice, similarly to triglyceride levels. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Nakashima, Ryosuke; Md, Khalequzzaman; Jia, Xiaofang; Wang, Dong; Naito, Hisao] Nagoya Univ, Dept Occupat & Environm Hlth, Grad Sch Med, Showa Ku, Nagoya, Aichi 4668550, Japan. [Hayashi, Yumi] Nagoya Univ, Grad Sch Med, Dept Pathophysiol Lab Sci, Higashi Ku, Nagoya, Aichi 4618673, Japan. [Ito, Yuki; Kamijima, Michihiro] Nagoya City Univ, Grad Sch Med Sci, Dept Occupat & Environm Hlth, Mizuho Ku, Nagoya, Aichi 4678601, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Nakajima, Tamie] Chubu Univ, Coll Life & Hlth Sci, Kasugai, Aichi 4878501, Japan. RP Nakajima, T (reprint author), Chubu Univ, Coll Life & Hlth Sci, 1200 Matsumoto Cho, Kasugai, Aichi 4878501, Japan. EM tnasu23@med.nagoya-u.ac.jp FU Japan Society for the Promotion of Science from Food Safety Commission, Japan [B20390171, 1002]; Health and Labour Sciences Research Grants from Research on Food Safety of the Ministry of Health, Labour and Welfare [200939055A] FX This work was supported by Grants-in-Aid for Scientific Research (B20390171) from the Japan Society for the Promotion of Science from Food Safety Commission, Japan (1002) and Health and Labour Sciences Research Grants from Research on Food Safety of the Ministry of Health, Labour and Welfare (200939055A). NR 36 TC 5 Z9 6 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUL 5 PY 2013 VL 309 BP 52 EP 60 DI 10.1016/j.tox.2013.04.010 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 178AS UT WOS:000321417100007 PM 23619606 ER PT J AU Vaisvaser, S Lin, T Admon, R Podlipsky, I Greenman, Y Stern, N Fruchter, E Wald, I Pine, DS Tarrasch, R Bar-Haim, Y Hendler, T AF Vaisvaser, Sharon Lin, Tamar Admon, Roee Podlipsky, Ilana Greenman, Yona Stern, Naftali Fruchter, Eyal Wald, Ilan Pine, Daniel S. Tarrasch, Ricardo Bar-Haim, Yair Hendler, Talma TI Neural traces of stress: cortisol related sustained enhancement of amygdala-hippocampal functional connectivity SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE fMRI; resting-state functional connectivity; default-mode network; recovery; limbic connectivity ID DEFAULT-MODE NETWORK; RESTING-STATE; PSYCHOLOGICAL STRESS; CINGULATE CORTEX; HUMAN BRAIN; MEMORY; DYNAMICS; DISEASE; FLUCTUATIONS; HYPOTHESIS AB Stressful experiences modulate neuro-circuitry function, and the temporal trajectory of these alterations, elapsing from early disturbances to late recovery, heavily influences resilience and vulnerability to stress. Such effects of stress may depend on processes that are engaged during resting-state, through active recollection of past experiences and anticipation of future events, all known to involve the default mode network (DMN). By inducing social stress and acquiring resting-state functional magnetic resonance imaging (fMRI) before stress, immediately following it, and 2 h later, we expanded the time-window for examining the trajectory of the stress response. Throughout the study repeated cortisol samplings and self-reports of stress levels were obtained from 51 healthy young males. Post-stress alterations were investigated by whole brain resting-state functional connectivity (rsFC) of two central hubs of the DMN: the posterior cingulate cortex (PCC) and hippocampus. Results indicate a 'recovery' pattern of DMN connectivity, in which all alterations, ascribed to the intervening stress, returned to pre-stress levels. The only exception to this pattern was a stress-induced rise in amygdala-hippocampal connectivity, which was sustained for as long as 2 h following stress induction. Furthermore, this sustained enhancement of limbic connectivity was inversely correlated to individual stress-induced cortisol responsiveness (AUCi) and characterized only the group lacking such increased cortisol (i.e., non-responders). Our observations provide evidence of a prolonged post-stress response profile, characterized by both the comprehensive balance of most DMN functional connections and the distinct time and cortisol dependent ascent of intra-limbic connectivity. These novel insights into neuro-endocrine relations are another milestone in the ongoing search for individual markers in stress-related psychopathologies. C1 [Vaisvaser, Sharon; Lin, Tamar; Podlipsky, Ilana; Hendler, Talma] Sourasky Med Ctr, Wohl Inst Adv Imaging, Funct Brain Ctr, Tel Aviv, Israel. [Vaisvaser, Sharon; Greenman, Yona; Stern, Naftali; Hendler, Talma] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Vaisvaser, Sharon; Tarrasch, Ricardo; Bar-Haim, Yair; Hendler, Talma] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. [Lin, Tamar; Wald, Ilan; Bar-Haim, Yair; Hendler, Talma] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Admon, Roee] Harvard Univ, McLean Hosp, Sch Med, Ctr Depress Anxiety & Stress Res, Belmont, MA USA. [Greenman, Yona; Stern, Naftali] Sourasky Med Ctr, Inst Endocrinol Metab & Hypertens, Tel Aviv, Israel. [Fruchter, Eyal] IDF, Med Corps, Div Mental Hlth, Tel Hashomer, Israel. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, NIH, Bethesda, MD 20892 USA. [Tarrasch, Ricardo] Tel Aviv Univ, Sch Educ, IL-69978 Tel Aviv, Israel. RP Hendler, T (reprint author), Tel Sourasky Med Ctr, Wohl Inst Adv Imaging, 6 Weizman St, IL-64239 Tel Aviv, Israel. EM ysharonv@gmail.com; talma@tasmc.health.gov.il FU U.S. Department of Defense [W81XWH-11-2-0008]; Israel Ministry of Defense; Tel-Aviv University; I-CORE Program of the Planning and Budgeting Committee; Israel Science Foundation [51/11] FX This research was supported by the U.S. Department of Defense award number W81XWH-11-2-0008, Israel Ministry of Defense, Tel-Aviv University, and the I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation (Grant No. 51/11). The authors thank Aliya Solski for her help in editing the manuscript. NR 52 TC 28 Z9 28 U1 1 U2 26 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD JUL 5 PY 2013 VL 7 AR 313 DI 10.3389/fnhum.2013.00313 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 176SA UT WOS:000321323300001 PM 23847492 ER PT J AU Concheiro, M Lee, D Lendoiro, E Huestis, MA AF Concheiro, Marta Lee, Dayong Lendoiro, Elena Huestis, Marilyn A. TI Simultaneous quantification of Delta(9)-tetrahydrocannabinol, 11-nor-9-carboxy-tetrahydrocannabinol, cannabidiol and cannabinol in oral fluid by microflow-liquid chromatography-high resolution mass spectrometry SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Oral fluid; THC; THCCOOH; CBN; CBD; LC-MS ID CONTROLLED SMOKED CANNABIS; METABOLITE 11-NOR-DELTA(9)-TETRAHYDROCANNABINOL-9-CARBOXYLIC ACID; MARIJUANA; THC; DISPOSITION; SPECIMENS; THCCOOH; BLOOD AB Delta(9)-Tetrahydrocannabinol (THC) is the primary target in oral fluid (OF) for detecting cannabis intake. However, additional biomarkers are needed to solve interpretation issues, such as the possibility of passive inhalation by identifying 11-nor-9-carboxy-THC (THCCOOH), and determining recent cannabis smoking by identifying cannabidiol (CBD) and/or cannabinol (CBN). We developed and comprehensively validated a microflow liquid chromatography (LC)-high resolution mass spectrometry method for simultaneous quantification of THC, THCCOOH, CBD and CBN in OF collected with the Oral-Eze (R) and Quantisal (TM) devices. One milliliter OF-buffer solution (0.25 mL OF and 0.5 mL of Oral-Eze buffer, 1:3 dilution, or 0.75 mL Quantisal buffer, 1:4 dilution) had proteins precipitated, and the supernatant subjected to CEREX (TM) Polycrom (TM) THC solid-phase extraction (SPE). Microflow LC reverse-phase separation was achieved with a gradient mobile phase of 10 mM ammonium acetate pH 6 and acetonitrile over 10 min. We employed a Q Exactive high resolution mass spectrometer, with compounds identified and quantified by targeted-MSMS experiments. The assay was linear 0.5-50 ng/mL for THC, CBD and CBN, and 15-500 pg/mL for THCCOOH. Intra- and inter-day and total imprecision were <10.8%CV and bias 86.5-104.9%. Extraction efficiency was 52.4-109.2%, process efficiency 12.2-88.9% and matrix effect ranged from -86 to -6.9%. All analytes were stable for 24h at 5 degrees C on the autosampler. The method was applied to authentic OF specimens collected with Quantisal and Oral-Eze devices. This method provides a rapid simultaneous quantification of THCCOOH and THC, CBD, CBN, with good selectivity and sensitivity, providing the opportunity to improve interpretation of cannabinoid OF results by eliminating the possibility of passive inhalation and providing markers of recent cannabis smoking. Published by Elsevier B.V. C1 [Concheiro, Marta; Lee, Dayong; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Lendoiro, Elena] Univ Santiago de Compostela, Fac Med, Dpto Anat Patol & Ciencias Forenses, Serv Toxicol Forense, Santiago De Compostela 15782, A Coruna, Spain. RP Huestis, MA (reprint author), NIDA, Biomed Res Ctr, NIH, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH); Ministerio de Sanidad, Gobierno de Espana [2011/097]; Conselleria de Cultura, Educacion e Ordenacion Universitaria, Xunta de Galicia [PRE/2011/072] FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH). E. Lendoiro thanks the Ministerio de Sanidad, Gobierno de Espana (Project #2011/097) and the Conselleria de Cultura, Educacion e Ordenacion Universitaria, Xunta de Galicia (No. PRE/2011/072) for her support. The authors would like to thank Dr. Ryan Vandrey and the Behavioral Pharmacology Research Unit (BPRU) from Johns Hopkins Medical Center (Baltimore, MD) for their help in providing oral fluid specimens. NR 22 TC 18 Z9 18 U1 5 U2 53 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUL 5 PY 2013 VL 1297 BP 123 EP 130 DI 10.1016/j.chroma.2013.04.071 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 170AM UT WOS:000320821900014 PM 23726246 ER PT J AU Drahos, J Wu, MX Anderson, WF Trivers, KF King, J Rosenberg, PS Eheman, C Cook, MB AF Drahos, Jennifer Wu, Manxia Anderson, William F. Trivers, Katrina F. King, Jessica Rosenberg, Philip S. Eheman, Christie Cook, Michael B. TI Regional Variations in Esophageal Cancer Rates by Census Region in the United States, 1999-2008 SO PLOS ONE LA English DT Article ID HISTOLOGY DIFFERENCES; OVERLAPPING REGIONS; NATIONAL PROGRAM; COMPARING TRENDS; GASTRIC CARDIA; SEER PROGRAM; EPIDEMIOLOGY; SURVEILLANCE; COMPLETENESS; CARCINOMAS AB Background: Assessment of cancer incidence trends within the U.S. have mostly relied upon Surveillance, Epidemiology, and End Results (SEER) data, with implicit inference that such is representative of the general population. However, many cancer policy decisions are based at a more granular level. To help inform such, analyses of regional cancer incidence data are needed. Leveraging the unique resource of National Program of Cancer Registries (NPCR)-SEER, we assessed whether regional rates and trends of esophageal cancer significantly deviated from national estimates. Methods: From NPCR-SEER, we extracted cancer case counts and populations for whites aged 45-84 years by calendar year, histology, sex, and census region for the period 1999-2008. We calculated age-standardized incidence rates (ASRs), annual percent changes (APCs), and male-to-female incidence rate ratios (IRRs). Results: This analysis included 65,823 esophageal adenocarcinomas and 27,094 esophageal squamous cell carcinomas diagnosed during 778 million person-years. We observed significant geographic variability in incidence rates and trends, especially for esophageal adenocarcinomas in males: ASRs were highest in the Northeast (17.7 per 100,000) and Midwest (18.1). Both were significantly higher than the national estimate (16.0). In addition, the Northeast APC was 62% higher than the national estimate (3.19% vs. 1.97%). Lastly, IRRs remained fairly constant across calendar time, despite changes in incidence rates. Conclusion: Significant regional variations in esophageal cancer incidence trends exist in the U.S. Stable IRRs may indicate the predominant factors affecting incidence rates are similar in men and women. C1 [Drahos, Jennifer; Anderson, William F.; Rosenberg, Philip S.; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Drahos, Jennifer] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Wu, Manxia; Trivers, Katrina F.; King, Jessica; Eheman, Christie] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Drahos, J (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM jennifer.drahos@nih.gov RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 FU Intramural Program of the National Cancer Institute at the National Institutes of Health and Department of Health and Human Services [CA00350] FX This work was supported by the Intramural Program of the National Cancer Institute at the National Institutes of Health and Department of Health and Human Services (CA00350). There are no financial disclosures from any of the authors. The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 6 Z9 6 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 4 PY 2013 VL 8 IS 7 AR e67913 DI 10.1371/journal.pone.0067913 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 204FO UT WOS:000323350700058 PM 23861830 ER PT J AU Suthanthiran, M Schwartz, JE Ding, RC Abecassis, M Dadhania, D Samstein, B Knechtle, SJ Friedewald, J Becker, YT Sharma, VK Williams, NM Chang, CS Hoang, C Muthukumar, T August, P Keslar, KS Fairchild, RL Hricik, DE Heeger, PS Han, LY Liu, J Riggs, M Ikle, DN Bridges, ND Shaked, A AF Suthanthiran, Manikkam Schwartz, Joseph E. Ding, Ruchuang Abecassis, Michael Dadhania, Darshana Samstein, Benjamin Knechtle, Stuart J. Friedewald, John Becker, Yolanda T. Sharma, Vijay K. Williams, Nikki M. Chang, Christina S. Hoang, Christine Muthukumar, Thangamani August, Phyllis Keslar, Karen S. Fairchild, Robert L. Hricik, Donald E. Heeger, Peter S. Han, Leiya Liu, Jun Riggs, Michael Ikle, David N. Bridges, Nancy D. Shaked, Abraham CA CTOT-04 Study Investigators TI Urinary-Cell mRNA Profile and Acute Cellular Rejection in Kidney Allografts SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RENAL-ALLOGRAFT; PREDICTION; MODELS; TRANSPLANTATION; CLASSIFICATION; CURVE AB BACKGROUND The standard test for the diagnosis of acute rejection in kidney transplants is the renal biopsy. Noninvasive tests would be preferable. METHODS We prospectively collected 4300 urine specimens from 485 kidney-graft recipients from day 3 through month 12 after transplantation. Messenger RNA (mRNA) levels were measured in urinary cells and correlated with allograft-rejection status with the use of logistic regression. RESULTS A three-gene signature of 18S ribosomal (rRNA)-normalized measures of CD3 epsilon mRNA and interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA discriminated between biopsy specimens showing acute cellular rejection and those not showing rejection (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 by receiver-operating-characteristic curve analysis). The cross-validation estimate of the AUC was 0.83 by bootstrap resampling, and the Hosmer-Lemeshow test indicated good fit (P = 0.77). In an external-validation data set, the AUC was 0.74 (95% CI, 0.61 to 0.86; P<0.001) and did not differ significantly from the AUC in our primary data set (P = 0.13). The signature distinguished acute cellular rejection from acute antibody-mediated rejection and borderline rejection (AUC, 0.78; 95% CI, 0.68 to 0.89; P<0.001). It also distinguished patients who received anti-interleukin-2 receptor antibodies from those who received T-cell-depleting antibodies (P<0.001) and was diagnostic of acute cellular rejection in both groups. Urinary tract infection did not affect the signature (P = 0.69). The average trajectory of the signature in repeated urine samples remained below the diagnostic threshold for acute cellular rejection in the group of patients with no rejection, but in the group with rejection, there was a sharp rise during the weeks before the biopsy showing rejection (P<0.001). CONCLUSIONS A molecular signature of CD3 epsilon mRNA, IP-10 mRNA, and 18S rRNA levels in urinary cells appears to be diagnostic and prognostic of acute cellular rejection in kidney allografts. C1 [Suthanthiran, Manikkam; Ding, Ruchuang; Dadhania, Darshana; Sharma, Vijay K.; Chang, Christina S.; Hoang, Christine; Muthukumar, Thangamani; August, Phyllis] Weill Cornell Med Coll, New York, NY USA. [Samstein, Benjamin] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Heeger, Peter S.] Mt Sinai Sch Med, New York, NY USA. [Schwartz, Joseph E.] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Abecassis, Michael; Friedewald, John] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Becker, Yolanda T.] Univ Chicago, Chicago, IL 60637 USA. [Knechtle, Stuart J.] Emory Univ, Atlanta, GA 30322 USA. [Williams, Nikki M.; Bridges, Nancy D.] NIAID, Bethesda, MD 20892 USA. [Keslar, Karen S.; Fairchild, Robert L.] Cleveland Clin, Cleveland, OH USA. [Hricik, Donald E.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Han, Leiya; Liu, Jun] Pharmaceut Prod Dev, Wilmington, NC USA. [Riggs, Michael; Ikle, David N.] Rho Fed Syst, Chapel Hill, NC USA. [Shaked, Abraham] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Suthanthiran, M (reprint author), New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Med & Transplantat Med, Div Nephrol & Hypertens, Hamad bin Khalifa Med Res Bldg,525 E 68th St,Box, New York, NY 10065 USA. EM msuthan@med.cornell.edu OI Friedewald, John/0000-0002-9344-9928 FU National Institutes of Health [UO1AI63589, R37AI051652]; Qatar National Research Foundation [NPRP 08-503-3-111]; Clinical and Translational Science Center Award [UL1TR000457] FX Funded by the National Institutes of Health and others.; Supported in part by grants from the National Institutes of Health (UO1AI63589 and R37AI051652) and the Qatar National Research Foundation (NPRP 08-503-3-111) and by a Clinical and Translational Science Center Award (UL1TR000457, to Weill Cornell Medical College). NR 18 TC 100 Z9 101 U1 0 U2 20 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 4 PY 2013 VL 369 IS 1 BP 20 EP 31 DI 10.1056/NEJMoa1215555 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 175WE UT WOS:000321263500007 PM 23822777 ER PT J AU Vilboux, T Lev, A Malicdan, MCV Simon, AJ Jarvinen, P Racek, T Puchalka, J Sood, R Carrington, B Bishop, K Mullikin, J Huizing, M Garty, BZ Eyal, E Wolach, B Gavrieli, R Toren, A Soudack, M Atawneh, OM Babushkin, T Schiby, G Cullinane, A Avivi, C Polak-Charcon, S Barshack, I Amariglio, N Rechavi, G ten Bosch, JV Anikster, Y Klein, C Gahl, WA Somech, R AF Vilboux, Thierry Lev, Atar Malicdan, May Christine V. Simon, Amos J. Jaervinen, Paeivi Racek, Tomas Puchalka, Jacek Sood, Raman Carrington, Blake Bishop, Kevin Mullikin, James Huizing, Marjan Garty, Ben Zion Eyal, Eran Wolach, Baruch Gavrieli, Ronit Toren, Amos Soudack, Michalle Atawneh, Osama M. Babushkin, Tatiana Schiby, Ginette Cullinane, Andrew Avivi, Camila Polak-Charcon, Sylvie Barshack, Iris Amariglio, Ninette Rechavi, Gideon ten Bosch, Jutte van der Werff Anikster, Yair Klein, Christoph Gahl, William A. Somech, Raz TI A Congenital Neutrophil Defect Syndrome Associated with Mutations in VPS45 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HERMANSKY-PUDLAK-SYNDROME; OCULOCUTANEOUS ALBINISM; GENETIC-DEFECTS; PROTEIN; ZEBRAFISH; RABENOSYN-5; TRAFFICKING; DEFICIENCY; TRANSPORT; HOMOLOG AB BACKGROUND Neutrophils are the predominant phagocytes that provide protection against bacterial and fungal infections. Genetically determined neutrophil disorders confer a predisposition to severe infections and reveal novel mechanisms that control vesicular trafficking, hematopoiesis, and innate immunity. METHODS We clinically evaluated seven children from five families who had neutropenia, neutrophil dysfunction, bone marrow fibrosis, and nephromegaly. To identify the causative gene, we performed homozygosity mapping using single-nucleotide polymorphism arrays, whole-exome sequencing, immunoblotting, immunofluorescence, electron microscopy, a real-time quantitative polymerase-chain-reaction assay, immunohistochemistry, flow cytometry, fibroblast motility assays, measurements of apoptosis, and zebrafish models. Correction experiments were performed by transfecting mutant fibroblasts with the nonmutated gene. RESULTS All seven affected children had homozygous mutations (Thr224Asn or Glu238Lys, depending on the child's ethnic origin) in VPS45, which encodes a protein that regulates membrane trafficking through the endosomal system. The level of VPS45 protein was reduced, as were the VPS45 binding partners rabenosyn-5 and syntaxin-16. The level of beta 1 integrin was reduced on the surface of VPS45-deficient neutrophils and fibroblasts. VPS45-deficient fibroblasts were characterized by impaired motility and increased apoptosis. A zebrafish model of vps45 deficiency showed a marked paucity of myeloperoxidase-positive cells (i.e., neutrophils). Transfection of patient cells with nonmutated VPS45 corrected the migration defect and decreased apoptosis. CONCLUSIONS Defective endosomal intracellular protein trafficking due to biallelic mutations in VPS45 underlies a new immunodeficiency syndrome involving impaired neutrophil function. C1 [Vilboux, Thierry; Malicdan, May Christine V.; Huizing, Marjan; Cullinane, Andrew; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Sood, Raman; Carrington, Blake; Bishop, Kevin] NHGRI, Zebrafish Core Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Mullikin, James] NHGRI, Comparat Genom Unit, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Lev, Atar; Simon, Amos J.; Somech, Raz] Edmond & Lily Safra Childrens Hosp, Chaim Sheba Med Ctr, Jeffrey Modell Fdn, Pediat Immunol Serv, Tel Hashomer, Israel. [Eyal, Eran; Amariglio, Ninette; Rechavi, Gideon] Edmond & Lily Safra Childrens Hosp, Chaim Sheba Med Ctr, Canc Res Ctr, Tel Hashomer, Israel. [Toren, Amos] Edmond & Lily Safra Childrens Hosp, Chaim Sheba Med Ctr, Pediat Hemato Oncol Unit, Tel Hashomer, Israel. [Soudack, Michalle] Edmond & Lily Safra Childrens Hosp, Chaim Sheba Med Ctr, Imaging Unit, Tel Hashomer, Israel. [Babushkin, Tatiana; Schiby, Ginette; Avivi, Camila; Polak-Charcon, Sylvie; Barshack, Iris] Edmond & Lily Safra Childrens Hosp, Chaim Sheba Med Ctr, Dept Pathol, Tel Hashomer, Israel. [Anikster, Yair] Edmond & Lily Safra Childrens Hosp, Chaim Sheba Med Ctr, Metab Dis Unit, Tel Hashomer, Israel. [Garty, Ben Zion; Wolach, Baruch; Gavrieli, Ronit; Toren, Amos; Soudack, Michalle; Babushkin, Tatiana; Schiby, Ginette; Avivi, Camila; Polak-Charcon, Sylvie; Barshack, Iris; Rechavi, Gideon; Anikster, Yair; Somech, Raz] Tel Aviv Univ, Sackler Fac Med, IL-52621 Tel Aviv, Israel. [Garty, Ben Zion] Schneider Childrens Med Ctr Israel, Dept Pediat B, Petah Tiqwa, Israel. [Garty, Ben Zion] Felsenstein Med Res Ctr, Petah Tiqwa, Israel. [Wolach, Baruch; Gavrieli, Ronit] Meir Med Ctr, Dept Pediat, Kefar Sava, Israel. [Wolach, Baruch; Gavrieli, Ronit] Meir Med Ctr, Lab Leukocyte Funct, Kefar Sava, Israel. [Atawneh, Osama M.] Palestine Red Crescent Soc Hosp, Hebron City, Germany. [Jaervinen, Paeivi; Racek, Tomas; Puchalka, Jacek; Klein, Christoph] Univ Munich, Dr von Hauner Childrens Hosp, Dept Pediat, Munich, Germany. [ten Bosch, Jutte van der Werff] Vrije Univ Brussel, Univ Ziekenhuis Brussel, Dept Pediat, Brussels, Belgium. RP Somech, R (reprint author), Tel Aviv Univ, Sackler Fac Med, Chaim Sheba Med Ctr, Edmond & Lily Safra Childrens Hosp, IL-52621 Tel Aviv, Israel. EM raz.somech@sheba.health.gov.il FU National Human Genome Research Institute; Intramural Research Program of the National Human Genome Research Institute; European Research Council; Gottfried-Wilhelm-Leibniz Program of the Deutsche Forschungsgemeinschaft; Care-for-Rare Foundation; German Network on Primary Immunodeficiency Diseases; Jeffrey Modell Foundation; Israeli Science Foundation; Chief Scientist Office of the Israeli Ministry of Health FX Funded by the National Human Genome Research Institute and others.; Supported by the Intramural Research Program of the National Human Genome Research Institute, an advanced grant (EXPLORE) from the European Research Council, the Gottfried-Wilhelm-Leibniz Program of the Deutsche Forschungsgemeinschaft, the Care-for-Rare Foundation, and the German Network on Primary Immunodeficiency Diseases. Dr. Somech is the recipient of grants from the Jeffrey Modell Foundation, the Israeli Science Foundation, and the Chief Scientist Office of the Israeli Ministry of Health. NR 43 TC 29 Z9 30 U1 1 U2 15 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 4 PY 2013 VL 369 IS 1 BP 54 EP 65 DI 10.1056/NEJMoa1301296 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 175WE UT WOS:000321263500010 PM 23738510 ER PT J AU Creighton, CJ Morgan, M Gunaratne, PH Wheeler, DA Gibbs, RA Robertson, AG Chu, A Beroukhim, R Cibulskis, K Signoretti, S Vandin, F Wu, HT Raphael, BJ Verhaak, RGW Tamboli, P Torres-Garcia, W Akbani, R Weinstein, JN Reuter, V Hsieh, JJ Brannon, AR Hakimi, AA Jacobsen, A Ciriello, G Reva, B Ricketts, CJ Linehan, WM Stuart, JM Rathmell, WK Shen, H Laird, PW Muzny, D Davis, C Morgan, M Xi, L Chang, K Kakkar, N Trevino, LR Benton, S Reid, JG Morton, D Doddapaneni, H Han, Y Lewis, L Dinh, H Kovar, C Zhu, YM Santibanez, J Wang, M Hale, W Kalra, D Creighton, CJ Wheeler, DA Gibbs, RA Getz, G Cibulskis, K Lawrence, MS Sougnez, C Carter, SL Sivachenko, A Lichtenstein, L Stewart, C Voet, D Fisher, S Gabriel, SB Lander, E Beroukhim, R Schumacher, SE Tabak, B Saksena, G Onofrio, RC Carter, SL Cherniack, AD Gentry, J Ardlie, K Sougnez, C Getz, G Gabriel, SB Meyerson, M Robertson, AG Chu, AD Chun, HJE Mungall, AJ Sipahimalani, P Stoll, D Ally, A Balasundaram, M Butterfield, YSN Carlsen, R Carter, C Chuah, E Coope, RJN Dhalla, N Gorski, S Guin, R Hirst, C Hirst, M Holt, RA Lebovitz, C Lee, D Li, HYI Mayo, M Moore, RA Pleasance, E Plettner, P Schein, JE Shafiei, A Slobodan, JR Tam, A Thiessen, N Varhol, RJ Wye, N Zhao, YJ Birol, I Jones, SJM Marra, MA Auman, JT Tan, DH Jones, CD Hoadley, KA Mieczkowski, PA Mose, LE Jefferys, SR Topal, M Liquori, C Turman, YJ Shi, Y Waring, S Buda, E Walsh, J Wu, JY Bodenheimer, T Hoyle, AP Simons, JV Soloway, M Balu, S Parker, JS Hayes, DN Perou, CM Kucherlapati, R Park, P Shen, H Triche, T Weisenberger, DJ Lai, PH Bootwalla, MS Maglinte, DT Mahurkar, S Berman, BP Van den Berg, DJ Cope, L Baylin, SB Laird, PW Creighton, CJ Wheeler, DA Getz, G Noble, MS DiCara, D Zhang, HL Cho, J Heiman, DI Gehlenborg, N Voet, D Mallard, W Lin, P Frazer, S Stojanov, P Liu, YC Zhou, LH Kim, J Lawrence, MS Chin, L Vandin, F Wu, HT Raphael, BJ Benz, C Yau, C Reynolds, SM Shmulevich, I Verhaak, RGW Torres-Garcia, W Vegesna, R Kim, H Zhang, W Cogdell, D Jonasch, E Ding, ZY Lu, YL Akbani, R Zhang, NX Unruh, AK Casasent, TD Wakefield, C Tsavachidou, D Chin, L Mills, GB Weinstein, JN Jacobsen, A Brannon, AR Ciriello, G Schultz, N Hakimi, AA Reva, B Antipin, Y Gao, JJ Cerami, E Gross, B Aksoy, BA Sinha, R Weinhold, N Sumer, SO Taylor, BS Shen, RL Ostrovnaya, I Hsieh, JJ Berger, MF Ladanyi, M Sander, C Fei, SS Stout, A Spellman, PT Rubin, DL Liu, TT Stuart, JM Ng, S Paull, EO Carlin, D Goldstein, T Waltman, P Ellrott, K Zhu, J Haussler, D Gunaratne, PH Xiao, WM Shelton, C Gardner, J Penny, R Sherman, M Mallery, D Morris, S Paulauskis, J Burnett, K Shelton, T Signoretti, S Kaelin, WG Choueiri, T Atkins, MB Penny, R Burnett, K Mallery, D Curley, E Tickoo, S Reuter, V Rathmell, WK Thorne, L Boice, L Huang, M Fisher, JC Linehan, WM Vocke, CD Peterson, J Worrell, R Merino, MJ Schmidt, LS Tamboli, P Czerniak, BA Aldape, KD Wood, CG Boyd, J Weaver, J Iacocca, MV Petrelli, N Witkin, G Brown, J Czerwinski, C Huelsenbeck-Dill, L Rabeno, B Myers, J Morrison, C Bergsten, J Eckman, J Harr, J Smith, C Tucker, K Zach, LA Bshara, W Gaudioso, C Morrison, C Dhir, R Maranchie, J Nelson, J Parwani, A Potapova, O Fedosenko, K Cheville, JC Thompson, RH Signoretti, S Kaelin, WG Atkins, MB Tickoo, S Reuter, V Linehan, WM Vocke, CD Peterson, J Merino, MJ Schmidt, LS Tamboli, P Mosquera, JM Rubin, MA Blute, ML Rathmell, WK Pihl, T Jensen, M Sfeir, R Kahn, A Chu, A Kothiyal, P Snyder, E Pontius, J Ayala, B Backus, M Walton, J Baboud, J Berton, D Nicholls, M Srinivasan, D Raman, R Girshik, S Kigonya, P Alonso, S Sanbhadti, R Barletta, S Pot, D Sheth, M Demchok, JA Davidsen, T Wang, ZN Yang, LM Tarnuzzer, RW Zhang, JS Eley, G Ferguson, ML Shaw, KRM Guyer, MS Ozenberger, BA Sofia, HJ AF Creighton, Chad J. Morgan, Margaret Gunaratne, Preethi H. Wheeler, David A. Gibbs, Richard A. Robertson, A. Gordon Chu, Andy Beroukhim, Rameen Cibulskis, Kristian Signoretti, Sabina Vandin, Fabio Wu, Hsin-Ta Raphael, Benjamin J. Verhaak, Roel G. W. Tamboli, Pheroze Torres-Garcia, Wandaliz Akbani, Rehan Weinstein, John N. Reuter, Victor Hsieh, James J. Brannon, A. Rose Hakimi, A. Ari Jacobsen, Anders Ciriello, Giovanni Reva, Boris Ricketts, Christopher J. Linehan, W. Marston Stuart, Joshua M. Rathmell, W. Kimryn Shen, Hui Laird, Peter W. Muzny, Donna Davis, Caleb Morgan, Margaret Xi, Liu Chang, Kyle Kakkar, Nipun Trevino, Lisa R. Benton, Susan Reid, Jeffrey G. Morton, Donna Doddapaneni, Harsha Han, Yi Lewis, Lora Dinh, Huyen Kovar, Christie Zhu, Yiming Santibanez, Jireh Wang, Min Hale, Walker Kalra, Divya Creighton, Chad J. Wheeler, David A. Gibbs, Richard A. Getz, Gad Cibulskis, Kristian Lawrence, Michael S. Sougnez, Carrie Carter, Scott L. Sivachenko, Andrey Lichtenstein, Lee Stewart, Chip Voet, Doug Fisher, Sheila Gabriel, Stacey B. Lander, Eric Beroukhim, Rameen Schumacher, Steve E. Tabak, Barbara Saksena, Gordon Onofrio, Robert C. Carter, Scott L. Cherniack, Andrew D. Gentry, Jeff Ardlie, Kristin Sougnez, Carrie Getz, Gad Gabriel, Stacey B. Meyerson, Matthew Robertson, A. Gordon Chu, Andy Chun, Hye-Jung E. Mungall, Andrew J. Sipahimalani, Payal Stoll, Dominik Ally, Adrian Balasundaram, Miruna Butterfield, Yaron S. N. Carlsen, Rebecca Carter, Candace Chuah, Eric Coope, Robin J. N. Dhalla, Noreen Gorski, Sharon Guin, Ranabir Hirst, Carrie Hirst, Martin Holt, Robert A. Lebovitz, Chandra Lee, Darlene Li, Haiyan I. Mayo, Michael Moore, Richard A. Pleasance, Erin Plettner, Patrick Schein, Jacqueline E. Shafiei, Arash Slobodan, Jared R. Tam, Angela Thiessen, Nina Varhol, Richard J. Wye, Natasja Zhao, Yongjun Birol, Inanc Jones, Steven J. M. Marra, Marco A. Auman, J. Todd Tan, Donghui Jones, Corbin D. Hoadley, Katherine A. Mieczkowski, Piotr A. Mose, Lisle E. Jefferys, Stuart R. Topal, MichaelD. Liquori, Christina Turman, Yidi J. Shi, Yan Waring, Scot Buda, Elizabeth Walsh, Jesse Wu, Junyuan Bodenheimer, Tom Hoyle, Alan P. Simons, Janae V. Soloway, MathewG. Balu, Saianand Parker, Joel S. Hayes, D. Neil Perou, Charles M. Kucherlapati, Raju Park, Peter Shen, Hui Triche, Timothy, Jr. Weisenberger, Daniel J. Lai, Phillip H. Bootwalla, Moiz S. Maglinte, Dennis T. Mahurkar, Swapna Berman, Benjamin P. Van den Berg, David J. Cope, Leslie Baylin, Stephen B. Laird, Peter W. Creighton, Chad J. Wheeler, David A. Getz, Gad Noble, Michael S. DiCara, Daniel Zhang, Hailei Cho, Juok Heiman, David I. Gehlenborg, Nils Voet, Doug Mallard, William Lin, Pei Frazer, Scott Stojanov, Petar Liu, Yingchun Zhou, Lihua Kim, Jaegil Lawrence, Michael S. Chin, Lynda Vandin, Fabio Wu, Hsin-Ta Raphael, Benjamin J. Benz, Christopher Yau, Christina Reynolds, Sheila M. Shmulevich, Ilya Verhaak, Roel G. W. Torres-Garcia, Wandaliz Vegesna, Rahul Kim, Hoon Zhang, Wei Cogdell, David Jonasch, Eric Ding, Zhiyong Lu, Yiling Akbani, Rehan Zhang, Nianxiang Unruh, Anna K. Casasent, Tod D. Wakefield, Chris Tsavachidou, Dimitra Chin, Lynda Mills, Gordon B. Weinstein, John N. Jacobsen, Anders Brannon, A. Rose Ciriello, Giovanni Schultz, Nikolaus Hakimi, A. Ari Reva, Boris Antipin, Yevgeniy Gao, Jianjiong Cerami, Ethan Gross, Benjamin Aksoy, B. Arman Sinha, Rileen Weinhold, Nils Sumer, S. Onur Taylor, Barry S. Shen, Ronglai Ostrovnaya, Irina Hsieh, James J. Berger, Michael F. Ladanyi, Marc Sander, Chris Fei, Suzanne S. Stout, Andrew Spellman, Paul T. Rubin, Daniel L. Liu, Tiffany T. Stuart, Joshua M. Sam Ng Paull, Evan O. Carlin, Daniel Goldstein, Theodore Waltman, Peter Ellrott, Kyle Zhu, Jing Haussler, David Gunaratne, Preethi H. Xiao, Weimin Shelton, Candace Gardner, Johanna Penny, Robert Sherman, Mark Mallery, David Morris, Scott Paulauskis, Joseph Burnett, Ken Shelton, Troy Signoretti, Sabina Kaelin, William G. Choueiri, Toni Atkins, Michael B. Penny, Robert Burnett, Ken Mallery, David Curley, Erin Tickoo, Satish Reuter, Victor Rathmell, W. Kimryn Thorne, Leigh Boice, Lori Huang, Mei Fisher, Jennifer C. Linehan, W. Marston Vocke, Cathy D. Peterson, James Worrell, Robert Merino, Maria J. Schmidt, Laura S. Tamboli, Pheroze Czerniak, Bogdan A. Aldape, Kenneth D. Wood, Christopher G. Boyd, Jeff Weaver, JoEllen Iacocca, Mary V. Petrelli, Nicholas Witkin, Gary Brown, Jennifer Czerwinski, Christine Huelsenbeck-Dill, Lori Rabeno, Brenda Myers, Jerome Morrison, Carl Bergsten, Julie Eckman, John Harr, Jodi Smith, Christine Tucker, Kelinda Zach, Leigh Anne Bshara, Wiam Gaudioso, Carmelo Morrison, Carl Dhir, Rajiv Maranchie, Jodi Nelson, Joel Parwani, Anil Potapova, Olga Fedosenko, Konstantin Cheville, John C. Thompson, R. Houston Signoretti, Sabina Kaelin, William G. Atkins, Michael B. Tickoo, Satish Reuter, Victor Linehan, W. Marston Vocke, Cathy D. Peterson, James Merino, Maria J. Schmidt, Laura S. Tamboli, Pheroze Mosquera, Juan M. Rubin, Mark A. Blute, Michael L. Rathmell, W. Kimryn Pihl, Todd Jensen, Mark Sfeir, Robert Kahn, Ari Chu, Anna Kothiyal, Prachi Snyder, Eric Pontius, Joan Ayala, Brenda Backus, Mark Walton, Jessica Baboud, Julien Berton, Dominique Nicholls, Matthew Srinivasan, Deepak Raman, Rohini Girshik, Stanley Kigonya, Peter Alonso, Shelley Sanbhadti, Rashmi Barletta, Sean Pot, David Sheth, Margi Demchok, John A. Davidsen, Tanja Wang, Zhining Yang, Liming Tarnuzzer, Roy W. Zhang, Jiashan Eley, Greg Ferguson, Martin L. Shaw, Kenna R. Mills Guyer, Mark S. Ozenberger, Bradley A. Sofia, Heidi J. CA Canc Genome Atlas Res Network Anal Working Grp TI Comprehensivemolecular characterization of clear cell renal cell carcinoma SO NATURE LA English DT Article ID KIDNEY CANCER; TUMOR-SUPPRESSOR; DNA METHYLATION; GENETIC-BASIS; TARGETS; PROTEIN; TRIAL; ARM AB Genetic changes underlying clear cell renal cell carcinoma(ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3) K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment. C1 [Creighton, Chad J.; Morgan, Margaret; Gunaratne, Preethi H.; Wheeler, David A.; Gibbs, Richard A.; Muzny, Donna; Davis, Caleb; Xi, Liu; Chang, Kyle; Kakkar, Nipun; Trevino, Lisa R.; Benton, Susan; Reid, Jeffrey G.; Morton, Donna; Doddapaneni, Harsha; Han, Yi; Lewis, Lora; Dinh, Huyen; Kovar, Christie; Zhu, Yiming; Santibanez, Jireh; Wang, Min; Hale, Walker; Kalra, Divya] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Xiao, Weimin] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. [Robertson, A. Gordon; Chu, Andy; Chun, Hye-Jung E.; Mungall, Andrew J.; Sipahimalani, Payal; Stoll, Dominik; Ally, Adrian; Balasundaram, Miruna; Butterfield, Yaron S. N.; Carlsen, Rebecca; Carter, Candace; Chuah, Eric; Coope, Robin J. N.; Dhalla, Noreen; Gorski, Sharon; Guin, Ranabir; Hirst, Carrie; Hirst, Martin; Holt, Robert A.; Lebovitz, Chandra; Lee, Darlene; Li, Haiyan I.; Mayo, Michael; Moore, Richard A.; Pleasance, Erin; Plettner, Patrick; Schein, Jacqueline E.; Shafiei, Arash; Slobodan, Jared R.; Tam, Angela; Thiessen, Nina; Varhol, Richard J.; Wye, Natasja; Zhao, Yongjun; Birol, Inanc; Jones, Steven J. M.; Marra, Marco A.] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z, Canada. [Beroukhim, Rameen; Beroukhim, Rameen; Carter, Scott L.] Harvard Univ, Dept Med, Sch Med, Boston, MA 02215 USA. [Beroukhim, Rameen; Cibulskis, Kristian; Getz, Gad; Lawrence, Michael S.; Sougnez, Carrie; Carter, Scott L.; Sivachenko, Andrey; Lichtenstein, Lee; Stewart, Chip; Voet, Doug; Fisher, Sheila; Gabriel, Stacey B.; Lander, Eric; Beroukhim, Rameen; Schumacher, Steve E.; Tabak, Barbara; Saksena, Gordon; Onofrio, Robert C.; Cherniack, Andrew D.; Gentry, Jeff; Ardlie, Kristin; Meyerson, Matthew; Noble, Michael S.; DiCara, Daniel; Zhang, Hailei; Cho, Juok; Heiman, David I.; Gehlenborg, Nils; Mallard, William; Lin, Pei; Frazer, Scott; Stojanov, Petar; Liu, Yingchun; Zhou, Lihua; Kim, Jaegil; Chin, Lynda] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Beroukhim, Rameen; Carter, Scott L.; Sivachenko, Andrey; Lichtenstein, Lee; Stewart, Chip; Fisher, Sheila; Lander, Eric; Beroukhim, Rameen; Schumacher, Steve E.; Tabak, Barbara; Saksena, Gordon; Onofrio, Robert C.; Cherniack, Andrew D.; Gentry, Jeff; Ardlie, Kristin; Meyerson, Matthew; Noble, Michael S.; DiCara, Daniel; Zhang, Hailei; Cho, Juok; Heiman, David I.; Gehlenborg, Nils; Mallard, William; Lin, Pei; Frazer, Scott; Stojanov, Petar; Liu, Yingchun; Zhou, Lihua; Kim, Jaegil] Harvard Univ, Cambridge, MA 02142 USA. [Signoretti, Sabina; Meyerson, Matthew] Harvard Univ, Dept Pathol, Sch Med, Boston, MA 02215 USA. [Vandin, Fabio; Wu, Hsin-Ta; Raphael, Benjamin J.] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Verhaak, Roel G. W.; Torres-Garcia, Wandaliz; Akbani, Rehan; Weinstein, John N.; Vegesna, Rahul; Kim, Hoon; Jonasch, Eric; Ding, Zhiyong; Zhang, Nianxiang; Unruh, Anna K.; Casasent, Tod D.; Wakefield, Chris] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Tamboli, Pheroze; Zhang, Wei; Cogdell, David; Czerniak, Bogdan A.; Aldape, Kenneth D.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Reuter, Victor; Brannon, A. Rose; Berger, Michael F.; Tickoo, Satish] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Hsieh, James J.; Hakimi, A. Ari; Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Jacobsen, Anders; Ciriello, Giovanni; Reva, Boris; Schultz, Nikolaus; Antipin, Yevgeniy; Gao, Jianjiong; Cerami, Ethan; Gross, Benjamin; Aksoy, B. Arman; Sinha, Rileen; Weinhold, Nils; Sumer, S. Onur; Taylor, Barry S.; Shen, Ronglai; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Ricketts, Christopher J.; Linehan, W. Marston; Vocke, Cathy D.; Peterson, James; Worrell, Robert; Merino, Maria J.; Schmidt, Laura S.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Stuart, Joshua M.; Sam Ng; Paull, Evan O.; Carlin, Daniel; Goldstein, Theodore; Waltman, Peter; Ellrott, Kyle; Zhu, Jing; Haussler, David] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Sam Ng; Paull, Evan O.; Carlin, Daniel; Goldstein, Theodore; Waltman, Peter; Ellrott, Kyle; Zhu, Jing; Haussler, David] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Rathmell, W. Kimryn; Hoadley, Katherine A.; Liquori, Christina; Turman, Yidi J.; Shi, Yan; Waring, Scot; Buda, Elizabeth; Walsh, Jesse; Wu, Junyuan; Bodenheimer, Tom; Hoyle, Alan P.; Simons, Janae V.; Soloway, MathewG.; Balu, Saianand; Parker, Joel S.; Hayes, D. Neil; Perou, Charles M.; Thorne, Leigh; Boice, Lori; Huang, Mei; Fisher, Jennifer C.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Shen, Hui; Laird, Peter W.; Triche, Timothy, Jr.; Weisenberger, Daniel J.; Lai, Phillip H.; Bootwalla, Moiz S.; Maglinte, Dennis T.; Mahurkar, Swapna; Berman, Benjamin P.; Van den Berg, David J.] Univ So Calif, USC Epigenome Ctr, Los Angeles, CA 90033 USA. [Auman, J. Todd] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Tan, Donghui] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Jones, Corbin D.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Hoadley, Katherine A.; Mose, Lisle E.; Topal, MichaelD.; Perou, Charles M.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Hoadley, Katherine A.; Mieczkowski, Piotr A.; Jefferys, Stuart R.; Topal, MichaelD.; Perou, Charles M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Hayes, D. Neil] Univ N Carolina, Dept Internal Med, Div Med Oncol, Chapel Hill, NC 27599 USA. [Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA. [Kucherlapati, Raju; Park, Peter] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Park, Peter; Gehlenborg, Nils] Harvard Univ, Ctr Biomed Informat, Sch Med, Boston, MA 02115 USA. [Park, Peter] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Cope, Leslie; Baylin, Stephen B.] Johns Hopkins Univ, Canc Biol Div, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Reynolds, Sheila M.; Shmulevich, Ilya] Inst Syst Biol, Seattle, WA 98109 USA. [Lu, Yiling; Tsavachidou, Dimitra; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77054 USA. [Ostrovnaya, Irina] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Fei, Suzanne S.; Stout, Andrew; Spellman, Paul T.] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portand, OR 97239 USA. [Rubin, Daniel L.; Liu, Tiffany T.] Stanford Univ, Dept Radiol, Med Ctr, Stanford, CA 94305 USA. [Haussler, David] Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. [Shelton, Candace; Gardner, Johanna; Penny, Robert; Sherman, Mark; Mallery, David; Morris, Scott; Paulauskis, Joseph; Burnett, Ken; Shelton, Troy; Curley, Erin] Int Genom Consortium, Phoenix, AZ 85004 USA. [Atkins, Michael B.] Georgetown Univ, Georgetown Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. SAIC Frederick Inc, Basic Sci Program, Frederick Natl Lab, Frederick, MD 21702 USA. [Wood, Christopher G.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Boyd, Jeff; Weaver, JoEllen] Fox Chase Canc Ctr, Canc Biol Program, Philadelphia, PA 19111 USA. [Iacocca, Mary V.; Petrelli, Nicholas; Witkin, Gary; Brown, Jennifer; Czerwinski, Christine; Huelsenbeck-Dill, Lori; Rabeno, Brenda] Christiana Care, Helen F Graham Canc Ctr, Newark, DC 19713 USA. [Myers, Jerome; Morrison, Carl; Bergsten, Julie; Eckman, John; Harr, Jodi; Smith, Christine; Tucker, Kelinda; Zach, Leigh Anne] Penrose St Francis Hlth Serv, Colorado Springs, CO 80907 USA. [Bshara, Wiam; Gaudioso, Carmelo; Morrison, Carl] Roswell Pk Canc Inst, Dept Pathol, Buffalo, NY 14263 USA. [Dhir, Rajiv; Maranchie, Jodi; Nelson, Joel; Parwani, Anil] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Potapova, Olga] Cureline Inc, San Francisco, CA 94080 USA. [Fedosenko, Konstantin] St Petersburg City Clin Oncol Dispensary, St Petersburg 198255, Russia. [Mosquera, Juan M.; Rubin, Mark A.] Weill Cornell Coll Med, Dept Pathol & Lab Med, New York, NY 10065 USA. [Blute, Michael L.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Pihl, Todd; Jensen, Mark; Sfeir, Robert; Kahn, Ari; Chu, Anna; Kothiyal, Prachi; Snyder, Eric; Pontius, Joan; Ayala, Brenda; Backus, Mark; Walton, Jessica; Baboud, Julien; Berton, Dominique; Nicholls, Matthew; Srinivasan, Deepak; Raman, Rohini; Girshik, Stanley; Kigonya, Peter; Alonso, Shelley; Sanbhadti, Rashmi; Barletta, Sean; Pot, David] SRA Int, Fairfax, VA 22033 USA. [Sheth, Margi; Demchok, John A.; Davidsen, Tanja; Wang, Zhining; Yang, Liming; Tarnuzzer, Roy W.; Zhang, Jiashan; Shaw, Kenna R. Mills] NCI, Canc Genome Atlas Program Off, Ctr Canc Genom, Bethesda, MD 20892 USA. [Eley, Greg] TCGA Consultant Scimentis LLC, Atlanta, GA 30666 USA. [Ferguson, Martin L.] MLF Consulting, Arlington, MA 02474 USA. [Guyer, Mark S.; Ozenberger, Bradley A.; Sofia, Heidi J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Beroukhim, Rameen; Meyerson, Matthew; Stojanov, Petar; Kaelin, William G.; Choueiri, Toni] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Benz, Christopher; Yau, Christina] Buck Inst Res Aging, Novato, CA 94945 USA. [Beroukhim, Rameen; Schumacher, Steve E.; Tabak, Barbara] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cheville, John C.; Thompson, R. Houston] Mayo Clin, Rochester, MN 55905 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Gibbs, RA (reprint author), Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. EM agibbs@bcm.edu; linehanm@mail.nih.gov RI Birol, Inanc/G-5440-2011; Jacobsen, Anders/K-1081-2013; Schumacher, Steven/E-9821-2013; Jones, Steven/C-3621-2009; Marra, Marco/B-5987-2008; Reva, Boris/B-6436-2014; Berman, Benjamin/D-5942-2014; Gorski, Sharon/E-9375-2012; Holt, Robert/C-3303-2009; Kalra, Divya/N-5453-2014; Laird, Peter/G-8683-2012; Schein, Jacquie/G-3674-2015; Gao, Jianjiong/B-5673-2016; Hirst, Martin/B-7684-2016 OI Gehlenborg, Nils/0000-0003-0327-8297; Birol, Inanc/0000-0003-0950-7839; Schultz, Nikolaus/0000-0002-0131-4904; parwani, anil/0000-0002-7616-1666; Triche, Tim/0000-0001-5665-946X; Maranchie, Jodi/0000-0002-8534-9468; Rubin, Mark/0000-0002-8321-9950; Pot, David/0000-0002-1480-9826; Sinha, Rileen/0000-0001-5497-5055; Casasent, Anna/0000-0002-7857-179X; Perou, Charles/0000-0001-9827-2247; Jacobsen, Anders/0000-0001-6847-4980; Schumacher, Steven/0000-0002-6819-5647; Reva, Boris/0000-0002-8805-389X; Gorski, Sharon/0000-0002-3821-8289; Gao, Jianjiong/0000-0002-5739-1781; NR 33 TC 167 Z9 172 U1 9 U2 116 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 4 PY 2013 VL 499 IS 7456 BP 43 EP + DI 10.1038/nature12222 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176ED UT WOS:000321285600029 ER PT J AU Flood, TF Iguchi, S Gorczyca, M White, B Ito, K Yoshihara, M AF Flood, Thomas F. Iguchi, Shinya Gorczyca, Michael White, Benjamin Ito, Kei Yoshihara, Motojiro TI A single pair of interneurons commands the Drosophila feeding motor program SO NATURE LA English DT Article ID NEURONAL-SYNAPTOBREVIN; SYNAPTIC TRANSMISSION; NERVOUS-SYSTEM; BRAIN; EXPRESSION; BEHAVIOR; COURTSHIP; CIRCUIT; REVEALS; RELEASE AB Many feeding behaviours are the result of stereotyped, organized sequences of motor patterns. These patterns have been the subject of neuroethological studies(1,2), such as electrophysiological characterization of neurons governing prey capture in toads(1,3). However, technical limitations have prevented detailed study of the functional role of these neurons, a common problem for vertebrate organisms. Complexities involved in studies of whole-animal behaviour can be resolved in Drosophila, in which remote activation of brain cells by genetic means(4) enables us to examine the nervous system in freely moving animals to identify neurons that govern a specific behaviour, and then to repeatedly target and manipulate these neurons to characterize their function. Here we show neurons that generate the feeding motor program in Drosophila. We carried out an unbiased screen using remote neuronal activation and identified a critical pair of brain cells that induces the entire feeding sequence when activated. These 'feeding neurons' (here abbreviated to Fdg neurons for brevity) are also essential for normal feeding as their suppression or ablation eliminates sugar-induced feeding behaviour. Activation of a single Fdg neuron induces asymmetric feeding behaviour and ablation of a single Fdg neuron distorts the sugar-induced feeding behaviour to become asymmetric, indicating the direct role of these neurons in shaping motor-program execution. Furthermore, recording neuronal activity and calcium imaging simultaneously during feeding behaviour(5) reveals that the Fdg neurons respond to food presentation, but only in starved flies. Our results demonstrate that Fdg neurons operate firmly within the sensorimotor watershed, downstream of sensory and metabolic cues and at the top of the feeding motor hierarchy, to execute the decision to feed. C1 [Flood, Thomas F.; Iguchi, Shinya; Gorczyca, Michael; Yoshihara, Motojiro] Univ Massachusetts, Sch Med, Dept Neurobiol, Worcester, MA 01605 USA. [White, Benjamin] NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. [Ito, Kei] Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 1130032, Japan. RP Yoshihara, M (reprint author), Univ Massachusetts, Sch Med, Dept Neurobiol, Worcester, MA 01605 USA. EM Motojiro.Yoshihara@umassmed.edu FU National Institute of Mental Health [MH85958]; Worcester Foundation; National Institute of Mental Health Intramural Research Program; Japan Society for the Promotion of Science/National Science Foundation; Japan Science and Technology Agency CREST grant FX We thank S. Waddell for discussions, fly stocks and reading of the manuscript; T. Lee for discussions and fly stocks; A. Sakurai for reading of the manuscript; S. Reppert for support; M. Alkema and T. Ip for discussions; members of the NP consortium for NP lines; T. Awasaki., C. Kao, V. Budnik, P. Garrity, M. Freeman, M. Rosbash, Y.-N. Jan, L. Luo, S. Sigrist, K. Scott, T. Tanimura, L. Looger, M. Ramaswami and K. Gajewski for fly stocks; K. Ikeda, T. Tanimura and H. Ishimoto for technical advices; A. Taylor and R. Seeham for technical help; and N. Yoshihara for material information. This work was supported by National Institute of Mental Health Grant MH85958, and the Worcester Foundation (to M.Y.), the National Institute of Mental Health Intramural Research Program(B. W.), the summer program of the Japan Society for the Promotion of Science/National Science Foundation (to T. F. F.), and a Japan Science and Technology Agency CREST grant (to K.I.). NR 46 TC 37 Z9 37 U1 3 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 4 PY 2013 VL 499 IS 7456 BP 83 EP + DI 10.1038/nature12208 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176ED UT WOS:000321285600038 PM 23748445 ER PT J AU Kanekiyo, M Wei, CJ Yassine, HM McTamney, PM Boyington, JC Whittle, JRR Rao, SS Kong, WP Wang, LS Nabel, GJ AF Kanekiyo, Masaru Wei, Chih-Jen Yassine, Hadi M. McTamney, Patrick M. Boyington, Jeffrey C. Whittle, James R. R. Rao, Srinivas S. Kong, Wing-Pui Wang, Lingshu Nabel, Gary J. TI Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies SO NATURE LA English DT Article ID A VIRUSES; HEMAGGLUTININ; EPITOPE; IMMUNOGENICITY; VACCINATION; RECOGNIZES; INDUCTION; FERRITIN; IMMUNITY; PROTEIN AB Influenza viruses pose a significant threat to the public and are a burden on global health systems(1,2). Each year, influenza vaccines must be rapidly produced to match circulating viruses, a process constrained by dated technology and vulnerable to unexpected strains emerging from humans and animal reservoirs. Here we use knowledge of protein structure to design self-assembling nanoparticles that elicit broader and more potent immunity than traditional influenza vaccines. The viral haemagglutinin was genetically fused to ferritin, a protein that naturally forms nanoparticles composed of 24 identical polypeptides(3). Haemagglutinin was inserted at the interface of adjacent subunits so that it spontaneously assembled and generated eight trimeric viral spikes on its surface. Immunization with this influenza nanoparticle vaccine elicited haemagglutination inhibition antibody titres more than tenfold higher than those from the licensed inactivated vaccine. Furthermore, it elicited neutralizing antibodies to two highly conserved vulnerable haemagglutinin structures that are targets of universal vaccines: the stem(4,5) and the receptor binding site on the head(6,7). Antibodies elicited by a 1999 haemagglutinin-nanoparticle vaccine neutralized H1N1 viruses from 1934 to 2007 and protected ferrets from an unmatched 2007 H1N1 virus challenge. This structure-based, self-assembling synthetic nanoparticle vaccine improves the potency and breadth of influenza virus immunity, and it provides a foundation for building broader vaccine protection against emerging influenza viruses and other pathogens. C1 [Kanekiyo, Masaru; Wei, Chih-Jen; Yassine, Hadi M.; McTamney, Patrick M.; Boyington, Jeffrey C.; Whittle, James R. R.; Rao, Srinivas S.; Kong, Wing-Pui; Wang, Lingshu; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), Sanofi, 640 Mem Dr, Cambridge, MA 02139 USA. EM Gary.Nabel@sanofi.com FU Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health FX We thank H. Andersen, A. Taylor, A. Zajac and C. Chiedi for help with the animal studies; U. Baxa, K. Nagashima and A. Harned for electron microscopy studies; X. Chen for technical support; A. Panet, B. Graham, R. Schwartz and members of the Nabel lab for discussions; S. Sun and M. Rossmann for technical and conceptual advice; A. Tislerics, B. Hartman and J. Farrar for manuscript preparation. The MF59 adjuvant was kindly provided by Novartis. This work was supported by the Intramural Research Program of the Vaccine Research Center, NIAID, National Institutes of Health. NR 33 TC 122 Z9 125 U1 12 U2 162 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 4 PY 2013 VL 499 IS 7456 BP 102 EP + DI 10.1038/nature12202 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176ED UT WOS:000321285600042 PM 23698367 ER PT J AU Aprelikova, O Palla, J Hibler, B Yu, X Greer, YE Yi, M Stephens, R Maxwell, GL Jazaeri, A Risinger, JI Rubin, JS Niederhuber, J AF Aprelikova, O. Palla, J. Hibler, B. Yu, X. Greer, Y. E. Yi, M. Stephens, R. Maxwell, G. L. Jazaeri, A. Risinger, J. I. Rubin, J. S. Niederhuber, J. TI Silencing of miR-148a in cancer-associated fibroblasts results in WNT10B-mediated stimulation of tumor cell motility SO ONCOGENE LA English DT Article DE cancer-associated fibroblasts; endometrial cancer; microRNA; miR-148a; WNT10B ID NUCLEAR BETA-CATENIN; BREAST-CANCER; GASTRIC-CANCER; STROMAL CELLS; ENDOMETRIAL CANCER; OVARIAN CARCINOMAS; PROLIFERATION; MICRORNAS; DNA; CARCINOGENESIS AB The tumor microenvironment has an important role in cancer progression. Here we show that miR-148a is downregulated in 15 out of 16 samples (94%) of cancer-associated fibroblasts (CAFs) compared with matched normal tissue fibroblasts (NFs) established from patients with endometrial cancer. Laser-capture microdissection of stromal cells from normal tissue and endometrial cancer confirmed this observation. Treatment of cells with 5-aza-deoxycytidine stimulated the expression of miR-148a in the majority of CAFs implicating DNA methylation in the regulation of miR-148a expression. Investigation of miR-148a function in fibroblasts demonstrated that conditioned media (CM) from CAFs overexpressing miR-148a significantly impaired the migration of five endometrial cancer cell lines without affecting their growth rates in co-culture experiments. Among predicted miR-148a target genes are two WNT family members, WNT1 and WNT10B. Activation of the WNT/b-catenin pathway in CAFs was confirmed by microarray analysis of gene expression and increased activity of the SuperTOPFlash luciferase reporter. We found elevated levels of WNT10B protein in CAFs and its level decreased when miR-148a was re-introduced by lentiviral infection. The 3'-UTR of WNT10B, cloned downstream of luciferase cDNA, suppressed luciferase activity when co-expressed with miR-148a indicating that WNT10B is a direct target of miR-148a. In contrast to the effect of miR-148a, WNT10B stimulated migration of endometrial cancer cell lines. Our findings have defined a molecular mechanism in the tumor microenvironment that is a novel target for cancer therapy. C1 [Aprelikova, O.; Palla, J.; Hibler, B.; Yu, X.; Niederhuber, J.] Canc & Cell Biol Branch, Bethesda, MD USA. [Greer, Y. E.; Rubin, J. S.] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. [Yi, M.; Stephens, R.] SAIC Inc, Frederick, MD USA. [Maxwell, G. L.] Walter Reed Army Med Ctr, US Mil Canc Inst, Washington, DC 20307 USA. [Jazaeri, A.] Univ Virginia, Charlottesville, VA USA. [Risinger, J. I.] Michigan State Univ, Coll Human Med, Dept Obstet Gynecol & Reprod Biol, Grand Rapids, MI USA. RP Aprelikova, O (reprint author), NCI, Bldg 37,Rm 1042,9000 Rockville Pike, Bethesda, MD 20892 USA. EM apreliko@mail.nih.gov; rubinj@mail.nih.gov RI Jazaeri, Amir/I-3458-2015 OI Jazaeri, Amir/0000-0003-4335-4151 FU Intramural Research Program of National Institutes of Health; National Cancer Institute; Center for Cancer Research FX We thank Julie Oliver, Tracy Litzi, and Shelley Hoover for help with laser capture microdissection, Dr Xin Wei Wang (NCI) for the WNT10B expression vector and Dr Randall Moon (University of Washington) for the SuperTOPFlash and SuperFOPFlash constructs. This work was supported by the Intramural Research Program of National Institutes of Health, National Cancer Institute, and Center for Cancer Research. NR 50 TC 47 Z9 49 U1 0 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 4 PY 2013 VL 32 IS 27 BP 3246 EP 3253 DI 10.1038/onc.2012.351 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 176JZ UT WOS:000321301600004 PM 22890324 ER PT J AU Levens, D Aplan, PD AF Levens, David Aplan, Peter D. TI Notching Up MYC Gives a LIC SO CELL STEM CELL LA English DT Editorial Material ID C-MYC; INHIBITION; CELLS AB In a recent issue of Cell, King et al. (2013) show that mutations in the ubiquitin ligase subcomponent FBXW7 increase MYC protein levels and expand the number of leukemia-initiating cells (LICs) in Notch1-induced T-ALL. Genetic and pharmacological inhibition of MYC abolishes LIC activity with broader therapeutic implications. C1 [Levens, David] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Aplan, Peter D.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Levens, D (reprint author), NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. EM levensd@mail.nih.gov; peter.aplan@nih.gov RI Levens, David/C-9216-2009; Aplan, Peter/K-9064-2016 OI Levens, David/0000-0002-7616-922X; FU Intramural NIH HHS [Z99 CA999999] NR 10 TC 2 Z9 2 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 3 PY 2013 VL 13 IS 1 BP 8 EP 9 DI 10.1016/j.stem.2013.06.008 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 287VJ UT WOS:000329570100005 PM 23827704 ER PT J AU Rinsky, JL Hoppin, JA Blair, A He, K Freeman, LEB Chen, HL AF Rinsky, Jessica L. Hoppin, Jane A. Blair, Aaron He, Ka Freeman, Laura E. Beane Chen, Honglei TI Agricultural Exposures and Stroke Mortality in the Agricultural Health Study SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES LA English DT Article ID LICENSED PESTICIDE APPLICATORS; PERSISTENT ORGANIC POLLUTANTS; PARTICULATE AIR-POLLUTION; ISCHEMIC-STROKE; RISK-FACTORS; CARDIAC MANIFESTATIONS; CARDIOVASCULAR-DISEASE; OCCUPATIONAL-EXPOSURE; ENDOTOXIN TOLERANCE; HEART-DISEASE AB Exposures associated with common agricultural activities may increase risk of stroke. The authors evaluated associations between self-reported agricultural activities including pesticide use and handling of crops and stroke mortality among 51,603 male pesticide applicators enrolled in the Agricultural Health Study (AHS). Vital status was obtained through 2008. Stroke mortality was defined by underlying or contributing cause of death (ICD-9 430-438, ICD-10 I60-I69). Information regarding lifetime pesticide use, working with crops or animals, engagement in other agricultural activities, and potential confounders was self-reported at enrollment. Cox proportional hazards models, with age as the time scale, were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for state of residence, smoking status, and alcohol consumption. Median follow-up time was 13 yr, during which 308 stroke deaths occurred. No measure of overall or specific pesticide use was positively associated with mortality due to stroke. Stroke mortality was inversely associated with handling hay, grain, or silage at least once each year as reported at enrollment (HR: 0.75; 95% CI: 0.58, 0.98). There was no evidence of an association between pesticide use and stroke mortality. The inverse association between handling of hays and grains and stroke mortality may be due to (1) those engaging in such activities being healthier than those who did not or (2) exposure to some biological agent present in hays and grains. Further investigation of incident stroke, rather than stroke mortality, as well as stroke subtypes, is needed to determine the full role of agricultural exposures and stroke. C1 [Rinsky, Jessica L.; He, Ka] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Hoppin, Jane A.; Chen, Honglei] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Blair, Aaron; Freeman, Laura E. Beane] NCI, Occupat & Environm Epidemiol Branch, NIH, Dept Hlth & Human Services, Bethesda, MD 20892 USA. [He, Ka] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC USA. [He, Ka] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, NIH, DHHS, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM hoppin1@niehs.nih.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Chen, Honglei/0000-0003-3446-7779 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES049030]; National Institutes of Health National Cancer Institute [Z01-CP010119]; National Institute of Environmental Health Sciences (NIEHS) [T32ES007018] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01-ES049030) and the National Institutes of Health National Cancer Institute (Z01-CP010119). JLR was supported by the National Institute of Environmental Health Sciences (NIEHS; award no. T32ES007018. The authors thank Stuart Long for assistance with data analysis. We especially thank the participants of the Agricultural Health Study for their continued support. NR 63 TC 3 Z9 3 U1 0 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1528-7394 EI 1087-2620 J9 J TOXICOL ENV HEAL A JI J. Toxicol. Env. Health Part A PD JUL 3 PY 2013 VL 76 IS 13 BP 798 EP 814 DI 10.1080/15287394.2013.819308 PG 17 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 217LA UT WOS:000324359800003 PM 24028665 ER PT J AU Anthis, NJ Clore, GM AF Anthis, Nicholas J. Clore, G. Marius TI The Length of the Calmodulin Linker Determines the Extent of Transient Interdomain Association and Target Affinity SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PARAMAGNETIC RELAXATION ENHANCEMENT; CENTRAL HELIX; PEPTIDE COMPLEX; PROTEINS; NMR; MACROMOLECULES; FLEXIBILITY; ACTIVATION; DELETIONS; DYNAMICS AB Calmodulin (CaM), the prototypical calcium sensing protein in eukaryotes, comprises two domains separated by a short flexible linker, which allows CaM to assume a wide range of extended and compact conformations. Here we use NMR relaxation measurements to explore the role of the linker in CaM function and dynamics. Using paramagnetic relaxation enhancement (PRE) measurements, we examine the effect of changes in the length and rigidity of the linker on the transient association between the two domains of Ca2+-bound CaM (CaM-4Ca(2+)). We observe that transient interdomain association, represented by an effective molarity (M-eff), is maximal for a linker extended by one residue from the wild-type length and decreases for lengths longer or shorter than that. The results can be quantitatively rationalized using a simplified model of a random coil whose two ends must be a specific distance apart for an interaction to occur. The results correlate well with the affinity of CaM-4Ca(2+) for a target peptide, suggesting that the transient compact states adopted by CaM-4Ca(2+) in the absence of peptide play a direct role in facilitating target binding. C1 [Anthis, Nicholas J.; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural Program of the NIH, NIDDK; Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH FX We thank Ad Bax for useful discussions. This work was supported by the Intramural Program of the NIH, NIDDK, and the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.) NR 17 TC 9 Z9 9 U1 1 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 3 PY 2013 VL 135 IS 26 BP 9648 EP 9651 DI 10.1021/ja4051422 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 179SO UT WOS:000321541800023 PM 23782151 ER PT J AU Enciso-Rodriguez, FE Gonzalez, C Rodriguez, EA Lopez, CE Landsman, D Barrero, LS Marino-Ramirez, L AF Enciso-Rodriguez, Felix E. Gonzalez, Carolina Rodriguez, Edwin A. Lopez, Camilo E. Landsman, David Stella Barrero, Luz Marino-Ramirez, Leonardo TI Identification of Immunity Related Genes to Study the Physalis peruviana - Fusarium oxysporum Pathosystem SO PLOS ONE LA English DT Article ID DISEASE RESISTANCE GENES; GENOME-WIDE IDENTIFICATION; LEUCINE-RICH REPEATS; NBS-LRR PROTEINS; ANTIINFLAMMATORY ACTIVITY; BINDING-PROTEINS; ATP-BINDING; IN-VITRO; SEQUENCES; ARABIDOPSIS AB The Cape gooseberry (Physalis peruviana L) is an Andean exotic fruit with high nutritional value and appealing medicinal properties. However, its cultivation faces important phytosanitary problems mainly due to pathogens like Fusarium oxysporum, Cercospora physalidis and Alternaria spp. Here we used the Cape gooseberry foliar transcriptome to search for proteins that encode conserved domains related to plant immunity including: NBS (Nucleotide Binding Site), CC (Coiled-Coil), TIR (Toll/Interleukin-1 Receptor). We identified 74 immunity related gene candidates in P. peruviana which have the typical resistance gene (R-gene) architecture, 17 Receptor like kinase (RLKs) candidates related to PAMP-Triggered Immunity (PTI), eight (TIR-NBS-LRR, or TNL) and nine (CC-NBS-LRR, or CNL) candidates related to Effector-Triggered Immunity (ETI) genes among others. These candidate genes were categorized by molecular function (98%), biological process (85%) and cellular component (79%) using gene ontology. Some of the most interesting predicted roles were those associated with binding and transferase activity. We designed 94 primers pairs from the 74 immunity-related genes (IRGs) to amplify the corresponding genomic regions on six genotypes that included resistant and susceptible materials. From these, we selected 17 single band amplicons and sequenced them in 14 F. oxysporum resistant and susceptible genotypes. Sequence polymorphisms were analyzed through preliminary candidate gene association, which allowed the detection of one SNP at the PpIRG-63 marker revealing a nonsynonymous mutation in the predicted LRR domain suggesting functional roles for resistance. C1 [Enciso-Rodriguez, Felix E.; Stella Barrero, Luz; Marino-Ramirez, Leonardo] Colombian Corp Agr Res CORPOICA, CBB, Plant Mol Genet Lab, Bogota, Colombia. [Gonzalez, Carolina; Rodriguez, Edwin A.] Colombian Corp Agr Res CORPOICA, CBB, Mol Microbiol Lab, Bogota, Colombia. [Lopez, Camilo E.] Univ Nacl Colombia, Lab Fitopatol Mol, Dept Biol, Bogota, Colombia. [Landsman, David; Marino-Ramirez, Leonardo] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Stella Barrero, Luz; Marino-Ramirez, Leonardo] PanAmer Bioinformat Inst, Santa Marta, Magdalena, Colombia. RP Marino-Ramirez, L (reprint author), Colombian Corp Agr Res CORPOICA, CBB, Plant Mol Genet Lab, Bogota, Colombia. EM marino@ncbi.nlm.nih.gov RI Marino-Ramirez, Leonardo/I-5759-2013; OI Marino-Ramirez, Leonardo/0000-0002-5716-8512; Landsman, David/0000-0002-9819-6675 FU Colombian Ministry of Agriculture [054/08072-2008L4787-3281, 054/08190-2008L7922-3322]; Intramural Research Program of the National Institutes of Health; National Library of Medicine; National Center for Biotechnology Information FX Support for this research was provided by a grant from the Colombian Ministry of Agriculture Contract Nos. 054/08072-2008L4787-3281 to Luz Stella Barrero and 054/08190-2008L7922-3322 to Victor Manuel Nunez Zarantes. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine, and National Center for Biotechnology Information. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 7 Z9 7 U1 2 U2 20 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 3 PY 2013 VL 8 IS 7 AR e68500 DI 10.1371/journal.pone.0068500 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182HT UT WOS:000321733000011 PM 23844210 ER PT J AU Wang, MY Verdier, J Benedito, VA Tang, YH Murray, JD Ge, YB Becker, JD Carvalho, H Rogers, C Udvardi, M He, J AF Wang, Mingyi Verdier, Jerome Benedito, Vagner A. Tang, Yuhong Murray, Jeremy D. Ge, Yinbing Becker, Joerg D. Carvalho, Helena Rogers, Christian Udvardi, Michael He, Ji TI LegumeGRN: A Gene Regulatory Network Prediction Server for Functional and Comparative Studies SO PLOS ONE LA English DT Article ID EXPRESSION ATLAS; ARABIDOPSIS-THALIANA; MEDICAGO-TRUNCATULA; GENOME ARRAYS; INFERENCE; DATABASE; ASSOCIATION; INFORMATION; PATHWAY; MODULES AB Building accurate gene regulatory networks (GRNs) from high-throughput gene expression data is a long-standing challenge. However, with the emergence of new algorithms combined with the increase of transcriptomic data availability, it is now reachable. To help biologists to investigate gene regulatory relationships, we developed a web-based computational service to build, analyze and visualize GRNs that govern various biological processes. The web server is preloaded with all available Affymetrix GeneChip-based transcriptomic and annotation data from the three model legume species, i.e., Medicago truncatula, Lotus japonicus and Glycine max. Users can also upload their own transcriptomic and transcription factor datasets from any other species/organisms to analyze their in-house experiments. Users are able to select which experiments, genes and algorithms they will consider to perform their GRN analysis. To achieve this flexibility and improve prediction performance, we have implemented multiple mainstream GRN prediction algorithms including co-expression, Graphical Gaussian Models (GGMs), Context Likelihood of Relatedness (CLR), and parallelized versions of TIGRESS and GENIE3. Besides these existing algorithms, we also proposed a parallel Bayesian network learning algorithm, which can infer causal relationships (i.e., directionality of interaction) and scale up to several thousands of genes. Moreover, this web server also provides tools to allow integrative and comparative analysis between predicted GRNs obtained from different algorithms or experiments, as well as comparisons between legume species. The web site is available at http://legumegrn.noble.org. C1 [Wang, Mingyi; Verdier, Jerome; Tang, Yuhong; Ge, Yinbing; Udvardi, Michael; He, Ji] Samuel Roberts Noble Fdn Inc, Div Plant Biol, Ardmore, OK 73402 USA. [Benedito, Vagner A.] W Virginia Univ, Div Plant & Soil Sci, Morgantown, WV 26506 USA. [Murray, Jeremy D.; Rogers, Christian] John Innes Ctr Plant Sci Res, Dept Cell & Dev Biol, Norwich NR4 7UH, Norfolk, England. [Becker, Joerg D.] Inst Gulbenkian Ciencias, Plant Genom Lab, Oeiras, Portugal. [Carvalho, Helena] Univ Porto, Inst Mol & Cell Biol, P-4100 Oporto, Portugal. [He, Ji] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, SAIC Frederick Inc, Bethesda, MD 20892 USA. RP Wang, MY (reprint author), Samuel Roberts Noble Fdn Inc, Div Plant Biol, POB 2180, Ardmore, OK 73402 USA. EM mwang@noble.org RI Becker, Jorg/A-5930-2011; Carvalho, Helena/E-9357-2012; Murray, Jeremy/F-8409-2011 OI Becker, Jorg/0000-0002-6845-6122; Carvalho, Helena/0000-0003-0651-7601; Murray, Jeremy/0000-0003-3000-9199 FU Oklahoma Center for The Advancement of Science and Technology (OCAST) [PSB11-031] FX This research was supported by grants from the Oklahoma Center for The Advancement of Science and Technology (OCAST Grant No. PSB11-031). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 3 Z9 6 U1 1 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 3 PY 2013 VL 8 IS 7 AR e67434 DI 10.1371/journal.pone.0067434 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182HT UT WOS:000321733000072 PM 23844010 ER PT J AU Collins, FS Li, R Tjian, R Weinberg, R Pollard, TD Johnson, EB AF Collins, Francis S. Li, Rong Tjian, Robert Weinberg, Robert Pollard, Thomas D. Johnson, Eddie Bernice TI Sequester Impact on Biomedical Research SO CELL LA English DT Editorial Material C1 [Collins, Francis S.] NIH, Bethesda, MD 20892 USA. [Tjian, Robert] Univ Calif Berkeley, Berkeley, CA USA. [Weinberg, Robert] MIT, Whitehead Inst, Cambridge, MA 02139 USA. [Pollard, Thomas D.] Yale Univ, New Haven, CT 06520 USA. RP Collins, FS (reprint author), NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 3 PY 2013 VL 154 IS 1 BP 14 EP 15 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 176TM UT WOS:000321327900003 ER PT J AU Freudenthal, BD Beard, WA Shock, DD Wilson, SH AF Freudenthal, Bret D. Beard, William A. Shock, David D. Wilson, Samuel H. TI Observing a DNA Polymerase Choose Right from Wrong SO CELL LA English DT Article ID INDUCED-FIT MECHANISM; BETA; MISINCORPORATION; INTERMEDIATE; FIDELITY AB DNA polymerase (pol) beta is a model polymerase involved in gap-filling DNA synthesis utilizing two metals to facilitate nucleotidyl transfer. Previous structural studies have trapped catalytic intermediates by utilizing substrate analogs (dideoxy-terminated primer or nonhydrolysable incoming nucleotide). To identify additional intermediates during catalysis, we now employ natural substrates (correct and incorrect nucleotides) and follow product formation in real time with 15 different crystal structures. We are able to observe molecular adjustments at the active site that hasten correct nucleotide insertion and deter incorrect insertion not appreciated previously. A third metal binding site is transiently formed during correct, but not incorrect, nucleotide insertion. Additionally, long incubations indicate that pyrophosphate more easily dissociates after incorrect, compared to correct, nucleotide insertion. This appears to be coupled to subdomain repositioning that is required for catalytic activation/deactivation. The structures provide insights into a fundamental chemical reaction that impacts polymerase fidelity and genome stability. C1 [Freudenthal, Bret D.; Beard, William A.; Shock, David D.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; Intramural Research Program of the NIH; National Institute of Environmental Health Sciences [ZO1-ES050158, Z01-ES050161]; National Institutes of Health [1U19CA105010] FX We thank Lars Pedersen, Juno Krahn, and the Collaborative Crystallography group at the NIEHS for help with data collection and analysis. Use of the advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract W-31-109-Eng-38. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (project numbers ZO1-ES050158 and Z01-ES050161) and in association with the National Institutes of Health grant 1U19CA105010. NR 23 TC 57 Z9 57 U1 1 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 3 PY 2013 VL 154 IS 1 BP 157 EP 168 DI 10.1016/j.cell.2013.05.048 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 176TM UT WOS:000321327900017 PM 23827680 ER PT J AU Brandes, M Klauschen, F Kuchen, S Germain, RN AF Brandes, Marlene Klauschen, Frederick Kuchen, Stefan Germain, Ronald N. TI A Systems Analysis Identifies a Feedforward Inflammatory Circuit Leading to Lethal Influenza Infection SO CELL LA English DT Article ID 1918 PANDEMIC VIRUS; KAPPA-B-ALPHA; A VIRUS; IMMUNE-RESPONSE; DENDRITIC CELLS; PROTECTS MICE; HOST IMMUNE; NEUTROPHILS; RECEPTOR; A20 AB For acutely lethal influenza infections, the relative pathogenic contributions of direct viral damage to lung epithelium versus dysregulated immunity remain unresolved. Here, we take a top-down systems approach to this question. Multigene transcriptional signatures from infected lungs suggested that elevated activation of inflammatory signaling networks distinguished lethal from sublethal infections. Flow cytometry and gene expression analysis involving isolated cell subpopulations from infected lungs showed that neutrophil influx largely accounted for the predictive transcriptional signature. Automated imaging analysis, together with these gene expression and flow data, identified a chemokine-driven feedforward circuit involving proinflammatory neutrophils potently driven by poorly contained lethal viruses. Consistent with these data, attenuation, but not ablation, of the neutrophil-driven response increased survival without changing viral spread. These findings establish the primacy of damaging innate inflammation in at least some forms of influenza-induced lethality and provide a roadmap for the systematic dissection of infection-associated pathology. C1 [Brandes, Marlene; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Kuchen, Stefan] NIAMSD, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. [Klauschen, Frederick] Univ Med Berlin, Inst Pathol, D-10117 Berlin, Germany. RP Brandes, M (reprint author), NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM marlene.brandes@insel.ch; rgermain@nih.gov RI Klauschen, Frederick/C-5637-2015; OI Kuchen, Stefan/0000-0003-4899-8132 FU Intramural Research Program of NIAID, NIH; Swiss Science Foundation [PA00A-1114666]; Human Frontier Science Program Young Investigator Award [RGY0077/2011] FX We thank J.R. Bennink and S.E. Hensley for virus seeds and initial advice; T.A. Torrey, C.L. Thomas, and the animal facility team for support and animal health observations; K.L. Holmes and C.L. Eigsti for FACS Aria operation; T.G. Myers, G. Owens, and A. Godinez for microarray hybridization and QC analysis; R. Kastenmayer, M.S. Orandle, O.M. Schwartz, and L. Koo for slide scanner access and advice; Y. Belkaid for bones from germ-free mice; and B. Dutta, J.R. Bennink, W. Resch, and I. Fraser for critical reading of the manuscript and valuable comments. This work was supported by the Intramural Research Program of NIAID, NIH, a fellowship from the Swiss Science Foundation PA00A-1114666 (M.B.), and a Human Frontier Science Program Young Investigator Award RGY0077/2011 (F.K.). NR 54 TC 92 Z9 92 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 3 PY 2013 VL 154 IS 1 BP 197 EP 212 DI 10.1016/j.cell.2013.06.013 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 176TM UT WOS:000321327900020 PM 23827683 ER PT J AU Siddoway, BA Altimimi, HF Hou, HL Petralia, RS Xu, B Stellwagen, D Xia, HH AF Siddoway, Benjamin A. Altimimi, Haider F. Hou, Hailong Petralia, Ronald S. Xu, Bo Stellwagen, David Xia, Houhui TI An Essential Role for Inhibitor-2 Regulation of Protein Phosphatase-1 in Synaptic Scaling SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM DEPRESSION; CENTRAL-NERVOUS-SYSTEM; HIPPOCAMPAL-NEURONS; GENE-EXPRESSION; PHOSPHORYLATION; PLASTICITY; KINASE; AMPA; WORTMANNIN; MECHANISMS AB Protein phosphatase-1 (PP1) activity is important form any calcium-dependent neuronal functions including Hebbian synaptic plasticity and learning and memory. PP1 activity is necessary for the induction of long-term depression, whereas downregulation of PP1 activity is required for the normal induction of long-term potentiation. However, how PP1 is activated is not clear. Moreover, it is not known whether PP1 plays a role in homeostatic synaptic scaling, another form of synaptic plasticity which functions to reset the neuronal firing rate in response to chronic neuronal activity perturbations. In this study, we found that PP1 inhibitor-2 (I-2) is phosphorylated at serine 43 (S43) in rat and mouse cortical neurons in response to bicuculine application. Expression of I-2 phosphorylation-blocking mutant I-2 (S43A) blocked the dephosphorylation of GluA2 at serine 880, AMPA receptor trafficking, and synaptic downscaling induced by bicuculline application. Our data suggest that the phosphorylation of I-2 at S43 appears to be mediated by L-type calcium channels and calcium/calmodulin-dependent myosin light-chain kinase. Our work thus reveals a novel calcium-induced PP1 activation pathway critical for homeostatic synaptic plasticity. C1 [Siddoway, Benjamin A.; Hou, Hailong; Xia, Houhui] Louisiana State Univ, Hlth Sci Ctr, Ctr Neurosci, New Orleans, LA 70112 USA. [Altimimi, Haider F.; Stellwagen, David] McGill Univ, Ctr Res Neurosci, Montreal, PQ H3A 2B4, Canada. [Altimimi, Haider F.; Stellwagen, David] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. [Petralia, Ronald S.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. [Xu, Bo] So Res Inst, Mol Radiat Biol Lab, Birmingham, AL 35205 USA. RP Xia, HH (reprint author), Louisiana State Univ, Hlth Sci Ctr, Ctr Neurosci, 2020 Gravier St,Suite D, New Orleans, LA 70112 USA. EM hxia@lsuhsc.edu RI Altimimi, Haider/K-8658-2012 OI Altimimi, Haider/0000-0002-4516-141X FU NIH [R01NS060879, R01ES016354]; NSF [IOS-0824393]; NARSAD [2006YI]; LSU REF (Research Enhancement Fund); CIHR (Canadian Institute of Health Research); NSERC (Natural Science and Engineering Research Council); NIDCD Intramural Research Program; HSFC (Heart and Stroke Foundation Canada) FX This work is supported by NIH R01NS060879, NSF IOS-0824393, NARSAD (2006YI), and LSU REF (Research Enhancement Fund) to H. X., CIHR (Canadian Institute of Health Research) and NSERC (Natural Science and Engineering Research Council) to D. S., NIH (R01ES016354) to B. X., the NIDCD Intramural Research Program to R. S. P., and HSFC (Heart and Stroke Foundation Canada) for H. F. A. We thank Dr. Ya-Xian Wang for help with the immunogold study. We thank Dr. Shyamal Desai for providing founder ATM (+/-) mice used in this study. The authors declare no competing financial interests. NR 37 TC 9 Z9 9 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 3 PY 2013 VL 33 IS 27 BP 11206 EP 11211 DI 10.1523/JNEUROSCI.5241-12.2013 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 175UC UT WOS:000321258000025 PM 23825423 ER PT J AU Yamamoto, S Kim, HF Hikosaka, O AF Yamamoto, Shinya Kim, Hyoung F. Hikosaka, Okihide TI Reward Value-Contingent Changes of Visual Responses in the Primate Caudate Tail Associated with a Visuomotor Skill SO JOURNAL OF NEUROSCIENCE LA English DT Article ID INFERIOR TEMPORAL CORTEX; INVARIANT OBJECT REPRESENTATION; LONG-TERM RETENTION; INFEROTEMPORAL CORTEX; MACAQUE MONKEYS; HABIT FORMATION; RHESUS-MONKEY; BASAL GANGLIA; EYE-MOVEMENTS; MOTOR-SKILLS AB A goal-directed action aiming at an incentive outcome, if repeated, becomes a skill that may be initiated automatically. We now report that the tail of the caudate nucleus (CDt) may serve to control a visuomotor skill. Monkeys looked at many fractal objects, half of which were always associated with a large reward (high-valued objects) and the other half with a small reward (low-valued objects). After several daily sessions, they developed a gaze bias, looking at high-valued objects even when no reward was associated. CDt neurons developed a response bias, typically showing stronger responses to high-valued objects. In contrast, their responses showed no change when object values were reversed frequently, although monkeys showed a strong gaze bias, looking at high-valued objects in a goal-directed manner. The biased activity of CDt neurons may be transmitted to the oculomotor region so that animals can choose high-valued objects automatically based on stable reward experiences. C1 [Yamamoto, Shinya; Kim, Hyoung F.; Hikosaka, Okihide] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Yamamoto, Shinya] Natl Inst Adv Ind Sci & Technol, Human Technol Res Inst, Tsukuba, Ibaraki 3058568, Japan. RP Yamamoto, S (reprint author), Natl Inst Adv Ind Sci & Technol, Human Technol Res Inst, 1-1-1 Umezono, Tsukuba, Ibaraki 3058568, Japan. EM yamamoto-s@aist.go.jp RI Yamamoto, Shinya/S-3134-2016 OI Yamamoto, Shinya/0000-0002-0505-8848 FU Intramural Research Program at the National Eye Institute FX This work was supported by the Intramural Research Program at the National Eye Institute. We thank M. Yasuda, I. E. Monosov, E. S. Bromberg-Martin, S. Hong, and Y. Tachibana for valuable discussions and A. Hays, J. W. McClurkin, B. Nagy, A. M. Nichols, D. Parker, T. W. Ruffner, M. K. Smith, G. Tansey, N. Phipps, C. Zhu, F. Ye, and D. Leopold for technical assistance. NR 52 TC 30 Z9 30 U1 6 U2 14 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 3 PY 2013 VL 33 IS 27 BP 11227 EP 11238 DI 10.1523/JNEUROSCI.0318-13.2013 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 175UC UT WOS:000321258000028 PM 23825426 ER PT J AU McDermott, MM Liu, K Guralnik, JM Criqui, MH Spring, B Tian, L Domanchuk, K Ferrucci, L Lloyd-Jones, D Kibbe, M Tao, HM Zhao, LH Liao, YH Rejeski, WJ AF McDermott, Mary M. Liu, Kiang Guralnik, Jack M. Criqui, Michael H. Spring, Bonnie Tian, Lu Domanchuk, Kathryn Ferrucci, Luigi Lloyd-Jones, Donald Kibbe, Melina Tao, Huimin Zhao, Lihui Liao, Yihua Rejeski, W. Jack TI Home-Based Walking Exercise Intervention in Peripheral Artery Disease A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID FUNCTIONAL PERFORMANCE PREDICTS; LOWER-EXTREMITY FUNCTION; ANKLE BRACHIAL INDEX; INTERMITTENT CLAUDICATION; PHYSICAL-ACTIVITY; PRACTICE GUIDELINES; TREADMILL WALKING; MOBILITY LOSS; LEG SYMPTOMS; TASK-FORCE AB IMPORTANCE Clinical practice guidelines state there is insufficient evidence to support advising patients with peripheral artery disease (PAD) to participate in a home-based walking exercise program. OBJECTIVE To determine whether a home-based walking exercise program that uses a group-mediated cognitive behavioral intervention, incorporating both group support and self-regulatory skills, can improve functional performance compared with a health education control group in patients with PAD with and without intermittent claudication. DESIGN, SETTING, AND PATIENTS Randomized controlled clinical trial of 194 patients with PAD, including 72.2% without classic symptoms of intermittent claudication, performed in Chicago, Illinois between July 22, 2008, and December 14, 2012. INTERVENTIONS Participants were randomized to 1 of 2 parallel groups: a home-based group-mediated cognitive behavioral walking intervention or an attention control condition. MAIN OUTCOMES AND MEASURES The primary outcomewas 6-month change in 6-minute walk performance. Secondary outcomes included 6-month change in treadmill walking, physical activity, the Walking Impairment Questionnaire (WIQ), and Physical and Mental Health Composite Scores from the 12-item Short-Form Health Survey. RESULTS Participants randomized to the intervention group significantly increased their 6-minute walk distance ([reported in meters] 357.4 to 399.8 vs 353.3 to 342.2 for those in the control group; mean difference, 53.5 [95% CI, 33.2 to 73.8]; P<.001), maximal treadmill walking time (intervention, 7.91 to 9.44 minutes vs control, 7.56 to 8.09; mean difference, 1.01 minutes [95% CI, 0.07 to 1.95]; P=.04), accelerometer-measured physical activity over 7 days (intervention, 778.0 to 866.1 vs control, 671.6 to 645.0; mean difference, 114.7 activity units [95% CI, 12.82 to 216.5]; P=.03), WIQ distance score (intervention, 35.3 to 47.4 vs control, 33.3 to 34.4; mean difference, 11.1 [95% CI, 3.9 to 18.1]; P=.003), and WIQ speed score (intervention, 36.1 to 47.7 vs control, 35.3-36.6; mean difference, 10.4 [95% CI, 3.4 to 17.4]; P=.004). CONCLUSION AND RELEVANCE A home-based walking exercise program significantly improved walking endurance, physical activity, and patient-perceived walking endurance and speed in PAD participants with and without classic claudication symptoms. These findings have implications for the large number of patients with PAD who are unable or unwilling to participate in supervised exercise programs. C1 [McDermott, Mary M.; Liu, Kiang; Domanchuk, Kathryn] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [McDermott, Mary M.; Liu, Kiang; Spring, Bonnie; Lloyd-Jones, Donald; Tao, Huimin; Zhao, Lihui; Liao, Yihua] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Guralnik, Jack M.] Univ Maryland, Dept Epidemiol, Baltimore, MD 21201 USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Tian, Lu] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Ferrucci, Luigi] NIA, Div Intramural Res, Baltimore, MD 21224 USA. [Kibbe, Melina] Northwestern Univ, Dept Surg, Chicago, IL 60611 USA. [Rejeski, W. Jack] Wake Forest Univ, Dept Hlth & Exercise Sci, Winston Salem, NC 27109 USA. [Rejeski, W. Jack] Wake Forest Univ, Dept Geriatr Med, Winston Salem, NC 27109 USA. RP McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med, 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU National Heart, Lung, and Blood Institute [R01-HL088589, R01-HL107510]; Intramural Research Program, National Institutes on Aging (NIA), National Institutes of Health FX Supported by R01-HL088589 and R01-HL107510 from the National Heart, Lung, and Blood Institute. Supported in part by the Intramural Research Program, National Institutes on Aging (NIA), National Institutes of Health. No other funding was used to carry out the study or complete the manuscript. NR 45 TC 68 Z9 69 U1 5 U2 39 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 3 PY 2013 VL 310 IS 1 BP 57 EP 65 DI 10.1001/jama.2013.7231 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 175SK UT WOS:000321253000023 PM 23821089 ER PT J AU Luo, JH Rossouw, J Margolis, KL AF Luo, Juhua Rossouw, Jacques Margolis, Karen L. TI Smoking Cessation, Weight Change, and Coronary Heart Disease Among Postmenopausal Women With and Without Diabetes SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID CARDIOVASCULAR-DISEASE C1 [Luo, Juhua] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN 47405 USA. [Rossouw, Jacques] NHLBI, Bethesda, MD 20892 USA. [Margolis, Karen L.] HealthPartners Inst Educ & Res, Minneapolis, MN USA. RP Luo, JH (reprint author), Indiana Univ, Sch Publ Hlth, 1025 E 7th St, Bloomington, IN 47405 USA. EM juhluo@indiana.edu FU NIDDK NIH HHS [R21 DK074646]; WHI NIH HHS [N01WH32109, N01WH42119, N01WH32122, N01WH42121, N01WH32115, N01WH42131, N01WH42129, N01WH32113, N01WH42110, N01WH32100, N01WH42123, N01WH32105, N01WH32108, N01WH24152, N01WH32112, N01WH42116, N01WH42120, N01WH42111, N01WH42122, N01 WH032109, N01WH42117, N01WH42132, N01WH32118, N01WH42108, N01WH22110, N01WH42130, N01WH42112, N01WH42113, N01WH42114, N01WH42125, N01WH32106, N01WH42126, N01WH42109, N01WH42115, N01WH32101, N01WH42107, N01WH32111, N01WH32119, N01WH42118, N01WH32102, N01WH42124, N01WH44221] NR 6 TC 7 Z9 8 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 3 PY 2013 VL 310 IS 1 BP 94 EP 96 DI 10.1001/jama.2013.6871 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 175SK UT WOS:000321253000028 PM 23821094 ER PT J AU Liu, J Finkel, T AF Liu, Jie Finkel, Toren TI Stem Cells and Oxidants: Too Little of a Bad Thing SO CELL METABOLISM LA English DT Editorial Material ID REACTIVE-OXYGEN; SELF-RENEWAL; DIFFERENTIATION; GENERATION AB Oxidants are thought to damage cells, and stem cells are viewed as particularly vulnerable to oxidative stress. Now, a new study (Morimoto et al., 2013) suggests that the self-renewal of certain stem cells may actually require reactive oxygen species (ROS). C1 [Liu, Jie; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU Intramural NIH HHS [ZIA HL005012-13] NR 9 TC 4 Z9 5 U1 0 U2 6 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 2 PY 2013 VL 18 IS 1 BP 1 EP 2 DI 10.1016/j.cmet.2013.06.007 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242UE UT WOS:000326267100001 PM 23823470 ER PT J AU Rhee, EP Ho, JE Chen, MH Shen, DX Cheng, S Larson, MG Ghorbani, A Shi, X Helenius, IT O'Donnell, CJ Souza, AL Deik, A Pierce, KA Bullock, K Walford, GA Vasan, RS Florez, JC Clish, C Yeh, JRJ Wang, TJ Gerszten, RE AF Rhee, Eugene P. Ho, Jennifer E. Chen, Ming-Huei Shen, Dongxiao Cheng, Susan Larson, Martin G. Ghorbani, Anahita Shi, Xu Helenius, Iiro T. O'Donnell, Christopher J. Souza, Amanda L. Deik, Amy Pierce, Kerry A. Bullock, Kevin Walford, Geoffrey A. Vasan, Ramachandran S. Florez, Jose C. Clish, Clary Yeh, J. -R. Joanna Wang, Thomas J. Gerszten, Robert E. TI A Genome-wide Association Study of the Human Metabolome in a Community-Based Cohort SO CELL METABOLISM LA English DT Article ID LECITHIN-CHOLESTEROL ACYLTRANSFERASE; CORONARY-ARTERY-DISEASE; CHRONIC KIDNEY-DISEASE; C-REACTIVE PROTEIN; SUSCEPTIBILITY LOCI; GENETIC-VARIATION; CARDIOVASCULAR-DISEASE; BILIRUBIN LEVELS; RISK; GLUCOSE AB Because metabolites are hypothesized to play key roles as markers and effectors of cardiometabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We report a genome-wide association study (GWAS) of 217 plasma metabolites, including >100 not measured in prior GWAS, in 2076 participants of the Framingham Heart Study (FHS). For the majority of analytes, we find that estimated heritability explains >20% of interindividual variation, and that variation attributable to heritable factors is greater than that attributable to clinical factors. Further, we identify 31 genetic loci associated with plasma metabolites, including 23 that have not previously been reported. Importantly, we include GWAS results for all surveyed metabolites and demonstrate how this information highlights a role for AGXT2 in cholesterol ester and triacylglycerol metabolism. Thus, our study outlines the relative contributions of inherited and clinical factors on the plasma metabolome and provides a resource for metabolism research. C1 [Rhee, Eugene P.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Shen, Dongxiao; Shi, Xu; Helenius, Iiro T.; Yeh, J. -R. Joanna; Gerszten, Robert E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ghorbani, Anahita; O'Donnell, Christopher J.; Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Walford, Geoffrey A.; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Walford, Geoffrey A.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Rhee, Eugene P.; Souza, Amanda L.; Deik, Amy; Pierce, Kerry A.; Bullock, Kevin; Clish, Clary; Gerszten, Robert E.] Broad Inst, Metabolite Profiling Platform, Cambridge, MA 02142 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Ho, Jennifer E.] Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02118 USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Ho, Jennifer E.; Chen, Ming-Huei; Cheng, Susan; Larson, Martin G.; O'Donnell, Christopher J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Ho, Jennifer E.; Chen, Ming-Huei; Cheng, Susan; Larson, Martin G.; O'Donnell, Christopher J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Framingham, MA 01702 USA. [Chen, Ming-Huei] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Cheng, Susan] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Wang, Thomas J.] Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN 37232 USA. [Wang, Thomas J.] Vanderbilt Univ, Med Ctr, Vanderbilt Heart & Vasc Inst, Nashville, TN 37232 USA. RP Wang, TJ (reprint author), Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN 37232 USA. EM thomas.j.wang@vanderbilt.edu; rgerszten@partners.org OI Larson, Martin/0000-0002-9631-1254; Helenius, Iiro Taneli/0000-0002-0887-7830; Ho, Jennifer/0000-0002-7987-4768; Ramachandran, Vasan/0000-0001-7357-5970 FU NIH [N01-HC-25195, R01-DK-HL-081572, R01-HL-098280, R-01-HL-093328, U01-HL-107440, K23-HL-116780, K08-DK-090142]; Leducq Foundation; American Heart Association [12IRG9130006, 0940109N]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center FX This work was supported by NIH contracts N01-HC-25195, R01-DK-HL-081572 (R. E. G. and T.J.W.), R01-HL-098280 (R. E. G.), R-01-HL-093328 (R. S. V.), U01-HL-107440 (R. E. G.), K23-HL-116780 (J.E.H.), K08-DK-090142 (E. P. R.), the Leducq Foundation (to R. E. G.), and the American Heart Association 12IRG9130006 (J.-R.J.Y. and I. T. H.) and 0940109N (R. E. G.). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. NR 73 TC 53 Z9 56 U1 0 U2 16 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 2 PY 2013 VL 18 IS 1 BP 130 EP 143 DI 10.1016/j.cmet.2013.06.013 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242UE UT WOS:000326267100016 PM 23823483 ER PT J AU Tomasi, D Volkow, ND AF Tomasi, Dardo Volkow, Nora D. TI Brain activation and neurochemistry SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID DOPAMINE; RECEPTORS; FMRI C1 [Tomasi, Dardo; Volkow, Nora D.] NIAAA, NIH, Bethesda, MD USA. [Volkow, Nora D.] Natl Inst Drug Abuse, NIH, Bethesda, MD USA. RP Tomasi, D (reprint author), NIAAA, NIH, Bethesda, MD USA. EM dardo.tomasi@nih.gov RI Tomasi, Dardo/J-2127-2015 NR 10 TC 3 Z9 3 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 2 PY 2013 VL 110 IS 27 BP 10888 EP 10889 DI 10.1073/pnas.1309471110 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185OF UT WOS:000321978000020 PM 23784782 ER PT J AU Feng, SJ Li, HY Tai, YL Huang, JB Su, YJ Abramowitz, J Zhu, MX Birnbaumer, L Wang, YZ AF Feng, Shengjie Li, Hongyu Tai, Yilin Huang, Junbo Su, Yujuan Abramowitz, Joel Zhu, Michael X. Birnbaumer, Lutz Wang, Yizheng TI Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRP CHANNELS; ESSENTIAL COMPONENT; RELEASE CHANNEL; CATION CHANNEL; CA2+ UNIPORTER; PROTEIN TRPML1; MEMBRANE; OSCILLATIONS; PROPAGATION; MECHANISMS AB Mitochondrial Ca2+ homeostasis is fundamental to regulation of mitochondrial membrane potential, ATP production, and cellular Ca2+ homeostasis. It has been known for decades that isolated mitochondria can take up Ca2+ from the extramitochondrial solution, but the molecular identity of the Ca2+ channels involved in this action is largely unknown. Here, we show that a fraction of canonical transient receptor potential 3 (TRPC3) channels is localized to mitochondria, a significant fraction of mitochondrial Ca2+ uptake that relies on extramitochondrial Ca2+ concentration is TRPC3-dependent, and the up-and down-regulation of TRPC3 expression in the cell influences the mitochondrial membrane potential. Our findings suggest that TRPC3 channels contribute to mitochondrial Ca2+ uptake. We anticipate our observations may provide insights into the mechanisms of mitochondrial Ca2+ uptake and advance understanding of the physiological role of TRPC3. C1 [Feng, Shengjie; Li, Hongyu; Tai, Yilin; Huang, Junbo; Su, Yujuan; Wang, Yizheng] Shanghai Inst Biol Sci, Lab Neural Signal Transduct, Inst Neurosci, State Key Lab Neurosci, Shanghai 200031, Peoples R China. [Feng, Shengjie; Li, Hongyu; Huang, Junbo; Su, Yujuan] Univ Chinese Acad Sci, Shanghai 200031, Peoples R China. [Abramowitz, Joel; Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Zhu, Michael X.] Univ Texas Hlth Sci Ctr Houston, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA. RP Birnbaumer, L (reprint author), NIEHS, Neurobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbau1@niehs.nih.gov; yzwang@ion.ac.cn RI Abramowitz, Joel/A-2620-2015 FU National Neural Science Foundation of China (NNSF) [81130081]; 973 program [2011CBA00400]; National Institutes of Health (NIH) [Z01-ES-101684, R01 GM081658] FX We thank C. Montell and W. P. Schilling for TRPC3 antibodies, A. Miyawaki for Pericam, V. Flockerzi for comments, and Q. Hu and Z. J. Fan for technical assistance. This work was supported in part by a grant (81130081) from National Neural Science Foundation of China (NNSF), the 973 program (2011CBA00400), the Intramural Research Program of the National Institutes of Health (NIH; Z01-ES-101684; to L. B.), and NIH Grant R01 GM081658 (to M. X. Z.). NR 36 TC 23 Z9 24 U1 4 U2 19 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 2 PY 2013 VL 110 IS 27 BP 11011 EP 11016 DI 10.1073/pnas.1309531110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185OF UT WOS:000321978000041 PM 23776229 ER PT J AU Wang, Y Lu, XL Zhu, LN Shen, Y Chengedza, S Feng, H Wang, L Jung, JU Gutkind, JS Feng, PH AF Wang, Yi Lu, Xiaolu Zhu, Lining Shen, Yan Chengedza, Shylet Feng, Hao Wang, Laiyee Jung, Jae U. Gutkind, J. Silvio Feng, Pinghui TI IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE sarcomagenesis; inflammation associated ID NF-KAPPA-B; SARCOMA-ASSOCIATED HERPESVIRUS; KAPOSIS-SARCOMA; DNA-SEQUENCES; GENE-EXPRESSION; PATHWAY; CANCER; PHOSPHORYLATION; LYMPHOMA; IMMUNITY AB G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that transmit diverse extracellular signals across a membrane. Herpesvirus genomes encode multiple GPCRs implicated in viral pathogenesis. Kaposi sarcoma-associated herpesvirus GPCR (kGPCR) activates proliferative pathways and, when expressed in endothelium in mice, sufficiently induces angiogenic tumor resembling human Kaposi's sarcoma. IKK epsilon, an I kappa B kinase (IKK)-related kinase, is implicated in inflammation-driven tumorigenesis. We report here that IKK epsilon is critically required for kGPCR tumorigenesis and links kGPCR to NF-kappa B activation. Using kGPCR-induced tumor models, we found that IKK epsilon expression was drastically up-regulated in Kaposi sarcoma-like lesions and that loss of IKK epsilon abolished tumor formation. Moreover, kGPCR interacted with and activated IKK epsilon. Activated IKK epsilon promoted NF-kappa B subunit RelA (also known as p65) phosphorylation, which correlated with NF-kappa B activation and inflammatory cytokine expression. The robust expression of IKK epsilon and phosphorylated RelA was observed in human Kaposi sarcoma. Finally, a kinase-defective mutant of IKK epsilon effectively abrogated NF-kappa B activation and tumorigenesis induced by kGPCR. Collectively, our findings uncover a critical IKK epsilon in promoting NF-kappa B activation and tumorigenesis induced by a viral GPCR. C1 [Wang, Yi; Lu, Xiaolu; Zhu, Lining; Shen, Yan; Chengedza, Shylet; Wang, Laiyee; Jung, Jae U.; Feng, Pinghui] Univ So Calif, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. [Feng, Hao] Hunan Normal Univ, Coll Life Sci, Natl Educ Minist China, Key Lab Prot Chem & Dev Biol, Changsha 410081, Hunan, Peoples R China. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Feng, PH (reprint author), Univ So Calif, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. EM pinghui.feng@usc.edu FU National Cancer Institute [R01 CA134241]; National Institute of Health [DE021445, U19:A1083025]; American Cancer Society [RSG-11-162-01-MPC] FX We thank Ms. Yuqi Wang and Lisa Arneson for assistance with the maintenance of mouse colonies and John Shelton and Lillian Young for histology. This work was supported by National Cancer Institute Grant R01 CA134241, National Institute of Health DE021445, American Cancer Society Grant RSG-11-162-01-MPC (to P.F.), and National Institute of Health U19:A1083025 (to J.U.J.). NR 36 TC 14 Z9 14 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 2 PY 2013 VL 110 IS 27 BP 11139 EP 11144 DI 10.1073/pnas.1219829110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185OF UT WOS:000321978000064 PM 23771900 ER PT J AU Mizuno, N Dramicanin, M Mizuuchi, M Adam, J Wang, Y Han, YW Yang, W Steven, AC Mizuuchi, K Ramon-Maiques, S AF Mizuno, Naoko Dramicanin, Marija Mizuuchi, Michiyo Adam, Julia Wang, Yi Han, Yong-Woon Yang, Wei Steven, Alasdair C. Mizuuchi, Kiyoshi Ramon-Maiques, Santiago TI MuB is an AAA plus ATPase that forms helical filaments to control target selection for DNA transposition SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Phage Mu; nucleoprotein filament ID C-TERMINAL DOMAIN; BACTERIOPHAGE-MU; B-PROTEIN; ELECTRON-MICROSCOPY; STRAND-TRANSFER; PHAGE-MU; STRUCTURE PREDICTION; IMMUNITY; BINDING; COMPLEX AB MuB is an ATP-dependent nonspecific DNA-binding protein that regulates the activity of the MuA transposase and captures target DNA for transposition. Mechanistic understanding of MuB function has previously been hindered by MuB's poor solubility. Here we combine bioinformatic, mutagenic, biochemical, and electron microscopic analyses to unmask the structure and function of MuB. We demonstrate that MuB is an ATPase associated with diverse cellular activities (AAA+ ATPase) and forms ATP-dependent filaments with or without DNA. We also identify critical residues for MuB's ATPase, DNA binding, protein polymerization, and MuA interaction activities. Using single-particle electron microscopy, we show that MuB assembles into a helical filament, which binds the DNA in the axial channel. The helical parameters of the MuB filament do not match those of the coated DNA. Despite this protein-DNA symmetry mismatch, MuB does not deform the DNA duplex. These findings, together with the influence of MuB filament size on strand-transfer efficiency, lead to a model in which MuB-imposed symmetry transiently deforms the DNA at the boundary of the MuB filament and results in a bent DNA favored by MuA for transposition. C1 [Mizuno, Naoko; Steven, Alasdair C.] NIAMSD, Lab Struct Biol, Bethesda, MD 20892 USA. [Mizuuchi, Michiyo; Wang, Yi; Han, Yong-Woon; Yang, Wei; Mizuuchi, Kiyoshi; Ramon-Maiques, Santiago] NIDDK, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. [Mizuno, Naoko; Adam, Julia] Max Planck Inst Biochem, D-82152 Martinsried, Germany. [Dramicanin, Marija; Ramon-Maiques, Santiago] Spanish Natl Canc Res Ctr CNIO, Struct Biol & Biocomp Programme, Struct Bases Genome Integr Grp, Madrid 28029, Spain. [Wang, Yi] Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Han, Yong-Woon] Kyoto Univ, Inst Integrated Cell Mat Sci, Kyoto 6068501, Japan. RP Mizuuchi, K (reprint author), NIDDK, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. EM kiyoshimi@helix.nih.gov; sramon@cnio.es RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Arthritis, Musculoskeletal and Skin Diseases of the National Institutes of Health; Spanish Ministry of Science and Innovation [BFU2010-16812]; Graduiertenkolleg (GRK) of the Deutsche Forschungsgemeinschaft [1721]; "La Caixa" Foundation FX We thank Dr. P. A. Rice for the preliminary sequence-based structural similarity search, which alerted us that MuB belongs to the AAA+ ATPase family; and Dr. U. Baxa for help with the handedness determination. This work was supported by the intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the National Institutes of Health; the Spanish Ministry of Science and Innovation (BFU2010-16812); and Graduiertenkolleg (GRK) 1721 of the Deutsche Forschungsgemeinschaft. M.D. was a recipient of a predoctoral fellowship from the "La Caixa" Foundation. S.R.-M. is a Researcher of the Ramon y Cajal Program of the Spanish Ministry of Economy and Competitiveness. NR 49 TC 11 Z9 12 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 2 PY 2013 VL 110 IS 27 BP E2441 EP E2450 DI 10.1073/pnas.1309499110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185OF UT WOS:000321978000005 PM 23776210 ER PT J AU Schaetzlein, S Chahwan, R Avdievich, E Roa, S Wei, K Eoff, RL Sellers, RS Clark, AB Kunkel, TA Scharff, MD Edelmann, W AF Schaetzlein, Sonja Chahwan, Richard Avdievich, Elena Roa, Sergio Wei, Kaichun Eoff, Robert L. Sellers, Rani S. Clark, Alan B. Kunkel, Thomas A. Scharff, Matthew D. Edelmann, Winfried TI Mammalian Exo1 encodes both structural and catalytic functions that play distinct roles in essential biological processes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE somatic hypermuation; scaffold function; ssDNA ID DNA MISMATCH REPAIR; NONPOLYPOSIS COLORECTAL-CANCER; CLASS-SWITCH RECOMBINATION; HUMAN EXONUCLEASE 1; STRAND BREAK RESECTION; SACCHAROMYCES-CEREVISIAE; SOMATIC HYPERMUTATION; MICE; MUTATIONS; GENE AB Mammalian Exonuclease 1 (EXO1) is an evolutionarily conserved, multifunctional exonuclease involved in DNA damage repair, replication, immunoglobulin diversity, meiosis, and telomere maintenance. It has been assumed that EXO1 participates in these processes primarily through its exonuclease activity, but recent studies also suggest that EXO1 has a structural function in the assembly of higher-order protein complexes. To dissect the enzymatic and nonenzymatic roles of EXO1 in the different biological processes in vivo, we generated an EXO1-E109K knockin (Exo1(EK)) mouse expressing a stable exonuclease-deficient protein and, for comparison, a fully EXO1-deficient (Exo1(null)) mouse. In contrast to Exo1(null/null) mice, Exo1(EK/EK) mice retained mismatch repair activity and displayed normal class switch recombination and meiosis. However, both Exo1-mutant lines showed defects in DNA damage response including DNA double-strand break repair (DSBR) through DNA end resection, chromosomal stability, and tumor suppression, indicating that the enzymatic function is required for those processes. On a transformation-related protein 53 (Trp53)-null background, the DSBR defect caused by the E109K mutation altered the tumor spectrum but did not affect the overall survival as compared with p53-Exo1(null) mice, whose defects in both DSBR and mismatch repair also compromised survival. The separation of these functions demonstrates the differential requirement for the structural function and nuclease activity of mammalian EXO1 in distinct DNA repair processes and tumorigenesis in vivo. C1 [Schaetzlein, Sonja; Chahwan, Richard; Avdievich, Elena; Roa, Sergio; Scharff, Matthew D.; Edelmann, Winfried] Yeshiva Univ Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Sellers, Rani S.] Yeshiva Univ Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. [Roa, Sergio] Univ Navarra, Ctr Appl Med Res, Oncol Div, Pamplona 31008, Spain. [Wei, Kaichun] Univ Missouri, Dept Obstet & Gynecol, Kansas City, MO 64108 USA. [Eoff, Robert L.] Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA. [Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Lab Mol Genet, NIH, Res Triangle Pk, NC 27709 USA. [Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Lab Struct Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Scharff, MD (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Cell Biol, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM matthew.scharff@einstein.yu.edu; winfried.edelmann@einstein.yu.edu RI Roa, Sergio/H-9293-2015; OI Roa, Sergio/0000-0003-1095-0715; Chahwan, Richard/0000-0002-8672-7790 FU National Institutes of Health (NIH) [CA72649, CA102705, CA76329, CA93484]; Division of Intramural Research of the National Institute of Environmental Health Sciences, NIH [Z01 ES065089]; National Cancer Institute [P30CA013330]; National Women's Division of the Albert Einstein College of Medicine; Deutsche Forschungsgemeinschaft [SCHA 1557/1-1] FX This work was supported by the National Institutes of Health (NIH) Grants CA72649 and CA102705 (to M.D.S.) and CA76329 and CA93484 (to W.E.) and by Project Z01 ES065089 from the Division of Intramural Research of the National Institute of Environmental Health Sciences, NIH (to T.A.K.). R.S.S. is supported by P30CA013330 from the National Cancer Institute. M.D.S. is supported by the Harry Eagle Chair, provided by the National Women's Division of the Albert Einstein College of Medicine. S.S. was supported by Deutsche Forschungsgemeinschaft Grant SCHA 1557/1-1. NR 71 TC 26 Z9 26 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 2 PY 2013 VL 110 IS 27 BP E2470 EP E2479 DI 10.1073/pnas.1308512110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185OF UT WOS:000321978000008 PM 23754438 ER PT J AU Goldfine, AB Fonseca, V Jablonski, KA Chen, YDI Tipton, L Staten, MA Shoelson, SE AF Goldfine, Allison B. Fonseca, Vivian Jablonski, Kathleen A. Chen, Yii-Der Ida Tipton, Laura Staten, Myrlene A. Shoelson, Steven E. CA Targeting Inflammation Using Salsa TI Salicylate (Salsalate) in Patients With Type 2 Diabetes A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID NF-KAPPA-B; ACTIVATED PROTEIN-KINASE; HEAT-SHOCK RESPONSE; BLOOD-CELL COUNT; SODIUM-SALICYLATE; INSULIN-RESISTANCE; NONACETYLATED SALICYLATE; ALPHA PHOSPHORYLATION; ASPIRIN; INHIBITION AB Background: Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM). Objective: To assess 1-year efficacy and safety of salsalate in T2DM. Design: Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment. (ClinicalTrials.gov: NCT00799643) Setting: 3 private practices and 18 academic centers in the United States. Patients: Persons aged 18 to 75 years with fasting glucose levels of 12.5 mmol/L or less (<= 225 mg/dL) and hemoglobin A(1c) (HbA(1c)) levels of 7.0% to 9.5% who were treated for diabetes. Intervention: 286 participants were randomly assigned (between January 2009 and July 2011) to 48 weeks of placebo (n = 140) or salsalate, 3.5 g/d (n = 146), in addition to current therapies, and 283 participants were analyzed (placebo, n = 137; salsalate, n = 146). Measurements: Change in hemoglobin A(1c) level (primary outcome) and safety and efficacy measures. Results: The mean HbA(1c) level over 48 weeks was 0.37% lower in the salsalate group than in the placebo group (95% CI, -0.53% to -0.21%; P < 0.001). Glycemia improved despite more reductions in concomitant diabetes medications in salsalate recipients than in placebo recipients. Lower circulating leukocyte, neutrophil, and lymphocyte counts show the anti-inflammatory effects of salsalate. Adiponectin and hematocrit levels increased more and fasting glucose, uric acid, and triglyceride levels decreased with salsalate, but weight and low-density lipoprotein cholesterol levels also increased. Urinary albumin levels increased but reversed on discontinuation; estimated glomerular filtration rates were unchanged. Limitation: Trial duration and number of patients studied were insufficient to determine long-term risk-benefit of salsalate in T2DM. Conclusion: Salsalate improves glycemia in patients with T2DM and decreases inflammatory mediators. Continued evaluation of mixed cardiorenal signals is warranted. C1 [Shoelson, Steven E.] Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. Tulane Univ, New Orleans, LA 70118 USA. George Washington Univ, Rockville, MD USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Natl Inst Diabet & Digest & Kidney Dis, Washington, DC USA. RP Shoelson, SE (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM steven.shoelson@joslin.harvard.edu FU National Institutes of Health [U01 DK74556, P50 HL83813, P30 DK03836]; National Institutes of Health (General Clinical Research Center); National Institutes of Health (Clinical and Translational Science Award); Tullis-Tulane Chair; Helen and Morton Adler Chair FX Grant Support: By National Institutes of Health (U01 DK74556, P50 HL83813, P30 DK03836, and General Clinical Research Center and Clinical and Translational Science Award at several sites) and the Tullis-Tulane (Dr. Fonseca) and Helen and Morton Adler (Dr. Shoelson) Chairs. Caraco Pharmaceutical Laboratories (Detroit, Michigan) supplied the salsalate and placebo, LifeScan (Milpitas, California) supplied the home glucose-monitoring kits, and Mercodia (Uppsala, Sweden) supplied the insulin assay kits. NR 53 TC 80 Z9 84 U1 0 U2 9 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 2 PY 2013 VL 159 IS 1 BP 1 EP + DI 10.7326/0003-4819-159-1-201307020-00003 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 179JJ UT WOS:000321516200001 PM 23817699 ER PT J AU Zarin, DA Tse, T AF Zarin, Deborah A. Tse, Tony TI Trust but Verify: Trial Registration and Determining Fidelity to the Protocol SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID PEGINTERFERON-ALPHA-2A-ASSOCIATED DEPRESSION; ESCITALOPRAM; PREVENTION C1 [Zarin, Deborah A.; Tse, Tony] Natl Lib Med, Bethesda, MD USA. RP Zarin, DA (reprint author), NIH, US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM dzarin@mail.nih.gov NR 10 TC 12 Z9 12 U1 0 U2 5 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 2 PY 2013 VL 159 IS 1 BP 65 EP + DI 10.7326/0003-4819-159-1-201307020-00011 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 179JJ UT WOS:000321516200009 PM 23817705 ER PT J AU Prasad, V AF Prasad, Vinay TI Treatment of Moderate to Severe Hidradenitis Suppurativa SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Prasad, Vinay] NCI, Bethesda, MD 20892 USA. [Prasad, Vinay] NIH, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Bethesda, MD 20892 USA. NR 2 TC 2 Z9 2 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 2 PY 2013 VL 159 IS 1 BP 72 EP 72 DI 10.7326/0003-4819-159-1-201307020-00015 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 179JJ UT WOS:000321516200010 PM 23817709 ER PT J AU Burroughs, AM Hoppe, RW Goebel, NC Sayyed, BH Voegtline, TJ Schwabacher, AW Zabriskie, TM Silvaggi, NR AF Burroughs, A. Maxwell Hoppe, Robert W. Goebel, Neal C. Sayyed, Bilal H. Voegtline, Tyler J. Schwabacher, Alan W. Zabriskie, T. Mark Silvaggi, Nicholas R. TI Structural and Functional Characterization of MppR, an Enduracididine Biosynthetic Enzyme from Streptomyces hygroscopicus: Functional Diversity in the Acetoacetate Decarboxylase-like Superfamily SO BIOCHEMISTRY LA English DT Article ID GRAM-POSITIVE BACTERIA; GLYCOPEPTIDE ANTIBIOTICS; ACTIVE-SITE; VIOMYCIN BIOSYNTHESIS; NOSOCOMIAL INFECTIONS; IONIZATION CONSTANT; PROTEIN-STRUCTURE; REPORTER GROUP; X-RAY; MANNOPEPTIMYCINS AB The nonproteinogenic amino acid enduracididine is a critical component of the mannopeptimycins, cyclic glycopeptide antibiotics with activity against drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus. Enduracididine is produced in Streptomyces hygroscopicus by three enzymes, MppP, MppQ, and MppR. On the basis of primary sequence analysis, MppP and MppQ are pyridoxal 5'-phosphate-dependent aminotransferases; MppR shares a low, but significant, level of sequence identity with acetoacetate decarboxylase. The exact reactions catalyzed by each enzyme and the intermediates involved in the route to enduracididine are currently unknown. Herein, we present biochemical and structural characterization of MppR that demonstrates a catalytic activity for this enzyme and provides clues about its role in enduracididine biosynthesis. Bioinformatic analysis shows that MppR belongs to a previously uncharacterized family within the acetoacetate decarboxylase-like superfamily (ADCSF) and suggests that MppR-like enzymes may catalyze reactions diverging from the well-characterized, prototypical ADCSF decarboxylase activity. MppR shares a high degree of structural similarity with acetoacetate decarboxylase, though the respective quaternary structures differ markedly and structural differences in the active site explain the observed loss of decarboxylase activity. The crystal structure of MppR in the presence of a mixture of pyruvate and 4-imidazolecarboxaldehyde shows that MppR catalyzes the aldol condensation of these compounds and subsequent dehydration. Surprisingly, the structure of MppR in the presence of "4-hydroxy-2-ketoarginine" shows the correct 4R enantiomer of "2-ketoenduracididine" bound to the enzyme. These data, together with bioinformatic analysis of MppR homologues, identify a novel family within the acetoacetate decarboxylase-like superfamily with divergent active site structure and, consequently, biochemical function. C1 [Burroughs, A. Maxwell] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Hoppe, Robert W.; Sayyed, Bilal H.; Voegtline, Tyler J.; Schwabacher, Alan W.; Silvaggi, Nicholas R.] Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. [Goebel, Neal C.; Zabriskie, T. Mark] Oregon State Univ, Dept Pharmaceut Sci, Corvallis, OR 97331 USA. RP Silvaggi, NR (reprint author), Univ Wisconsin, Dept Chem & Biochem, 3210 North Cramer St, Milwaukee, WI 53211 USA. EM silvaggi@uwm.edu FU National Institute of Allergy and Infectious Diseases Grant [AI073784, 1R03AI090339-01A1]; National Science Foundation MRI Grant [0959442]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Michigan Economic Development Corp.; Michigan Technology Tri-Corridor [085P1000817] FX Work at Oregon State University was supported by National Institute of Allergy and Infectious Diseases Grant AI073784. This work is presently supported by National Science Foundation MRI Grant 0959442 and by National Institute of Allergy and Infectious Diseases Grant 1R03AI090339-01A1.; Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract DE-AC02-06CH11357. Use of LS-CAT Sector 21 was supported by the Michigan Economic Development Corp. and the Michigan Technology Tri-Corridor (Grant 085P1000817). NR 55 TC 7 Z9 7 U1 3 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 2 PY 2013 VL 52 IS 26 BP 4492 EP 4506 DI 10.1021/bi400397k PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 179LW UT WOS:000321522800006 PM 23758195 ER PT J AU Hull, SC Colloca, L Avins, A Gordon, NP Somkin, CP Kaptchuk, TJ Miller, FG AF Hull, Sara Chandros Colloca, Luana Avins, Andrew Gordon, Nancy P. Somkin, Carol P. Kaptchuk, Ted J. Miller, Franklin G. TI Patients' attitudes about the use of placebo treatments: telephone survey SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID CLINICAL-PRACTICE; QUESTIONNAIRE SURVEY; PHYSICIANS; ETHICS; INTERVENTIONS AB Objective To examine the attitudes of US patients about the use of placebo treatments in medical care. Design One time telephone surveys. Setting Northern California. Participants 853 members of Kaiser Permanente Northern California, aged 18-75, who had been seen by a primary care provider for a chronic health problem at least once in the prior six months. Results The response rate was 53.4% (853/1598) of all members who were eligible to participate, and 73.2% (853/1165) of all who could be reached by telephone. Most respondents (50-84%) judged it acceptable for doctors to recommend placebo treatments under conditions that varied according to doctors' level of certainty about the benefits and safety of the treatment, the purpose of the treatment, and the transparency with which the treatment was described to patients. Only 21.9% of respondents judged that it was never acceptable for doctors to recommend placebo treatments. Respondents valued honesty by physicians regarding the use of placebos and believed that non-transparent use could undermine the relationship between patients and physicians. Conclusions Most patients in this survey seemed favorable to the idea of placebo treatments and valued honesty and transparency in this context, suggesting that physicians should consider engaging with patients to discuss their values and attitudes about the appropriateness of using treatments aimed at promoting placebo responses in the context of clinical decision making. C1 [Hull, Sara Chandros] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Hull, Sara Chandros; Colloca, Luana; Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Colloca, Luana; Miller, Franklin G.] NIMH, NIH, Bethesda, MD 20892 USA. [Colloca, Luana] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Avins, Andrew; Gordon, Nancy P.; Somkin, Carol P.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Kaptchuk, Ted J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Program Placebo Studies, Boston, MA 02215 USA. RP Hull, SC (reprint author), NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. EM shull@mail.nih.gov OI Colloca, Luana/0000-0002-6503-4709 FU National Center for Complementary and Alternative Medicine; Clinical Center; National Human Genome Research Institute, National Institutes of Health FX This research was supported by the National Center for Complementary and Alternative Medicine, the Clinical Center, and the intramural research program of the National Human Genome Research Institute, National Institutes of Health. The opinions expressed are those of the authors and do not necessarily reflect the policies or views of the National Institutes of Health or the Department of Health and Human Services. The study funders played no role in the study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the article for publication. Researchers were independent of influence from study funders. NR 22 TC 14 Z9 14 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD JUL 2 PY 2013 VL 347 AR f3757 DI 10.1136/bmj.f3757 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 180CL UT WOS:000321570400002 PM 23819963 ER PT J AU Furth, KE Mastwal, S Wang, KH Buonanno, A Vullhorst, D AF Furth, Katrina E. Mastwal, Surjeet Wang, Kuan H. Buonanno, Andres Vullhorst, Detlef TI Dopamine, cognitive function, and gamma oscillations: role of D4 receptors SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Review DE dopamine; D4 receptor; gamma oscillations; parvalbumin; fast-spiking interneurons; prefrontal cortex; schizophrenia; ADHD ID DEFICIT HYPERACTIVITY DISORDER; RAT PREFRONTAL CORTEX; PARVALBUMIN-POSITIVE INTERNEURONS; FAST-SPIKING INTERNEURONS; CORTICAL PYRAMIDAL NEURONS; PROTEIN-COUPLED RECEPTORS; MEDIATED PHOSPHOLIPID METHYLATION; THALAMIC RETICULAR NUCLEUS; GLUTAMATE NMDA RECEPTORS; LONG-TERM POTENTIATION AB Cognitive deficits in individuals with schizophrenia (SCZ) are considered core symptoms of this disorder, and can manifest at the prodromal stage. Antipsychotics ameliorate positive symptoms but only modestly improve cognitive symptoms. The lack of treatments that improve cognitive abilities currently represents a major obstacle in developing more effective therapeutic strategies for this debilitating disorder. While D4 receptor (D4R)-specific antagonists are ineffective in the treatment of positive symptoms, animal studies suggest that D4R drugs can improve cognitive deficits. Moreover, recent work from our group suggests that D4Rs synergize with the neuregulin/ErbB4 signaling pathway, genetically identified as risk factors for SCZ, in parvalbumin (PV)-expressing interneurons to modulate gamma oscillations. These high-frequency network oscillations correlate with attention and increase during cognitive tasks in healthy subjects, and this correlation is attenuated in affected individuals. This finding, along with other observations indicating impaired GABAergic function, has led to the idea that abnormal neural activity in the prefrontal cortex (PFC) in individuals with SCZ reflects a perturbation in the balance of excitation and inhibition. Here we review the current state of knowledge of D4R functions in the PFC and hippocampus, two major brain areas implicated in SCZ. Special emphasis is given to studies focusing on the potential role of D4Rs in modulating GABAergic transmission and to an emerging concept of a close synergistic relationship between dopamine/D4R and neuregulin/ErbB4 signaling pathways that tunes the activity of PV interneurons to regulate gamma frequency network oscillations and potentially cognitive processes. C1 [Furth, Katrina E.; Buonanno, Andres; Vullhorst, Detlef] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Furth, Katrina E.] Boston Univ, Grad Program Neurosci, Boston, MA 02215 USA. [Mastwal, Surjeet; Wang, Kuan H.] NIMH, Unit Neural Circuits & Adapt Behav, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. RP Vullhorst, D (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Neurobiol Sect, NIH, Bldg 35,Room 2C-1002,35 Lincoln Dr, Bethesda, MD 20892 USA. EM vullhord@mail.nih.gov RI Wang, Kuan Hong/J-1150-2016 OI Wang, Kuan Hong/0000-0002-2249-5417 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health FX The authors thank Drs. Judith Walters, Nancy Kopell, Jorg Neddens, and Eric Denovellis for their insightful comments and suggestions. This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health. NR 243 TC 15 Z9 15 U1 1 U2 24 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD JUL 2 PY 2013 VL 7 AR 102 DI 10.3389/fncel.2013.00102 PG 19 WC Neurosciences SC Neurosciences & Neurology GA 176NJ UT WOS:000321311100001 PM 23847468 ER PT J AU Bivalacqua, TJ Musicki, B Hsu, LL Berkowitz, DE Champion, HC Burnett, AL AF Bivalacqua, Trinity J. Musicki, Biljana Hsu, Lewis L. Berkowitz, Dan E. Champion, Hunter C. Burnett, Arthur L. TI Sildenafil Citrate-Restored eNOS and PDE5 Regulation in Sickle Cell Mouse Penis Prevents Priapism Via Control of Oxidative/Nitrosative Stress SO PLOS ONE LA English DT Article ID NITRIC-OXIDE SYNTHASE; ENDOTHELIAL DYSFUNCTION; PULMONARY-HYPERTENSION; RECURRENT PRIAPISM; OXIDATIVE STRESS; ANIMAL-MODEL; MICE; ERECTION; REVERSES; THERAPY AB Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders. C1 [Bivalacqua, Trinity J.; Musicki, Biljana; Burnett, Arthur L.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Hsu, Lewis L.] NHLBI, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Hsu, Lewis L.] Univ Illinois, Dept Pediat, Chicago, IL USA. [Berkowitz, Dan E.] Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Berkowitz, Dan E.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Champion, Hunter C.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. RP Burnett, AL (reprint author), Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. EM aburnet1@jhmi.edu FU US Public Service Grants [HL090515, RO1DK067223] FX This work was supported by US Public Service Grants HL090515 and RO1DK067223 (to ALB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 17 Z9 17 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 2 PY 2013 VL 8 IS 7 AR e68028 DI 10.1371/journal.pone.0068028 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176XV UT WOS:000321341000131 PM 23844149 ER PT J AU Bode, C Yang, XP Kiu, H Klinman, DM AF Bode, Christian Yang, Xiang-Ping Kiu, Hiu Klinman, Dennis M. TI Suppressive Oligodeoxynucleotides Promote the Development of Th17 Cells SO PLOS ONE LA English DT Article ID T-HELPER-CELLS; CANDIDA-ALBICANS INFECTIONS; CYTOKINE GM-CSF; TGF-BETA; HOST-DEFENSE; T(H)17 CELLS; MICE; DIFFERENTIATION; INFLAMMATION; GENERATION AB Synthetic oligonucleotides containing repetitive TTAGGG motifs mimic the immunosuppressive activity of telomeric DNA. These suppressive oligonucleotides (Sup ODN) are effective in the treatment/prevention of various inflammatory and autoimmune diseases in mice. The therapeutic activity of Sup ODN was originally attributed to the inhibition of Th1 cell activation. Current results indicate that Sup ODN also promote the maturation of naive CD4(+) T cells into Th17 effectors. The generation of Th17 cells is linked to the prolonged activation of signal transducer and activator of transcription (STAT) 3 mediated by suppressor of cytokine signaling 3 (SOCS3) inhibition. In vivo studies show that treatment with Sup ODN promotes Th17 responsiveness under physiological conditions, increasing host resistance to Candida albicans infection. These findings support the development of Sup ODN to suppress pathological inflammatory conditions and improve host resistance to fungal pathogens. C1 [Bode, Christian; Kiu, Hiu; Klinman, Dennis M.] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA. [Yang, Xiang-Ping] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Klinman, DM (reprint author), NCI, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA. EM klinmand@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 5 Z9 5 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 2013 VL 8 IS 7 AR e67991 DI 10.1371/journal.pone.0067991 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176XV UT WOS:000321341000127 PM 23844143 ER PT J AU de Wit, E Prescott, J Baseler, L Bushmaker, T Thomas, T Lackemeyer, MG Martellaro, C Milne-Price, S Haddock, E Haagmans, BL Feldmann, H Munster, VJ AF de Wit, Emmie Prescott, Joseph Baseler, Laura Bushmaker, Trenton Thomas, Tina Lackemeyer, Matthew G. Martellaro, Cynthia Milne-Price, Shauna Haddock, Elaine Haagmans, Bart L. Feldmann, Heinz Munster, Vincent J. TI The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Does Not Replicate in Syrian Hamsters SO PLOS ONE LA English DT Article ID INFECTION AB In 2012 a novel coronavirus, MERS-CoV, associated with severe respiratory disease emerged in the Arabian Peninsula. To date, 55 human cases have been reported, including 31 fatal cases. Several of the cases were likely a result of human-to-human transmission. The emergence of this novel coronavirus prompts the need for a small animal model to study the pathogenesis of this virus and to test the efficacy of potential intervention strategies. In this study we explored the use of Syrian hamsters as a small animal disease model, using intratracheal inoculation and inoculation via aerosol. Clinical signs of disease, virus replication, histological lesions, cytokine upregulation nor seroconversion were observed in any of the inoculated animals, indicating that MERS-CoV does not replicate in Syrian hamsters. C1 [de Wit, Emmie; Prescott, Joseph; Baseler, Laura; Bushmaker, Trenton; Thomas, Tina; Martellaro, Cynthia; Milne-Price, Shauna; Haddock, Elaine; Feldmann, Heinz; Munster, Vincent J.] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Lackemeyer, Matthew G.] NIAID, Div Clin Res, Div Intramural Res, NIH, Frederick, MD USA. [Haagmans, Bart L.] Erasmus MC, Dept Virosci, Rotterdam, Netherlands. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP de Wit, E (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. EM emmie.dewit@nih.gov OI de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; European Union [223498] FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. BLH was financed by the European Union FP7 project EMPERIE (contract number 223498). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 16 TC 50 Z9 51 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 2 PY 2013 VL 8 IS 7 AR e69127 DI 10.1371/journal.pone.0069127 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176XV UT WOS:000321341000183 PM 23844250 ER PT J AU Horovitz, SG Gallea, C Najee-ullah, MA Hallett, M AF Horovitz, Silvina G. Gallea, Cecile Najee-ullah, Muslimah 'Ali Hallett, Mark TI Functional Anatomy of Writing with the Dominant Hand SO PLOS ONE LA English DT Article ID VENTRAL PREMOTOR AREAS; SUPPLEMENTARY MOTOR AREA; BASAL GANGLIA; PARIETAL CORTEX; CEREBRAL-CORTEX; MACAQUE MONKEY; RHESUS-MONKEY; WRITERS CRAMP; DORSAL; BRAIN AB While writing performed by any body part is similar in style, indicating a common program, writing with the dominant hand is particularly skilled. We hypothesized that this skill utilizes a special motor network supplementing the motor equivalence areas. Using functional magnetic resonance imaging in 13 normal subjects, we studied nine conditions: writing, zigzagging and tapping, each with the right hand, left hand and right foot. We identified brain regions activated with the right (dominant) hand writing task, exceeding the activation common to right-hand use and the writing program, both identified without right-hand writing itself. Right-hand writing significantly differed from the other tasks. First, we observed stronger activations in the left dorsal prefrontal cortex, left intraparietal sulcus and right cerebellum. Second, the left anterior putamen was required to initiate all the tested tasks, but only showed sustained activation during the right-hand writing condition. Lastly, an exploratory analysis showed clusters in the left ventral premotor cortex and inferior and superior parietal cortices were only significantly active for right-hand writing. The increased activation with right-hand writing cannot be ascribed to increased effort, since this is a well-practiced task much easier to perform than some of the other tasks studied. Because parietal-premotor connections code for particular skills, it would seem that the parietal and premotor regions, together with basal ganglia-sustained activation likely underlie the special skill of handwriting with the dominant hand. C1 [Horovitz, Silvina G.; Gallea, Cecile; Najee-ullah, Muslimah 'Ali; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Gallea, Cecile] Hop La Pitie Salpetriere, Ctr Neuroimagerie Rech, INSERM, Paris, France. RP Horovitz, SG (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM silvina.horovitz@nih.gov FU The NINDS Intramural Program FX The NINDS Intramural Program supported this work. The funder had no role in study design, data collection and analysis, or preparation of the manuscript. NR 54 TC 5 Z9 5 U1 2 U2 16 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 2013 VL 8 IS 7 AR e67931 DI 10.1371/journal.pone.0067931 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176XV UT WOS:000321341000122 PM 23844132 ER PT J AU Han, PKJ Kobrin, S Breen, N Joseph, DA Li, J Frosch, DL Klabunde, CN AF Han, Paul K. J. Kobrin, Sarah Breen, Nancy Joseph, Djenaba A. Li, Jun Frosch, Dominick L. Klabunde, Carrie N. TI National Evidence on the Use of Shared Decision Making in Prostate-Specific Antigen Screening SO ANNALS OF FAMILY MEDICINE LA English DT Article DE prostate-specific antigen; mass screening; decision making ID SERVICES TASK-FORCE; PRIMARY-CARE PHYSICIANS; RANDOMIZED CONTROLLED-TRIAL; HEALTH INTERVIEW SURVEY; PREVENTIVE SERVICES; INFORMED DECISIONS; UNITED-STATES; SELF-REPORTS; CANCER; MEN AB PURPOSE Recent clinical practice guidelines on prostate cancer screening using the prostate-specific antigen (PSA) test (PSA screening) have recommended that clinicians practice shared decision making-a process involving clinician-patient discussion of the pros, cons, and uncertainties of screening. We undertook a study to determine the prevalence of shared decision making in both PSA screening and nonscreening, as well as patient characteristics associated with shared decision making. METHODS A nationally representative sample of 3,427 men aged 50 to 74 years participating in the 2010 National Health Interview Survey responded to questions on the extent of shared decision making (past physician-patient discussion of advantages, disadvantages, and scientific uncertainty associated with PSA screening), PSA screening intensity (tests in past 5 years), and sociodemographic and health-related characteristics. RESULTS Nearly two-thirds (64.3%) of men reported no past physician-patient discussion of advantages, disadvantages, or scientific uncertainty (no shared decision making); 27.8% reported discussion of 1 to 2 elements only (partial shared decision making); 8.0% reported discussion of all 3 elements (full shared decision making). Nearly one-half (44.2%) reported no PSA screening, 27.8% reported low-intensity (less-than-annual) screening, and 25.1% reported high-intensity (nearly annual) screening. Absence of shared decision making was more prevalent in men who were not screened; 88% (95% CI, 86.2%-90.1%) of nonscreened men reported no shared decision making compared with 39% (95% CI, 35.0%-43.3%) of men undergoing high-intensity screening. Extent of shared decision making was associated with black race, Hispanic ethnicity, higher education, health insurance, and physician recommendation. Screening intensity was associated with older age, higher education, usual source of medical care, and physician recommendation, as well as with partial vs no or full shared decision making. CONCLUSIONS Most US men report little shared decision making in PSA screening, and the lack of shared decision making is more prevalent in nonscreened than in screened men. Screening intensity is greatest with partial shared decision making, and different elements of shared decision making are associated with distinct patient characteristics. Shared decision making needs to be improved in decisions for and against PSA screening. C1 [Han, Paul K. J.] Maine Med Ctr, Res Inst, Portland, ME 04101 USA. [Han, Paul K. J.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Kobrin, Sarah] Natl Canc Inst, Div Canc Control & Populat Sci, Behav Res Program, Rockville, MD USA. [Breen, Nancy; Klabunde, Carrie N.] Natl Canc Inst, Div Canc Control & Populat Sci, Appl Res Program, Rockville, MD USA. [Joseph, Djenaba A.; Li, Jun] Ctr Dis Control & Prevent, Atlanta, GA USA. [Frosch, Dominick L.] Palo Alto Med Fdn, Res Inst, Palo Alto, CA 94301 USA. [Frosch, Dominick L.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA USA. RP Han, PKJ (reprint author), Maine Med Ctr, Ctr Outcomes Res & Evaluat, 509 Forest Ave, Portland, ME 04101 USA. EM hanp@mmc.org OI Han, Paul/0000-0003-0165-1940 NR 55 TC 27 Z9 27 U1 0 U2 10 PU ANNALS FAMILY MEDICINE PI LEAWOOD PA 11400 TOMAHAWK CREEK PARKWAY, LEAWOOD, KS 66211-2672 USA SN 1544-1709 EI 1544-1717 J9 ANN FAM MED JI Ann. Fam. Med. PD JUL-AUG PY 2013 VL 11 IS 4 BP 306 EP 314 DI 10.1370/afm.1539 PG 9 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA AI3XH UT WOS:000336798500003 PM 23835816 ER PT J AU Loehr, LR Agarwal, SK Baggett, C Wruck, LM Chang, PP Solomon, SD Shahar, E Ni, HY Rosamond, WD Heiss, G AF Loehr, Laura R. Agarwal, Sunil K. Baggett, Chris Wruck, Lisa M. Chang, Patricia P. Solomon, Scott D. Shahar, Eyal Ni, Hanyu Rosamond, Wayne D. Heiss, Gerardo TI Classification of Acute Decompensated Heart Failure An Automated Algorithm Compared With a Physician Reviewer Panel: The Atherosclerosis Risk in Communities Study SO CIRCULATION-HEART FAILURE LA English DT Article DE ARIC; BNP; classification; ejection fraction; heart failure ID DIAGNOSTIC-CRITERIA; ADJUDICATION; PREVALENCE; VALIDATION; DISEASE AB Background An algorithm to classify heart failure (HF) end points inclusive of contemporary measures of biomarkers and echocardiography was recently proposed by an international expert panel. Our objective was to assess agreement of HF classification by this contemporaneous algorithm with that by a standardized physician reviewer panel, when applied to data abstracted from community-based hospital records. Methods and Results During 2005-2007, all hospitalizations were identified from 4 US communities under surveillance as part of the Atherosclerosis Risk in Communities (ARIC) study. Potential HF hospitalizations were sampled by International Classification of Diseases discharge codes and demographics from men and women aged 55 years. The HF classification algorithm was automated and applied to 2729 (n=13854 weighted hospitalizations) hospitalizations in which either brain natriuretic peptide measures or ejection fraction were documented (mean age, 75 years). There were 1403 (54%; n=7534 weighted) events classified as acute decompensated HF by the automated algorithm, and 1748 (68%; n=9276 weighted) such events by the ARIC reviewer panel. The chance-corrected agreement between acute decompensated HF by physician reviewer panel and the automated algorithm was moderate (=0.39). Sensitivity and specificity of the automated algorithm with ARIC reviewer panel as the referent standard were 0.68 (95% confidence interval, 0.67-0.69) and 0.75 (95% confidence interval, 0.74-0.76), respectively. Conclusions Although the automated classification improved efficiency and decreased costs, its accuracy in classifying HF hospitalizations was modest compared with a standardized physician reviewer panel. C1 [Loehr, Laura R.; Rosamond, Wayne D.; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA. [Wruck, Lisa M.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Chang, Patricia P.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Agarwal, Sunil K.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Baggett, Chris] RTI Int, Div Hlth Sci, Res Triangle Pk, NC USA. [Solomon, Scott D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Cardiovasc Med, Boston, MA 02115 USA. [Ni, Hanyu] NHLBI, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Shahar, Eyal] Univ Arizona, Epidemiol & Biostat Div, Tucson, AZ USA. RP Loehr, LR (reprint author), Univ N Carolina, Dept Epidemiol, 137 E Franklin St,Suite 306, Chapel Hill, NC 27515 USA. EM lloehr@email.unc.edu FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201 100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C] FX The Atherosclerosis Risk in Communities Study is performed as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201 100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). NR 16 TC 6 Z9 6 U1 0 U2 2 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 2013 VL 6 IS 4 BP 719 EP 726 DI 10.1161/CIRCHEARTFAILURE.112.000195 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AG1EL UT WOS:000335157800020 PM 23650310 ER PT J AU Givertz, MM Mann, DL Lee, KL Ibarra, JC Velazquez, EJ Hernandez, AF Mascette, AM Braunwald, E AF Givertz, Michael M. Mann, Douglas L. Lee, Kerry L. Ibarra, Jenny C. Velazquez, Eric J. Hernandez, Adrian F. Mascette, Alice M. Braunwald, Eugene TI Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients Design and Rationale of the EXACT- HF Study SO CIRCULATION-HEART FAILURE LA English DT Article DE allopurinol; clinical trial; heart failure; xanthine oxidase ID HIGH-DOSE ALLOPURINOL; IDIOPATHIC DILATED CARDIOMYOPATHY; 6-MINUTE WALK TEST; URIC-ACID; ENDOTHELIAL DYSFUNCTION; SURVIVAL; ASSOCIATION; OXYPURINOL; PREDICTION; EFFICIENCY C1 [Givertz, Michael M.; Braunwald, Eugene] Harvard Univ, Brigham & Womens Hosp, Cardiovasc Div, Dept Med,Med Sch, Boston, MA 02115 USA. [Mann, Douglas L.] Washington Univ, Dept Med, St Louis, MO USA. [Lee, Kerry L.; Ibarra, Jenny C.; Velazquez, Eric J.; Hernandez, Adrian F.] Duke Univ, Dept Med, Durham, NC USA. [Mascette, Alice M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Givertz, MM (reprint author), Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. EM mgivertz@partners.org RI Hernandez, Adrian F./A-7818-2016; OI Hernandez, Adrian F./0000-0003-3387-9616; Mann, Douglas /0000-0002-2516-0145 FU NHLBI, National Institutes of Health [U10HL084904, U10HL084861, U10HL084875, U10HL084877, U10HL084889, U10HL084890, U10HL084891, U10HL084899, U10HL084907, U10HL084931] FX The Heart Failure Clinical Research Network is supported by the NHLBI, National Institutes of Health (U10HL084904 for the coordinating center; and U10HL084861, U10HL084875, U10HL084877, U10HL084889, U10HL084890, U10HL084891, U10HL084899, U10HL084907, and U10HL084931 for the clinical centers). NR 43 TC 12 Z9 14 U1 0 U2 7 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 2013 VL 6 IS 4 BP 862 EP 868 DI 10.1161/CIRCHEARTFAILURE.113.000394 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AG1EL UT WOS:000335157800037 PM 23861505 ER PT J AU Harper, MT Londano, JEC Quick, K Londano, JC Phillip, SE Birnbaumer, L Freichel, M Poole, AW AF Harper, M. T. Londano, Camacho J. E. Quick, K. Londano, Camacho J. Phillip, S. E. Birnbaumer, L. Freichel, M. Poole, A. W. TI Transient receptor potential channels (TRPCs) contribute to platelet phosphatidylserine exposure SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Harper, M. T.; Poole, A. W.] Univ Bristol, Bristol, Avon, England. [Londano, Camacho J. E.; Freichel, M.] Heidelberg Univ, Heidelberg, Germany. [Quick, K.] UCL, London, England. [Londano, Camacho J.; Phillip, S. E.] Univ Saarland, Homburg, Germany. [Birnbaumer, L.] NIH, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 111 EP 112 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833601251 ER PT J AU Kim, YC Zhang, A Rossi, RJ Adair, P Yoon, JH Ettinger, RA Pratt, KP Scott, DW AF Kim, Y. C. Zhang, A. Rossi, R. J. Adair, P. Yoon, J. H. Ettinger, R. A. Pratt, K. P. Scott, D. W. TI FVIII-targeting specific regulatory T-cell therapy: a novel translational approach for tolerance in Hemophilia A patients SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Kim, Y. C.; Zhang, A.; Rossi, R. J.; Adair, P.; Scott, D. W.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Yoon, J. H.] NIAID, Rockville, MD USA. [Ettinger, R. A.; Pratt, K. P.] Puget Sound Blood Ctr, Res Inst, Seattle, WA 98104 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 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 191 EP 191 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833601431 ER PT J AU Johnsen, JM Auer, P Cushman, M O'Donnell, C Rich, S Green, D Morrison, AC Reiner, AP AF Johnsen, J. M. Auer, P. Cushman, M. O'Donnell, C. Rich, S. Green, D. Morrison, A. C. Reiner, A. P. CA NHBLI GO TI Common and rare VWF coding variants are associated with von Willebrand Factor and Factor VIII phenotypes in African Americans: the NHLBI Exome Sequencing Project SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Johnsen, J. M.] Puget Sound Blood Ctr, Seattle, WA 98104 USA. [Auer, P.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Cushman, M.] Univ Vermont, Burlington, VT USA. [O'Donnell, C.; NHBLI GO] NIH, Bethesda, MD 20892 USA. [Rich, S.] Univ Virginia, Charlottesville, VA USA. [Green, D.] Northwestern Univ, Chicago, IL 60611 USA. [Morrison, A. C.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Reiner, A. P.] Univ Washington, Seattle, WA 98195 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 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 231 EP 232 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833601526 ER PT J AU Lecchi, A Razzari, C Paoletta, S Nakamura, L Ohlman, P Gachet, C Jacobson, KA Cattaneo, M AF Lecchi, A. Razzari, C. Paoletta, S. Nakamura, L. Ohlman, Ph Gachet, C. Jacobson, K. A. Cattaneo, M. TI Identification of a patient with bleeding diathesis, associated with dysfunctional platelet P2Y12 receptor SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Lecchi, A.] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Milan, Italy. [Razzari, C.; Cattaneo, M.] Univ Milan, Milan, Italy. [Paoletta, S.; Jacobson, K. A.] NIDDK, NIH, Bethesda, MD 20892 USA. [Nakamura, L.] Univ Med Ctr Freiburg, Freiburg, Germany. [Ohlman, Ph] Univ Strasbourg, EFS Alsace, INSERM, Strasbourg, France. [Gachet, C.] Univ Strasbourg, EFS Alsace, INSERM, UMR S949, Strasbourg, France. RI Jacobson, Kenneth/A-1530-2009; Gachet, Christian/H-9156-2016 OI Jacobson, Kenneth/0000-0001-8104-1493; 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 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 283 EP 283 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833601642 ER PT J AU Parunov, LA Jha, K Andersen, JF Tucker, I Ataullakhanov, F Lee, TK Ovanesov, MV AF Parunov, L. A. Jha, K. Andersen, J. F. Tucker, I Ataullakhanov, F. Lee, T. K. Ovanesov, M., V TI Factors IXa and XIa promote uncontrolled clot growth under static conditions SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Parunov, L. A.; Jha, K.; Lee, T. K.; Ovanesov, M., V] US FDA, Bethesda, MD 20014 USA. [Andersen, J. F.] NIH, Bethesda, MD 20892 USA. [Tucker, I] Oregon Hlth & Sci Univ, Sch Med, Portland, OR 97201 USA. [Ataullakhanov, F.] Ctr Theoret Problems Physicochem Pharmacol, Moscow, Russia. 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 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 983 EP 983 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833604304 ER PT J AU Gruenewald, PJ Ponicki, WR Remer, LG Waller, LA Zhu, L Gorman, DM AF Gruenewald, Paul J. Ponicki, William R. Remer, Lillian G. Waller, Lance A. Zhu, Li Gorman, Dennis M. TI Mapping the Spread of Methamphetamine Abuse in California From 1995 to 2008 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID REGULATIONS; DISEASE; IMPACTS AB Objectives. From 1983 to 2008, the incidence of methamphetamine abuse and dependence (MA) presenting at hospitals in California increased 13-fold. We assessed whether this growth could be characterized as a drug epidemic. Methods. We geocoded MA discharges to residential zip codes from 1995 through 2008. We related discharges to population and environmental characteristics using Bayesian Poisson conditional autoregressive models, correcting for small area effects and spatial misalignment and enabling an assessment of contagion between areas. Results. MA incidence increased exponentially in 3 phases interrupted by implementation of laws limiting access to methamphetamine precursors. MA growth from 1999 through 2008 was 17% per year. MA was greatest in areas with larger White or Hispanic low-income populations, small household sizes, and good connections to highway systems. Spatial misalignment was a source of bias in estimated effects. Spatial autocorrelation was substantial, accounting for approximately 80% of error variance in the model. Conclusions. From 1995 through 2008, MA exhibited signs of growth and spatial spread characteristic of drug epidemics, spreading most rapidly through low-income White and Hispanic populations living outside dense urban areas. C1 [Gruenewald, Paul J.; Ponicki, William R.; Remer, Lillian G.] Prevent Res Ctr, Pacific Inst Res & Evaluat, Berkeley, CA 94704 USA. [Waller, Lance A.] Emory Univ, Dept Biostat & Bioinformat, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Zhu, Li] NCI, Surveillance Res Program, NIH, Bethesda, MD 20892 USA. [Gorman, Dennis M.] Texas A&M Hlth Sci Ctr, Dept Epidemiol & Biostat, Sch Rural Publ Hlth, College Stn, TX USA. RP Gruenewald, PJ (reprint author), Prevent Res Ctr, 1995 Univ Ave,Ste 450, Berkeley, CA 94704 USA. EM paul@prev.org FU National Institute on Drug Abuse, National Institutes of Health [R21 DA024341] FX Research presented in this article was supported by the National Institute on Drug Abuse, National Institutes of Health (grant R21 DA024341, to P.J.G.). NR 34 TC 5 Z9 5 U1 0 U2 7 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 2013 VL 103 IS 7 BP 1262 EP 1270 DI 10.2105/AJPH.2012.300779 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA3FP UT WOS:000330978600032 PM 23078474 ER PT J AU Rubio, M AF Rubio, Mercedes TI Addiction Treatment: Comparing Religion and Science in Application SO CONTEMPORARY SOCIOLOGY-A JOURNAL OF REVIEWS LA English DT Book Review C1 [Rubio, Mercedes] NIMH, Bethesda, MD 20892 USA. RP Rubio, M (reprint author), NIMH, Bethesda, MD 20892 USA. EM chelisrubio@yahoo.com NR 1 TC 0 Z9 0 U1 2 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0094-3061 EI 1939-8638 J9 CONTEMP SOCIOL JI Contemp. Sociol.-J. Rev. PD JUL PY 2013 VL 42 IS 4 BP 571 EP 572 DI 10.1177/0094306113491549t PG 4 WC Sociology SC Sociology GA 301HJ UT WOS:000330523100049 ER PT J AU Marcum, CS AF Marcum, Christopher Steven TI Aging Across the United States: Matching Needs to States' Differing Opportunities and Services SO CONTEMPORARY SOCIOLOGY-A JOURNAL OF REVIEWS LA English DT Book Review C1 [Marcum, Christopher Steven] NHGRI, Bethesda, MD 20892 USA. RP Marcum, CS (reprint author), NHGRI, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0094-3061 EI 1939-8638 J9 CONTEMP SOCIOL JI Contemp. Sociol.-J. Rev. PD JUL PY 2013 VL 42 IS 4 BP 584 EP 585 DI 10.1177/0094306113491549bb PG 2 WC Sociology SC Sociology GA 301HJ UT WOS:000330523100057 ER PT J AU Dubois, RW Lauer, M Perfetto, E AF Dubois, Robert W. Lauer, Michael Perfetto, Eleanor TI When is evidence sufficient for decision-making? A framework for understanding the pace of evidence adoption SO JOURNAL OF COMPARATIVE EFFECTIVENESS RESEARCH LA English DT Article DE adoption; evidence; evidence-based medicine; technology diffusion ID DRUG-ELUTING STENTS; CORONARY-HEART-DISEASE; AVERAGE CHOLESTEROL LEVELS; BARE-METAL STENTS; RANDOMIZED-TRIALS; CLINICAL-PRACTICE; ARTERY-DISEASE; METAANALYSIS; THROMBOSIS; RISK AB Translation of medical evidence into practice has not kept pace with the growth of medical technology and knowledge. We present three case studies - statins, drug eluting stents and bone marrow transplantation for breast cancer - to propose a framework for describing five factors that may influence the rate of adoption. The factors are: validity, reliability and maturity of the science available before widespread adoption; communication of the science; economic drivers; patients' and physicians' ability to apply published scientific findings to their specific clinical needs; and incorporation into practice guidelines. C1 [Dubois, Robert W.] Natl Pharmaceut Council, Washington, DC 20006 USA. [Lauer, Michael] NHLBI, Bethesda, MD 20892 USA. [Perfetto, Eleanor] Pfizer, Washington, DC USA. RP Dubois, RW (reprint author), Natl Pharmaceut Council, 1717 Penn Ave,NW,Suite 800, Washington, DC 20006 USA. EM rdubois@npcnow.org NR 49 TC 3 Z9 3 U1 2 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 2042-6305 EI 2042-6313 J9 J COMP EFFECT RES JI J. Comp. Eff. Res. PD JUL PY 2013 VL 2 IS 4 BP 383 EP 391 DI 10.2217/CER.13.39 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 301JH UT WOS:000330528100013 PM 24236680 ER PT J AU Zhou, H Hasni, SA Perez, P Tandon, M Jang, SI Zheng, CY Kopp, JB Austin, H Balow, JE Alevizos, I Illei, GG AF Zhou, Hua Hasni, Sarfaraz A. Perez, Paola Tandon, Mayank Jang, Shyh-Ing Zheng, Changyu Kopp, Jeffery B. Austin, Howard, III Balow, James E. Alevizos, Ilias Illei, Gabor G. TI miR-150 Promotes Renal Fibrosis in Lupus Nephritis by Downregulating SOCS1 SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; DIABETIC-NEPHROPATHY; TGF-BETA; COLLAGEN EXPRESSION; MICRORNA EXPRESSION; INTERSTITIAL FIBROSIS; AUTOIMMUNE-DISEASES; THERAPEUTIC TARGETS; TUMOR-SUPPRESSOR; MECHANISMS AB MicroRNAs (miRs) seem to mediate renal fibrosis in several renal diseases, with some miRs having profibrotic effects and others having opposing effects. Although differential expression of certain miRs has been described in lupus nephritis, it is unknown whether miRs contribute to fibrosis or could serve as biomarkers of specific histologic manifestations of lupus nephritis. Here, we compared miR expression in kidney biopsies from patients with lupus nephritis and identified miR-150 as the most differentially expressed miR in kidneys with high chronicity (chronicity index [CI] >= 4); miR-150 positively correlated with chronicity scores and the expression of profibrotic proteins. Overexpression of miR-150 significantly reduced expression of the antifibrotic protein suppressor of cytokine signaling 1 (SOCS1) and upregulated profibrotic proteins in both proximal tubular and mesangial cells. Directly targeting SOCS1 with a small interfering RNA produced similar results. Furthermore, TGF-beta 1 induced miR-150 expression, decreased SOCS1, and increased profibrotic proteins in proximal tubular cells and podocytes; a miR-150 inhibitor reversed these changes, suggesting that the profibrotic effects of TGF-beta 1 are, at least in part, mediated by miR-150. Consistent with these in vitro observations, biopsies with high miR-150 and high CI exhibited substantial expression of TGF-beta 1, reduced SOCS1, and an increase in profibrotic proteins. In summary, miR-150 is a promising quantitative renal biomarker of kidney injury in lupus nephritis. Our results suggest that miR-150 promotes renal fibrosis by increasing profibrotic molecules through downregulation of SOCS1. C1 [Zhou, Hua; Perez, Paola; Tandon, Mayank; Jang, Shyh-Ing; Zheng, Changyu; Alevizos, Ilias; Illei, Gabor G.] Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, NIH, Bethesda, MD 20892 USA. [Zhou, Hua] China Med Univ, Hosp 1, Dept Nephrol, Shenyang, Peoples R China. [Hasni, Sarfaraz A.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Kopp, Jeffery B.; Austin, Howard, III; Balow, James E.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Illei, GG (reprint author), Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, NIH, 10 Ctr Dr,Bldg 10,Room 1N110, Bethesda, MD 20892 USA. EM illeig@nidcr.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU National Institutes of Health Intramural Research Programs of the National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the National Institutes of Health Intramural Research Programs of the National Institute of Dental and Craniofacial Research and the National Institute of Diabetes and Digestive and Kidney Diseases. NR 45 TC 32 Z9 38 U1 0 U2 10 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 2013 VL 24 IS 7 BP 1073 EP 1087 DI 10.1681/ASN.2012080849 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA AA4UC UT WOS:000331090800010 PM 23723424 ER PT J AU Groffen, DAI Koster, A Bosma, H van den Akker, M Kempen, GIJM van Eijk, JTM van Gool, CH Penninx, BWJH Harris, TB Rubin, SM Pahor, M Schulz, R Simonsick, EM Perry, SE Ayonayon, HN Kritchevsky, SB AF Groffen, Danielle A. I. Koster, Annemarie Bosma, Hans van den Akker, Madan Kempen, Gertrudis I. J. M. van Eijk, Jacques Th M. van Gool, Coen H. Penninx, Brenda W. J. H. Harris, Tamara B. Rubin, Susan M. Pahor, Marco Schulz, Richard Simonsick, Eleanor M. Perry, Sara E. Ayonayon, Hilsa N. Kritchevsky, Stephen B. CA Hlth ABC Study TI Unhealthy Lifestyles Do Not Mediate the Relationship Between Socioeconomic Status and Incident Depressive Symptoms: The Health ABC study SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Depressive symptoms; elderly; Health ABC study; lifestyle factors; socioeconomic status; United States ID OLDER-ADULTS; WHITEHALL-II; NEGATIVE AFFECTIVITY; SOCIAL INEQUALITIES; BODY-COMPOSITION; DIETARY-INTAKE; RISK; ASSOCIATION; CONSUMPTION; POPULATION AB Background: The relationship between low socioeconomic status (SES) and depressive symptoms is well described, also in older persons. Although studies have found associations between low SES and unhealthy lifestyle factors, and between unhealthy lifestyle factors and depressive symptoms, not much is known about unhealthy lifestyles as a potential explanation of socioeconomic differences in depressive symptoms in older persons. Methods: To study the independent pathways between SES (education, income, perceived income, and financial assets), lifestyle factors (smoking, alcohol use, body mass index, and physical activity), and incident depressive symptoms (Center for Epidemiologic Studies Depression [CES-D 10] and reported use of antidepressant medication), we used 9 years of follow-up data (1997 2007) from 2,694 American black and white participants aged 70-79 years from the Health, Aging, and Body Composition (Health ABC) study. At baseline, 12.1% of the study population showed prevalent depressive symptoms, use of antidepressant medication, or treatment of depression in the 5 years prior to baseline. These persons were excluded from the analyses. Results: Over a period of 9 years time, 860 participants (31.9%) developed depressive symptoms. Adjusted hazard ratios for incident depressive symptoms were higher in participants from lower SES groups compared with the highest SES group. The strongest relationships were found for black men. Although unhealthy lifestyle factors were consistently associated with low SES, they were weakly related to incident depressive symptoms. Lifestyle factors did not significantly reduce hazard ratios for depressive symptoms by SES. Conclusion: In generally healthy persons aged 70-79 years, lifestyle factors do not explain the relationship between SES and depressive symptoms. C1 [Groffen, Danielle A. I.; Koster, Annemarie; Bosma, Hans; van den Akker, Madan; Kempen, Gertrudis I. J. M.; van Eijk, Jacques Th M.] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, NL-6200 MD Maastricht, Netherlands. [van den Akker, Madan] Katholieke Univ Leuven, Dept Gen Practice, Louvain, Belgium. [van Gool, Coen H.] Natl Inst Publ Hlth & Environm, Ctr Publ Hlth Forecasting, Bilthoven, Netherlands. [Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Dept Psychiat, EMGO Inst Hlth & Care Res, Med Ctr, Amsterdam, Netherlands. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Rubin, Susan M.; Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Pahor, Marco] Univ Florida, Coll Med, Dept Aging & Geriatr Res, Gainesville, FL USA. [Schulz, Richard] Univ Pittsburgh, Univ Ctr Social & Urban Res, Pittsburgh, PA USA. [Simonsick, Eleanor M.] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Simonsick, Eleanor M.] Johns Hopkins Sch Med, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Perry, Sara E.] NASA Lifetime Surveillance Astronaut Hlth, Houston, TX USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Sect Gerontol & Geriatr Med, Winston Salem, NC USA. RP Groffen, DAI (reprint author), Maastricht Univ, Dept Social Med, CAPHRI Sch Publ Hlth & Primary Care, POB 616, NL-6200 MD Maastricht, Netherlands. EM D.Groffen@maastrichtuniversity.nl RI Koster, Annemarie/E-7438-2010; Kempen, Gertrudis/H-5978-2016; Bosma, Hans/A-6184-2013; OI Kempen, Gertrudis/0000-0002-7053-2198; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; NINR [R01-NR012459]; Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported by National Institute on Aging (NIA) contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106; NIA grant R01-AG028050; and NINR grant R01-NR012459. This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 40 TC 3 Z9 3 U1 2 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD JUL PY 2013 VL 21 IS 7 BP 664 EP 674 DI 10.1016/j.jagp.2013.01.004 PG 11 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XY UT WOS:000330359200009 PM 23567402 ER PT J AU Rogers, NM Roberts, DD Isenberg, JS AF Rogers, Natasha M. Roberts, David D. Isenberg, Jeffrey S. TI Age-Associated Induction of Cell Membrane CD47 Limits Basal and Temperature-Induced Changes in Cutaneous Blood Flow SO ANNALS OF SURGERY LA English DT Article DE aging; blood flow; CD47; nitric oxide; skin; thermal stress; thrombospondin-1; wound healing ID NITRIC-OXIDE; HUMAN SKIN; ISCHEMIC TISSUE; TRANSGENIC MICE; THROMBOSPONDIN-1; RESPONSES; HUMANS; ACETYLCHOLINE; VASODILATION; SCLERODERMA AB Objective: We tested the hypothesis that the matricellular protein thrombospondin-1 (TSP1), through binding to and activation of the cell receptor CD47, inhibits basal and thermal-mediated cutaneous blood flow. Background: Abnormal and decreased cutaneous blood flow in response to temperature changes or vasoactive agents is a feature of cardiovascular disease and aging. The reasons for decreased cutaneous blood flow remain incompletely understood. Furthermore, a role for matricellular proteins in the regulation skin blood flow has never been proposed. Methods: C57BL/6 wild type, TSP1-null, and CD47-null 12- and 72-week-old male mice underwent analysis of skin blood flow (SkBF) via laser Doppler in response to thermal stress and vasoactive challenge. Results: Young and aged TSP1- and CD47-null mice displayed enhanced basal and thermal sensitive SkBF changes compared with age-matched wild type controls. Nitric oxide-mediated increases in SkBF were also greater in null mice. TSP1 and CD47 were expressed in skin from young wild type mice, and both were significantly upregulated in aged animals. Tissue 3', 5'-cyclic guanosine monophosphate, a potent vasodilator, was greater in skin samples from null mice compared with wild type regardless of age. Finally, treating wild type animals with a CD47 monoclonal antibody that inhibits TSP1 activation of CD47 enhanced SkBF in both young and aged animals. Conclusions: These results suggest that secreted TSP1, via its cognate receptor CD47, acutely modulates SkBF. These data further support therapeutically targeting CD47 to mitigate age-associated loss of SkBF and maximize wound healing. C1 [Isenberg, Jeffrey S.] Univ Pittsburgh, Sch Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15261 USA. [Rogers, Natasha M.; Isenberg, Jeffrey S.] Univ Pittsburgh, Sch Med, Vasc Med Inst, Pittsburgh, PA 15261 USA. [Isenberg, Jeffrey S.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15261 USA. [Roberts, David D.] NCI, Pathol Lab, CCR, Bethesda, MD 20892 USA. RP Isenberg, JS (reprint author), Univ Pittsburgh, Sch Med, Vasc Med Inst, E1258,BST,200 Lothrop St, Pittsburgh, PA 15261 USA. EM jsi5@pitt.edu RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU NIH/NHLBI [1RO1HL108954-01]; NIH [1P01HL103455-01]; AHA [11BGIA7210001]; Vascular Medicine Institute of the University of Pittsburgh; Institute for Transfusion Medicine; Western Pennsylvania Hemophilia Center; NCI/NIH; C.J. Martin Award (Australian NHMRC) [APP1016276] FX Funding for this work was provided to J.S.I. by 1RO1HL108954-01 (NIH/NHLBI), 1P01HL103455-01 (NIH), 11BGIA7210001 (AHA), the Vascular Medicine Institute of the University of Pittsburgh, the Institute for Transfusion Medicine, and the Western Pennsylvania Hemophilia Center; to D. D. R. by the Intramural Research Program of the NCI/NIH; and to N.A.R. by APP1016276 C.J. Martin Award (Australian NHMRC). J.S.I. is Chair of the Scientific Advisory Boards of Vasculox, Inc. (St. Louis, MO) and Radiation Control Technologies, Inc. (Gaithersburg, MD). NR 56 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD JUL PY 2013 VL 258 IS 1 BP 184 EP 191 DI 10.1097/SLA.0b013e31827e52e1 PG 8 WC Surgery SC Surgery GA 300JO UT WOS:000330460400033 PM 23275312 ER PT J AU Korzeniewski, SJ Kleyn, M Young, WI Chaiworapongsa, T Schwartz, AG Romero, R AF Korzeniewski, Steven J. Kleyn, Mary Young, William I. Chaiworapongsa, Tinnakorn Schwartz, Alyse G. Romero, Roberto TI Screening for congenital hypothyroidism in newborns transferred to neonatal intensive care SO ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION LA English DT Article ID LOW-BIRTH-WEIGHT; THYROID-STIMULATING HORMONE; PRETERM INFANTS; HYPERTHYROTROPINEMIA; AGE AB Objective To evaluate the effectiveness of four driedblood spot testing protocols used in newborn screening for congenital hypothyroidism (CH) among newborns transferred to the neonatal intensive care unit (NICU). Design, setting and patients Michigan newborns transferred to the NICU from 1998 to 2011 and screened for CH are included in this population-based retrospective cohort study. Main outcome measures Screening performance metrics are computed and logistic regression is used to test for differences in the likelihood of detection across four periods characterised by different testing protocols. Results Primary thyrotropin (TSH) plus retest at 30 days of life or discharge achieved the greatest detection rate (2.6: 1000 births screened). The odds of detection was also significantly greater in this period compared with the tandem thyroxine (T4) and TSH testing period and separately compared with TSH testing alone, adjusted for birth weight, sex and race (OR 1.5; CI 1.0 to 2.2; p=0.046, and OR 2.2; CI 1.5 to 3.4, respectively). Approximately half of the cases detected during primary TSH plus serial testing periods were identified by retest. Conclusions Primary TSH testing programmes that do not incorporate serial screening may fail to identify approximately half of newborns with congenital thyroid hormone deficiency transferred to the NICU. Tandem T4 and TSH testing programmes also likely miss cases who otherwise would receive treatment if serial testing were conducted. Further research is necessary to determine the optimal newborn screening protocol for CH; strategies combining tandem T4 and TSH with serial testing conditional on birthweight may be useful. C1 [Korzeniewski, Steven J.; Chaiworapongsa, Tinnakorn; Schwartz, Alyse G.; Romero, Roberto] NICHD, NICHHD, Perinatol Res Branch, NIH,DHHS, Detroit, MI 48201 USA. [Korzeniewski, Steven J.; Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Kleyn, Mary; Young, William I.] Michigan Dept Community Hlth, Lansing, MI USA. RP Korzeniewski, SJ (reprint author), NICHD, Perinatal Epidemiol Unit, Perinatol Res Branch, NIH, 4 Brush Off 4817,3990 John R, Detroit, MI 48201 USA. EM sKorzeni@med.wayne.edu FU Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported (in part) by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 28 TC 0 Z9 0 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 2013 VL 98 IS 4 BP F310 EP F315 DI 10.1136/archdischild-2012-302192 PG 6 WC Pediatrics SC Pediatrics GA 301EG UT WOS:000330515000006 PM 23183553 ER PT J AU Ho, J Turkbey, B Edgerly, M Alimchandani, M Quezado, M Camphausen, K Fojo, T Kaushal, A AF Ho, Jennifer Turkbey, Baris Edgerly, Maureen Alimchandani, Meghna Quezado, Martha Camphausen, Kevin Fojo, Tito Kaushal, Aradhana TI Role of Radiotherapy in Adrenocortical Carcinoma SO CANCER JOURNAL LA English DT Article DE Radiotherapy; radiation oncology; adrenocortical carcinoma; adrenal gland; palliative; adrenal cortex ID ADRENAL-CORTICAL CARCINOMA; ADJUNCTIVE TREATMENT; RADIATION-THERAPY; MANAGEMENT; RECURRENCE; SURVIVAL; CANCER AB Purpose: Adrenocortical carcinoma (ACC) is a rare and highly malignant tumor usually diagnosed in an advanced stage. Radiation therapy has been a poorly studied and underutilized therapeutic option. Methods: This retrospective analysis reviewed treatment courses for 14 patients with pathologically confirmed ACC treated between 1997 and 2012. Two patients were treated adjuvantly following surgery, and 12 were treated with palliative intent. Patients presented with stage II (n = 4), stage III (n = 7), and stage IV (n = 3) disease. Patients had a mean age of 51.5 years. Ten patients received chemotherapy before radiotherapy (RT), and 12 patients received surgery before RT, before receiving radiation at a mean of 17.8 months after diagnosis. Results: In total, 20 sites were treated, 2 of which were in an adjuvant setting, and 18 of which were for palliative indications in 12 patients as follows: (1) pain/neuropathy (n = 10), (2) prophylactic treatment of asymptomatic recurrences (n = 3), and (3) prevention of imminent metastatic complications (n = 2), hemoptysis (n = 1), severe mass effect (n = 1), and brain metastasis (n = 1). Sites were treated to a median dose of 36.3 Gy (range, 17.5-60 Gy) in a median of 2.5 Gy/fraction (range, 1.8-4 Gy). At a mean follow-up of 22.0 months for the 2 patients given adjuvant RT, 1 patient did not have a local recurrence during a 14.3-month period of follow-up, and the other had a local recurrence 14.5 months after RT. At a mean follow-up of 11.3 months for the 12 patients receiving palliative RT, 10 patients had either a clinical or radiographic response. Of the courses of palliative RT that had adequate radiographic follow-up, 4 treatments (27%) resulted in a partial response. Eleven treatments (73%) that were able to be evaluated resulted in clinical improvement. Acute Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicities observed in 7 patients included 3 grade 1, 4 grade 2, and 1 grade 3. No patient had acute toxicity of grade 4 or greater or any Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late toxicity of grade 1 or greater. Discussion: This report is one of the largest to date examining the role of modern radiation techniques in the management of ACC. We conclude that radiation can be effective in the management of metastatic ACC, palliating local symptoms, and preventing complications from large metastases. Radiation should be considered as an option in multimodality management of ACC patients. C1 [Ho, Jennifer; Camphausen, Kevin; Kaushal, Aradhana] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Edgerly, Maureen; Fojo, Tito] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Alimchandani, Meghna; Quezado, Martha] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Kaushal, A (reprint author), NCI, Radiat Oncol Branch, Bldg 10,Room B2-3561, Bethesda, MD 20892 USA. EM kaushala@mail.nih.gov NR 32 TC 9 Z9 9 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 EI 1540-336X J9 CANCER J JI Cancer J. PD JUL-AUG PY 2013 VL 19 IS 4 BP 288 EP 294 PG 7 WC Oncology SC Oncology GA 300OR UT WOS:000330473800002 PM 23867507 ER PT J AU Konig, G Brooks, BR AF Koenig, G. Brooks, B. R. TI A hybrid quantum-chemical approach for free energy simulations SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Meeting Abstract CT 9th European-Biophysical-Societies-Association Congress CY JUL 13-17, 2013 CL Lisbon, PORTUGAL SP European Biophys Soc Assoc, Soc Portuguesa Biofisica C1 [Koenig, G.; Brooks, B. R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7571 EI 1432-1017 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD JUL PY 2013 VL 42 SU 1 BP S87 EP S87 PG 1 WC Biophysics SC Biophysics GA 296WE UT WOS:000330215300197 ER PT J AU Sousa, T Coutinho, A Banerjee, S Lucas, SD Moreira, R Castro, RE Rodrigues, CM Prieto, M Fernandes, F AF Sousa, T. Coutinho, A. Banerjee, S. Lucas, S. D. Moreira, R. Castro, R. E. Rodrigues, C. M. Prieto, M. Fernandes, F. TI Cytoprotective bile acids are high affinity ligands for the apoptotic protein BAX SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Meeting Abstract CT 9th European-Biophysical-Societies-Association Congress CY JUL 13-17, 2013 CL Lisbon, PORTUGAL SP European Biophys Soc Assoc, Soc Portuguesa Biofisica C1 [Sousa, T.; Coutinho, A.; Prieto, M.; Fernandes, F.] CQFM IN, IST, UTL, Lisbon, Portugal. [Banerjee, S.] NIH, NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. [Lucas, S. D.; Moreira, R.; Castro, R. E.; Rodrigues, C. M.] FFUL, Res Inst Med & Pharmaceut Sci iMed UL, Lisbon, Portugal. RI Lucas, Susana/D-6201-2011; Moreira, Rui/G-7485-2011; iMed.ULisboa, iMed.ULisboa/C-6292-2014 OI Lucas, Susana/0000-0002-5555-5594; Moreira, Rui/0000-0003-0727-9852; NR 0 TC 0 Z9 0 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7571 EI 1432-1017 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD JUL PY 2013 VL 42 SU 1 BP S106 EP S106 PG 1 WC Biophysics SC Biophysics GA 296WE UT WOS:000330215300272 ER PT J AU White, JF Noinaj, N Shibata, Y Love, J Kloss, B Xu, F Gvozdenovic-Jeremic, J Shah, P Shiloach, J Tate, CG Grisshammer, R AF White, J. F. Noinaj, N. Shibata, Y. Love, J. Kloss, B. Xu, F. Gvozdenovic-Jeremic, J. Shah, P. Shiloach, J. Tate, C. G. Grisshammer, R. TI Structure of the agonist-bound neurotensin receptor NTS1 SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Meeting Abstract CT 9th European-Biophysical-Societies-Association Congress CY JUL 13-17, 2013 CL Lisbon, PORTUGAL SP European Biophys Soc Assoc, Soc Portuguesa Biofisica C1 [White, J. F.; Xu, F.; Gvozdenovic-Jeremic, J.; Shah, P.; Grisshammer, R.] NINDS, Membr Prot Struct Funct Unit, NIH, Rockville, MD USA. [Noinaj, N.; Shiloach, J.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Noinaj, N.; Shiloach, J.] NIDDK, Biotech Core Lab, NIH, Bethesda, MD 20892 USA. [Shibata, Y.; Tate, C. G.] MRC Lab Mol Biol, Cambridge, England. [Love, J.; Kloss, B.] Prot Prod Facil NYCOMPS, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7571 EI 1432-1017 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD JUL PY 2013 VL 42 SU 1 BP S172 EP S172 PG 1 WC Biophysics SC Biophysics GA 296WE UT WOS:000330215300523 ER PT J AU Fuchs, JD Sobieszczyk, ME Madenwald, T Grove, D Karuna, ST Andrasik, M Sherwat, A Broder, G Mayer, K Koblin, B Hammer, S AF Fuchs, Jonathan D. Sobieszczyk, Magdalena E. Madenwald, Tamra Grove, Doug Karuna, Shelly T. Andrasik, Michele Sherwat, Adam Broder, Gail Mayer, Kenneth Koblin, Beryl Hammer, Scott CA HVTN 505 Protocol Team TI Intentions to Use Preexposure Prophylaxis Among Current Phase 2B Preventive HIV-1 Vaccine Efficacy Trial Participants SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE clinical trials; HIV vaccines; HIV prevention; preexposure prophylaxis; good participatory practice ID ANTIRETROVIRAL PROPHYLAXIS; LIMITED KNOWLEDGE; MEN; INFECTION; WOMEN; SEX AB In November 2010, the iPrEx study reported that preexposure prophylaxis (PrEP) with daily tenofovir disoproxil fumarate/emtricitabine reduced HIV infections by 44% among men who have sex with men and subsequent trials corroborated efficacy among heterosexual men and women. During regularly scheduled follow-up visits from January to March 2011, participants in an ongoing phase 2b vaccine efficacy trial completed an anonymous Web survey about PrEP. Among 376 respondents, 17% reported they were very likely to use PrEP in the next year. Nonwhite participants were more likely to use PrEP. Among those with some level of interest, intent to use PrEP was greatest if the drug were available through the clinical trial or health insurance. Most (91%) believed taking PrEP would not change their willingness to stay in the vaccine trial and few thought it would affect recruitment. As key stakeholders, currently enrolled trial participants can offer vital input about emerging prevention technologies that may affect the design of future HIV vaccine and nonvaccine prevention trials. C1 [Fuchs, Jonathan D.] San Francisco Dept Publ Hlth, San Francisco, CA 94102 USA. [Fuchs, Jonathan D.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Sobieszczyk, Magdalena E.; Hammer, Scott] Columbia Univ Coll Phys & Surg, Dept Med, Div Infect Dis, New York, NY 10032 USA. [Madenwald, Tamra; Karuna, Shelly T.; Andrasik, Michele; Broder, Gail] HIV Vaccine Trials Network, Seattle, WA USA. [Grove, Doug] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Sherwat, Adam] NIAID, Bethesda, MD 20892 USA. [Mayer, Kenneth] Harvard Univ, Sch Med, Fenway Hlth, Boston, MA USA. [Mayer, Kenneth] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Infect Dis, Dept Med,Med Sch, Boston, MA 02215 USA. [Koblin, Beryl] New York Blood Ctr, Lindsley F Kimball Res Inst, Lab Infect Dis Prevent, New York, NY 10021 USA. RP Fuchs, JD (reprint author), San Francisco Dept Publ Hlth, 25 Van Ness Ave,Suite 100, San Francisco, CA 94102 USA. EM jonathan.fuchs@sfdph.org FU National Institute of Allergy and Infectious Diseases [AI068614AI068635]; Division of AIDS CTU Award [UO1AI069496]; CTSA Award [UO1AI69470, UL1RR024156]; CTU [UM1AI069480-05, UO1AI069412]; Gilead Sciences, Inc; CTU Award [UO1AI069496, UO1AI69470] FX The HVTN is supported through a cooperative agreement with the National Institute of Allergy and Infectious Diseases Grant AI068614AI068635, which supports T.M., D.G., S.K., M.A., and G.B.; J.F. is supported under a Division of AIDS CTU Award UO1AI069496; M.S. and S.H. are supported under CTU and CTSA Awards UO1AI69470 and UL1RR024156; K.M. is supported under CTU Awards UM1AI069480-05 and UO1AI069412 and unrestricted research grant support from Gilead Sciences, Inc; B.K. is supported under a CTU Award UO1AI69470. NR 21 TC 7 Z9 7 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 2013 VL 63 IS 3 BP 259 EP 262 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300FB UT WOS:000330448700010 PM 23614998 ER PT J AU Flach, B Naluyima, P Blom, K Gonzalez, VD Eller, LA Laeyendecker, O Quinn, TC Serwadda, D Sewankambo, NK Wawer, MJ Gray, RH Michael, NL Wabwire-Mangen, F Robb, ML Eller, MA Sandberg, JK AF Flach, Britta Naluyima, Prossy Blom, Kim Gonzalez, Veronica D. Eller, Leigh Anne Laeyendecker, Oliver Quinn, Thomas C. Serwadda, David Sewankambo, Nelson K. Wawer, Maria J. Gray, Ronald H. Michael, Nelson L. Wabwire-Mangen, Fred Robb, Merlin L. Eller, Michael A. Sandberg, Johan K. TI Differential Loss of Invariant Natural Killer T Cells and FoxP3(+) Regulatory T Cells in HIV-1 Subtype A and Subtype D Infections SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV-1; viral subtype; AIDS; iNKT cell; CD1d; T regulatory cell ID DISEASE PROGRESSION; NKT CELLS; VPU INTERFERENCE; TYPE-1 INFECTION; EXPRESSION; INDIVIDUALS; UGANDA; CD1D; ACTIVATION; MECHANISMS AB HIV-1 subtype D is associated with faster disease progression compared with subtype A. Immunological correlates of this difference remain undefined. We investigated invariant natural killer T (iNKT) cells and FoxP3(+) regulatory T cells (Tregs) in Ugandans infected with either subtype. Loss of iNKT cells was pronounced in subtype D, whereas Tregs displayed more profound loss in subtype A infection. The iNKT cell levels were associated with CD4 T-cell interleukin-2 production in subtype A, but not in D, infection. Thus, these viral subtypes are associated with differential loss of iNKT cells and Tregs that may influence the quality of the adaptive immune response. C1 [Flach, Britta; Naluyima, Prossy; Eller, Leigh Anne; Wabwire-Mangen, Fred; Eller, Michael A.] Makerere Univ, Walter Reed Project, Kampala, Uganda. [Blom, Kim; Gonzalez, Veronica D.; Sandberg, Johan K.] Karolinska Univ Hosp Huddinge, Dept Med, Ctr Infect Med, Karolinska Inst, S-14186 Stockholm, Sweden. [Eller, Leigh Anne; Michael, Nelson L.; Wabwire-Mangen, Fred; Robb, Merlin L.; Eller, Michael A.] US Mil HIV Res Program, Silver Spring, MD USA. [Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Laeyendecker, Oliver; Quinn, Thomas C.] Johns Hopkins Sch Med, Baltimore, MD USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Coll Hlth Sci, Kampala, Uganda. [Serwadda, David; Sewankambo, Nelson K.; Wawer, Maria J.; Gray, Ronald H.] Uganda Virus Res Inst, Rakai Hlth Sci Program, Entebbe, Uganda. [Sewankambo, Nelson K.] Makerere Univ, Coll Hlth Sci, Fac Med, Kampala, Uganda. [Wawer, Maria J.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Gray, Ronald H.] Johns Hopkins Ctr Global Hlth, Baltimore, MD USA. RP Sandberg, JK (reprint author), Karolinska Univ Hosp Huddinge, Dept Med, Ctr Infect Med, Karolinska Inst, F59, S-14186 Stockholm, Sweden. EM johan.sandberg@ki.se OI Sewankambo, Nelson/0000-0001-9362-053X; Laeyendecker, Oliver/0000-0002-6429-4760 FU Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc [W81XWH-07-2-0067]; US Department of Defense [W81XWH-07-2-0067]; National Institute of Allergy and Infectious Diseases (NIAID) [R01 A134826, R01 A134265]; National Institute of Child and Health Development [5P30HD06826]; Fogarty Foundation [5D43TW00010]; National Institutes of Health (NIH) [R01 A134826]; Swedish Research Council; Swedish Cancer Foundation; Stockholm County Council; Karolinska Institutet; Division of Intramural Research, NIAID, NIH FX Primary support was provided by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, and the US Department of Defense. Data collection was supported, in part, by grants R01 A134826 and R01 A134265 from the National Institute of Allergy and Infectious Diseases (NIAID); grant 5P30HD06826 from the National Institute of Child and Health Development; grant 5D43TW00010 from the Fogarty Foundation; and National Institutes of Health (NIH) grant R01 A134826. Additional support was provided by the Swedish Research Council, the Swedish Cancer Foundation, the Stockholm County Council, Karolinska Institutet, and the Division of Intramural Research, NIAID, NIH. NR 30 TC 3 Z9 4 U1 1 U2 2 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 2013 VL 63 IS 3 BP 289 EP 293 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300FB UT WOS:000330448700014 PM 23403863 ER PT J AU Naranbhai, V Samsunder, N Sandler, NG Roque, A Karim, QA Ndung'u, T Carr, WH Altfeld, M Douek, DC Karim, SSA AF Naranbhai, Vivek Samsunder, Natasha Sandler, Netanya G. Roque, Annalys Karim, Quarraisha Abdool Ndung'u, Thumbi Carr, William H. Altfeld, Marcus Douek, Daniel C. Karim, Salim S. Abdool CA CAPRISA 004 Trial Team TI Neither Microbial Translocation Nor TLR Responsiveness Are Likely Explanations for Preexisting Immune Activation in Women Who Subsequently Acquired HIV in CAPRISA 004 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; microbial translocation; LPS; sCD14; I-FABP; TLR2; TLR4; TLR7/8; immune activation ID SEX WORKERS; INFECTION; ACQUISITION; RESPONSES; PATHWAYS; TRIAL; GEL AB Innate immune activation was a strong predictor of HIV acquisition in women at risk for HIV in CAPRISA 004. Identifying the cause(s) of activation could enable targeted prevention interventions. In this study, plasma concentrations of lipopolysaccharide, soluble CD14, and intestinal fatty acid-binding protein did not differ between subjects who did or did not subsequently acquire HIV nor were these levels correlated with plasma cytokines or natural killer cell activation. There was no difference between HIV acquirers and non-acquirers in the chemokine and cytokine responses of peripheral blood mononuclear cells stimulated with TLR2, 4, or 7/8 agonists. Further studies are required. C1 [Naranbhai, Vivek; Samsunder, Natasha; Karim, Quarraisha Abdool; Karim, Salim S. Abdool] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Nelson R Mandela Sch Med, Durban, South Africa. [Naranbhai, Vivek; Ndung'u, Thumbi; Carr, William H.; Altfeld, Marcus] Univ KwaZulu Natal, HIV Pathogenesis Program, Nelson R Mandela Sch Med, Durban, South Africa. [Sandler, Netanya G.; Roque, Annalys; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Karim, Quarraisha Abdool; Karim, Salim S. Abdool] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Ndung'u, Thumbi; Carr, William H.; Altfeld, Marcus] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02114 USA. [Ndung'u, Thumbi; Carr, William H.; Altfeld, Marcus] Harvard Univ, Boston, MA 02115 USA. [Ndung'u, Thumbi] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV K RITH, Nelson R Mandela Sch Med, Durban, South Africa. [Carr, William H.] CUNY, Medgar Evers Coll, Brooklyn, NY 11210 USA. RP Karim, SSA (reprint author), Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Nelson R Mandela Sch Med, Private Bag X7, ZA-4013 Congella, Kwazulu Natal, South Africa. EM caprisa@ukzn.ac.za RI Abdool Karim, Salim Safurdeen/N-5947-2013; OI Abdool Karim, Salim Safurdeen/0000-0002-4986-2133; Utay, Netanya/0000-0002-6407-8670 FU South African HIV/AIDS Research Platform (SHARP); US National Institutes for Health [FIC K01-TW007793]; LIFELab; Columbia University-South Africa Fogarty AIDS International Training and Research Program (AITRP) [D43 TW000231]; Massachusetts General Hospital Physician Scientist Development Award; Howard Hughes Medical Institute; National Institute of Allergy and Infectious Diseases, National Institutes of Health; United States Agency for International Development (USAID) [FHI360, GPO-A-00-05-00,022-00, 132119]; Technology Innovation Agency (LIFElab) of the South African government's Department of Science Technology; CONRAD, Eastern Virginia Medical School (USAID) [GP00-08-00,005-00, PPA-09-046]; US National Institutes for Health's Comprehensive International Program of Research on AIDS (CIPRA) [AI51794] FX This work was supported by the South African HIV/AIDS Research Platform (SHARP), and US National Institutes for Health FIC K01-TW007793. V. Naranbhai was supported by LIFELab and the Columbia University-South Africa Fogarty AIDS International Training and Research Program (AITRP, grant D43 TW000231). W. H. Carr was supported by a Massachusetts General Hospital Physician Scientist Development Award. T. Ndung'u holds the South African Department of Science and Technology/National Research Foundation Research Chair in Systems Biology of HIV/AIDS and is also supported by the Howard Hughes Medical Institute. M. Altfeld is a Distinguished Clinical Scientist of the Doris Duke Charitable Foundation. D. C. Douek, N. G. Sandler, and A. Roque were supported by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The parent trial (CAPRISA 004) was supported by the United States Agency for International Development (USAID), FHI360 ([USAID co-operative agreement GPO-A-00-05-00,022-00, contract 132119), and the Technology Innovation Agency (LIFElab) of the South African government's Department of Science & Technology. The current studies are part of the CAPRISA TRAPS (Tenofovir gel Research for AIDS Prevention Science) Program, which is funded by CONRAD, Eastern Virginia Medical School (USAID co-operative grant GP00-08-00,005-00, subproject agreement PPA-09-046). The views expressed by the authors do not necessarily reflect the views of USAID, Gilead Sciences, Eastern Virginia Medical School or CONRAD. We thank the US National Institutes for Health's Comprehensive International Program of Research on AIDS (CIPRA grant AI51794) for the research infrastructure. Clinical trials registration number of parent trial: NCT00441298. NR 18 TC 6 Z9 6 U1 0 U2 0 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 2013 VL 63 IS 3 BP 294 EP 298 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300FB UT WOS:000330448700015 PM 23481666 ER PT J AU Boyd, SD Hadigan, C Mcmanus, M Chairez, C Nieman, LK Pau, AK Alfaro, RM Kovacs, JA Calderon, MM Penzak, SR AF Boyd, Sarita D. Hadigan, Colleen Mcmanus, Maryellen Chairez, Cheryl Nieman, Lynnette K. Pau, Alice K. Alfaro, Raul M. Kovacs, Joseph A. Calderon, Monica M. Penzak, Scott R. TI Influence of Low-Dose Ritonavir With and Without Darunavir on the Pharmacokinetics and Pharmacodynamics of Inhaled Beclomethasone SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE beclomethasone; darunavir; ritonavir; drug interactions; adrenal function ID IATROGENIC CUSHINGS-SYNDROME; BOOSTED PROTEASE INHIBITORS; 1 MU-G; FLUTICASONE PROPIONATE; INFECTED PATIENTS; STIMULATION TEST; DIPROPIONATE; PATIENT; CORTICOSTEROIDS; METABOLISM AB Objective: To identify an alternative inhaled corticosteroid to fluticasone propionate that can be safely coadministered with HIV protease inhibitors, the safety and pharmacokinetics of beclomethasone dipropionate (BDP) and its active metabolite, beclomethasone 17-monopropionate (17-BMP), in combination with ritonavir (RTV) and darunavir/ritonavir (DRV/r) were assessed. Design: Open-label, prospective, randomized pharmacokinetic and pharmacodynamic study in healthy volunteers. Methods: Thirty healthy volunteers received inhaled 160 mu g bid BDP for 14 days and were then randomized (1: 1: 1) into 3 groups: group 1 (control) remained on BDP alone for 28 days, group 2 received 100 mg bid BDP + RTV for 28 days, and group 3 received 600/100 mg bid BDP + DRV/r for 28 days. Pharmacokinetic sampling for 17-BMP was performed on days 14 and 28, and pharmacokinetic parameter values were compared within patients and between groups. Cortisol stimulation testing was also performed on days 1, 14, 28, and 42 and compared within and between groups. Results: Geometric mean ratios (day 28: day 14) (90% confidence interval) for 17-BMP area under the concentration-time curve in groups 1, 2, and 3, respectively, were 0.93 (0.81 to 1.06, P = 0.27), 2.08 (1.52 to 2.65, P = 0.006), and 0.89 (0.68 to 1.09, P = 0.61). There were no significant reductions in serum cortisol levels within or between groups (P > 0.05). Conclusions: DRV/r did not increase 17-BMP exposure, whereas RTV alone produced a statistically significant but clinically inconsequential 2-fold increase in 17-BMP exposure. Adrenal suppression was not observed in any of the study groups. These data suggest that BDP can be safely coadministered with DRV/r and likely other RTV-boosted protease inhibitors. C1 [Boyd, Sarita D.] US FDA, Off Safety & Epidemiol, Silver Spring, MD 20993 USA. [Boyd, Sarita D.; Hadigan, Colleen; Chairez, Cheryl; Pau, Alice K.] NIAID, NIH, Bethesda, MD 20892 USA. [Mcmanus, Maryellen; Calderon, Monica M.] SAIC Sci Applicat Int Corp Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Nieman, Lynnette K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Kovacs, Joseph A.] NIH, Dept Crit Care Med, Clin Res Ctr, Bethesda, MD 20892 USA. RP Boyd, SD (reprint author), US FDA, Off Safety & Epidemiol, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM sarita.boyd@fda.hhs.gov FU National Institutes of Health Clinical Center; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX Supported by the Intramural research programs of the National Institutes of Health Clinical Center, the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract no. HHSN261200800001E. NR 28 TC 11 Z9 11 U1 0 U2 0 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 2013 VL 63 IS 3 BP 355 EP 361 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300FB UT WOS:000330448700023 PM 23535292 ER PT J AU Williams, PL Chernoff, M Angelidou, K Brouwers, P Kacanek, D Deygoo, NS Nachman, S Gadow, KD AF Williams, Paige L. Chernoff, Miriam Angelidou, Konstantia Brouwers, Pim Kacanek, Deborah Deygoo, Nagamah S. Nachman, Sharon Gadow, Kenneth D. CA Int Maternal Pediat Adolescent TI Participation and Retention of Youth With Perinatal HIV Infection in Mental Health Research Studies: The IMPAACT P1055 Psychiatric Comorbidity Study SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; psychiatric disorders; ADHD; antiretroviral treatment; retention ID ANTIRETROVIRAL THERAPY; FOLLOW-UP; SOCIODEMOGRAPHIC PREDICTORS; SOCIAL SUPPORT; ANXIETY NESDA; ATTRITION; CHILDREN; ADOLESCENTS; DEPRESSION; HIV/AIDS AB Background: Obtaining accurate estimates of mental health problems among youth perinatally infected with HIV (PHIV) helps clinicians develop targeted interventions but requires enrollment and retention of representative youth into research studies. Methods: The study design for IMPAACT P1055, a US-based, multisite prospective study of psychiatric symptoms among PHIV youth and uninfected controls aged 6 to 17 years old, is described. Participants were compared with nonparticipants by demographic characteristics and reasons were summarized for study refusal. Adjusted logistic regression models were used to evaluate the association of psychiatric symptoms and other factors with loss to follow-up (LTFU). Results: Among 2281 youth screened between 2005 and 2006 at 29 IMPAACT research sites, 580 (25%) refused to participate, primarily because of time constraints. Among 1162 eligible youth approached, 582 (50%) enrolled (323 PHIV and 259 Control), with higher participation rates for Hispanic youth. Retention at 2 years was significantly higher for PHIV than Controls (84% vs 77%, P = 0.03). In logistic regression models adjusting for sociodemographic characteristics and HIV status, youth with any self-assessed psychiatric condition had higher odds of LTFU compared with those with no disorder (adjusted odds ratio = 1.56, 95% confidence interval: 1.00 to 2.43). Among PHIV youth, those with any psychiatric condition had 3-fold higher odds of LTFU (adjusted odds ratio = 3.11, 95% confidence interval: 1.61 to 6.01). Conclusions: Enrollment and retention of PHIV youth into mental health research studies is challenging for those with psychiatric conditions and may lead to underestimated risks for mental health problems. Creative approaches for engaging HIV-infected youth and their families are required for ensuring representative study populations. C1 [Williams, Paige L.; Chernoff, Miriam; Angelidou, Konstantia; Kacanek, Deborah] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Brouwers, Pim] NIMH, Div AIDS Res, NIH, Rockville, MD 20857 USA. [Deygoo, Nagamah S.] NYU, Dept Pediat, Sch Med, New York, NY 10016 USA. [Nachman, Sharon] SUNY Stony Brook, Div Pediat Infect Dis, Stony Brook, NY 11794 USA. [Gadow, Kenneth D.] SUNY Stony Brook, Dept Psychiat & Behav Sci, Stony Brook, NY 11794 USA. RP Williams, PL (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, 665 Huntington Ave, Boston, MA 02115 USA. EM paige@sdac.harvard.edu FU National Institute of Allergy and Infectious Diseases [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health; Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases [5 U01 AI-41110]; Pediatric AIDS Clinical Trials Group; IMPAACT Group [1 U01 AI-068616] FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (U01 AI068632) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI-41110 with the Pediatric AIDS Clinical Trials Group and #1 U01 AI-068616 with the IMPAACT Group. NR 57 TC 1 Z9 1 U1 3 U2 9 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 2013 VL 63 IS 3 BP 401 EP 409 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300FB UT WOS:000330448700030 PM 23714737 ER PT J AU Brookmeyer, R Laeyendecker, O Donnell, D Eshleman, SH AF Brookmeyer, Ron Laeyendecker, Oliver Donnell, Deborah Eshleman, Susan H. TI Cross-Sectional HIV Incidence Estimation in HIV Prevention Research SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; incidence; cross-sectional; multiassay algorithm ID COMMUNITY-BASED INTERVENTION; BED-ENZYME IMMUNOASSAY; VIRUS INCIDENCE RATES; UNITED-STATES; TYPE-1 SEROCONVERSION; PROJECT ACCEPT; HPTN 043; INFECTION; ASSAYS; THAILAND AB Accurate methods for estimating HIV incidence from cross-sectional samples would have great utility in prevention research. This report describes recent improvements in cross-sectional methods that significantly improve their accuracy. These improvements are based on the use of multiple biomarkers to identify recent HIV infections. These multiassay algorithms (MAAs) use assays in a hierarchical approach for testing that minimizes the effort and cost of incidence estimation. These MAAs do not require mathematical adjustments for accurate estimation of the incidence rates in study populations in the year before sample collection. MAAs provide a practical, accurate, and cost-effective approach for cross-sectional HIV incidence estimation that can be used for HIV prevention research and global epidemic monitoring. C1 [Brookmeyer, Ron] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. [Laeyendecker, Oliver] NIAID, Lab Immunoregulat, NIH, Baltimore, MD USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Donnell, Deborah] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Eshleman, SH (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Ross Bldg,Room 646,720 Rutland Ave, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu FU HIV Prevention Trials Network; National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Mental Health (NMH); National Institute of Drug Abuse (NIDA), Office of AIDS Research, of the National Institutes of Health (NIH), Department of Health and Human Services (DHHS) [UM1-AI068613, UM1-AI068617]; NIAID, NIH [R01-AI095068]; Division of Intramural Research, NIAID, NIH FX Supported by the HIV Prevention Trials Network, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Mental Health (NMH), and the National Institute of Drug Abuse (NIDA), Office of AIDS Research, of the National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Grants UM1-AI068613 (S. H. E) and UM1-AI068617 (D. D.), and the NIAID, NIH, Grant R01-AI095068 (S.H.E/R.B.). Additional support was provided by the Division of Intramural Research, NIAID, NIH. NR 53 TC 18 Z9 18 U1 0 U2 2 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 2013 VL 63 SU 2 BP S233 EP S239 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300JD UT WOS:000330459300021 PM 23764641 ER PT J AU Pettifor, A Bekker, LG Hosek, S DiClemente, R Rosenberg, M Bull, SS Allison, S Delany-Moretlwe, S Kapogiannis, BG Cowan, F AF Pettifor, Audrey Bekker, Linda-Gail Hosek, Sybil DiClemente, Ralph Rosenberg, Molly Bull, Sheana S. Allison, Susannah Delany-Moretlwe, Sinead Kapogiannis, Bill G. Cowan, Frances CA HIV Prevention Trials Network HPT TI Preventing HIV Among Young People: Research Priorities for the Future SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE adolescence; HIV; prevention ID COMMUNITY-RANDOMIZED-TRIAL; SOUTH-AFRICA; ANTIRETROVIRAL THERAPY; MALE CIRCUMCISION; BEHAVIOR-CHANGE; SEXUAL HEALTH; PREEXPOSURE PROPHYLAXIS; MEDICATION ADHERENCE; INTERVENTION TRIAL; VACCINE TRIALS AB Objective: To review the current state of knowledge on the prevention of sexual transmission of HIV in adolescents and to highlight the existing gaps and priority areas for future research. Background: A disproportionate burden of HIV infections falls on adolescents, a developmental stage marked by unique neural, biological, and social transition. Successful interventions are critical to prevent the spread of HIV in this vulnerable population. Methods: We summarized the current state of research on HIV prevention in adolescents by providing examples of successful interventions and best practices, and highlighting current research gaps. Results: Adolescent interventions fall into 3 main categories: biomedical, behavioral, and structural. The majority of current research has focused on individual behavior change, whereas promising biomedical and structural interventions have been largely understudied in adolescents. Combination prevention interventions may be particularly valuable to this group. Conclusions: Adolescents have unique needs with respect to HIV prevention, and, thus, interventions should be designed to most effectively reach out to this population with information and services that will be relevant to them. C1 [Pettifor, Audrey; Rosenberg, Molly] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Pettifor, Audrey; Delany-Moretlwe, Sinead] Univ Witwatersrand, Wits Reprod Hlth & HIV Inst WRHI, Johannesburg, South Africa. [Pettifor, Audrey] Univ Witwatersrand, MRC, Wits Rural Hlth & Hlth Transit Unit, Johannesburg, South Africa. [Bekker, Linda-Gail] Univ Cape Town, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. [Hosek, Sybil] John H Stroger Jr Hosp Cook Cty, Dept Psychiat, Chicago, IL USA. [DiClemente, Ralph] Emory Univ, Rollins Sch Publ Hlth, Dept Behav Sci & Hlth Educ, Atlanta, GA 30322 USA. [Bull, Sheana S.] Univ Colorado, Colorado Sch Publ Hlth, Dept Community & Behav Hlth, Denver, CO 80202 USA. [Allison, Susannah] NIMH, Infant Child & Adolescent Res Programs, Div AIDS Res, Bethesda, MD 20892 USA. [Kapogiannis, Bill G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Cowan, Frances] UCL, London, England. [Cowan, Frances] Ctr Sexual Hlth & HIV AIDS Res, Harare, Zimbabwe. RP Pettifor, A (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, CB 7435, Chapel Hill, NC 27599 USA. EM apet-tif@email.unc.edu FU NIH [T32 HD007168, R24 HD050924]; [UM1 AI068619] FX Supported by UM1 AI068619, S. Hosek: FHI 360 supported travel to HPTN ASC meeting where the article was conceptualized; F. Cowan: received support for travel to attend the HPTN meeting, has a number of grants/grants pending (UNFPA, DfID, PSI Zimbabwe, UK MRC); S. Delany-Moretlwe: %FTE on HPTN 068; M. Rosenberg: NIH-Training program and center grants (T32 HD007168, R24 HD050924). NR 82 TC 23 Z9 23 U1 0 U2 6 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 2013 VL 63 SU 2 BP S155 EP S160 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300JD UT WOS:000330459300009 PM 23764629 ER PT J AU Litten, RZ Ryan, ML Fertig, JB Falk, DE Johnson, B Dunn, KE Green, AI Pettinati, HM Ciraulo, DA Sarid-Segal, O Kampman, K Brunette, MF Strain, EC Tiouririne, NA Ransom, J Scott, C Stout, R AF Litten, Raye Z. Ryan, Megan L. Fertig, Joanne B. Falk, Daniel E. Johnson, Bankole Dunn, Kelly E. Green, Alan I. Pettinati, Helen M. Ciraulo, Domenic A. Sarid-Segal, Ofra Kampman, Kyle Brunette, Mary F. Strain, Eric C. Tiouririne, Nassima A. Ransom, Janet Scott, Charles Stout, Robert CA NCIG Natl Inst Alcohol Abuse TI A Double-Blind, Placebo-Controlled Trial Assessing the Efficacy of Varenicline Tartrate for Alcohol Dependence SO JOURNAL OF ADDICTION MEDICINE LA English DT Article DE alcohol dependence; alcohol use disorder; Champix; Chantix; randomized placebo-controlled clinical trial; varenicline ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; RECEPTOR PARTIAL AGONIST; DSM-IV; ACETYLCHOLINE-RECEPTORS; NICOTINIC RECEPTORS; SMOKING-CESSATION; GLOBAL BURDEN; USE DISORDERS; RISK-FACTORS; CONSUMPTION AB Objectives: To assess the efficacy and safety of varenicline (Chantix) for the treatment of alcohol dependence. Varenicline is a partial alpha 4 beta 2 nicotinic acetylcholine agonist approved by the Food and Drug Administration for smoking cessation. It has reduced drinking in animal studies and in small studies of humans who were both heavy drinkers and smokers. This is the first multisite clinical trial of varenicline in a population of smokers and nonsmokers with alcohol dependence. Methods: Men and women (n = 200) meeting the criteria for alcohol dependence were recruited across 5 clinical sites. Patients received double-blind varenicline or placebo and a computerized behavioral intervention. Varenicline was titrated during the first week to 2 mg/d, which was maintained during weeks 2 to 13. Results: The varenicline group had significantly lower weekly percent heavy drinking days (primary outcome) (adjusted mean difference = 10.4), drinks per day, drinks per drinking day, and alcohol craving compared with the placebo group (P < 0.05). The average treatment effect on alcohol use was similar for smokers and nonsmokers. Varenicline was well-tolerated; adverse events were expected and mild. Conclusions: Varenicline significantly reduced alcohol consumption and craving, making it a potentially viable option for the treatment of alcohol dependence. C1 [Litten, Raye Z.; Ryan, Megan L.; Fertig, Joanne B.; Falk, Daniel E.] NIAAA, Div Treatment & Recovery Res, Bethesda, MD 20892 USA. [Johnson, Bankole; Tiouririne, Nassima A.] Univ Virginia, Dept Psychiat Med, Charlottesville, VA USA. [Dunn, Kelly E.; Strain, Eric C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Green, Alan I.; Brunette, Mary F.] Dartmouth, Geisel Sch Med, Lebanon, NH USA. [Pettinati, Helen M.; Kampman, Kyle] Univ Penn, Treatment Res Ctr, Philadelphia, PA 19104 USA. [Ciraulo, Domenic A.; Sarid-Segal, Ofra] Boston Univ, Sch Med, Boston, MA 02118 USA. [Ransom, Janet; Scott, Charles] Fast Track Drugs & Biol, North Potomac, MD USA. [Stout, Robert] Pacific Inst Res & Evaluat, Decis Sci Inst, Pawtucket, RI USA. RP Litten, RZ (reprint author), NIAAA, Div Treatment & Recovery Res, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM rlitten@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [HHSN27200900005C] FX Supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Contract No. HHSN27200900005C); ClinicalTrials.gov NCT 01146613. NR 49 TC 69 Z9 70 U1 4 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1932-0620 EI 1935-3227 J9 J ADDICT MED JI J. Addict. Med. PD JUL-AUG PY 2013 VL 7 IS 4 BP 277 EP 286 DI 10.1097/ADM.0b013e31829623f4 PG 10 WC Substance Abuse SC Substance Abuse GA 300KO UT WOS:000330463000010 PM 23728065 ER PT J AU Chapa, DW Akintade, BF Schron, E Friedmann, E Thomas, SA AF Chapa, Deborah W. Akintade, Bimbola F. Schron, Eleanor Friedmann, Erika Thomas, Sue A. TI Predictors of Mortality in Men and Women With Atrial Fibrillation SO JOURNAL OF CARDIOVASCULAR NURSING LA English DT Meeting Abstract C1 [Chapa, Deborah W.] George Washington Univ, Washington, DC USA. [Akintade, Bimbola F.; Friedmann, Erika; Thomas, Sue A.] Univ Maryland, Baltimore, MD 21201 USA. [Schron, Eleanor] NEI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0889-4655 EI 1550-5049 J9 J CARDIOVASC NURS JI J. Cardiovasc. Nurs. PD JUL-AUG PY 2013 VL 28 IS 4 BP 305 EP 306 PG 2 WC Cardiac & Cardiovascular Systems; Nursing SC Cardiovascular System & Cardiology; Nursing GA 299DV UT WOS:000330376400015 ER PT J AU Wang, E Bedognetti, D Marincola, FM AF Wang, Ena Bedognetti, Davide Marincola, Francesco M. TI Prediction of Response to Anticancer Immunotherapy Using Gene Signatures SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID IMMUNOLOGICAL CONSTANT; MELANOMA METASTASES; REJECTION; CANCER; INTERLEUKIN-2; THERAPY; VACCINE; CELLS C1 [Wang, Ena; Bedognetti, Davide; Marincola, Francesco M.] NIH, Bethesda, MD 20892 USA. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. RP Wang, E (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. OI Bedognetti, Davide/0000-0002-5857-773X FU Intramural NIH HHS NR 25 TC 20 Z9 20 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2013 VL 31 IS 19 BP 2369 EP + DI 10.1200/JCO.2013.49.2157 PG 4 WC Oncology SC Oncology GA 301GK UT WOS:000330520600013 PM 23715576 ER PT J AU Kitahara, CM Berndt, SI de Gonzalez, AB Coleman, HG Schoen, RE Hayes, RB Huang, WY AF Kitahara, Cari M. Berndt, Sonja I. de Gonzalez, Amy Berrington Coleman, Helen G. Schoen, Robert E. Hayes, Richard B. Huang, Wen-Yi TI Prospective Investigation of Body Mass Index, Colorectal Adenoma, and Colorectal Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHYSICAL-ACTIVITY; COLON-CANCER; RISK-FACTORS; FAT DISTRIBUTION; POOLED ANALYSIS; RECTAL-CANCER; UNITED-STATES; DISTAL COLON; OBESITY; WOMEN AB Purpose Obesity has consistently been linked to an increased risk of colorectal cancer, particularly among men. Whether body mass index (BMI) differentially influences the risk across the stages of colorectal cancer development remains unclear. We evaluated the associations of BMI with colorectal adenoma incidence, adenoma recurrence, and cancer in the context of a large screening trial, in which cases and controls had an equal chance for disease detection. Methods We prospectively evaluated the association between baseline BMI and the risk of incident distal adenoma (1,213 cases), recurrent adenoma (752 cases), and incident colorectal cancer (966 cases) among men and women, ages 55 to 74 years, randomly assigned to receive flexible sigmoidoscopy screening as part of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We calculated odds ratios (ORs) and 95% CIs for adenoma incidence and recurrence, and hazard ratios (HRs) and 95% CIs for colorectal cancer incidence, using multivariable-adjusted models. Results Compared with normal-weight men (18.5 to 24.9 kg/m(2)), obese men ( 30 kg/m(2)) had significantly higher risk of incident adenoma (OR, 1.32; 95% CI, 1.06 to 1.65) and colorectal cancer (HR, 1.48; 95% CI, 1.16 to 1.89) and a borderline increased risk of recurrent adenoma (OR, 1.50; 95% CI, 0.98 to 2.30). No associations were observed for either adenoma or cancer in women. Conclusion Data from this large prospective study suggest that obesity is important throughout the natural history of colorectal cancer, at least in men, and colorectal cancer prevention efforts should encourage the achievement and maintenance of a healthy body weight in addition to regular screenings. C1 [Kitahara, Cari M.; Berndt, Sonja I.; de Gonzalez, Amy Berrington; Huang, Wen-Yi] NCI, Rockville, MD 20852 USA. [Coleman, Helen G.] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Schoen, Robert E.] Univ Pittsburgh, Pittsburgh, PA USA. [Hayes, Richard B.] NYU, Langone Med Ctr, New York, NY USA. RP Kitahara, CM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, EPS 7056,6120 Execut Blvd, Rockville, MD 20852 USA. EM meinholdc@mail.nih.gov RI Kitahara, Cari/R-8267-2016; OI Coleman, Helen/0000-0003-4872-7877; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute, National Institutes of Health FX Supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 49 TC 19 Z9 19 U1 2 U2 10 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2013 VL 31 IS 19 BP 2450 EP + DI 10.1200/JCO.2012.48.4691 PG 11 WC Oncology SC Oncology GA 301GK UT WOS:000330520600025 PM 23715565 ER PT J AU Juthani-Mehta, M De Rekeneire, N Allore, H Chen, S O'Leary, JR Bauer, DC Harris, TB Newman, AB Yende, S Weyant, RJ Kritchevsky, S Quagliarello, V AF Juthani-Mehta, Manisha De Rekeneire, Nathalie Allore, Heather Chen, Shu O'Leary, John R. Bauer, Douglas C. Harris, Tamara B. Newman, Anne B. Yende, Sachin Weyant, Robert J. Kritchevsky, Stephen Quagliarello, Vincent CA Hlth ABC Study TI Modifiable Risk Factors for Pneumonia Requiring Hospitalization of Community-Dwelling Older Adults: The Health, Aging, and Body Composition Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE pneumonia; community-dwelling; risk factors ID VENTILATOR-ASSOCIATED PNEUMONIA; PLAQUE ANTISEPTIC DECONTAMINATION; RANDOMIZED CONTROLLED-TRIAL; ACTIVE LIFE EXPECTANCY; INTENSIVE-CARE-UNIT; ACQUIRED PNEUMONIA; CHLORHEXIDINE GLUCONATE; DENTAL PLAQUE; NURSING-HOME; RESPIRATORY PATHOGENS AB OBJECTIVES: To identify novel modifiable risk factors, focusing on oral hygiene, for pneumonia requiring hospitalization of community-dwelling older adults. DESIGN: Prospective observational cohort study. SETTING: Memphis, Tennessee, and Pittsburgh, Pennsylvania. PARTICIPANTS: Of 3,075 well-functioning community-dwelling adults aged 70 to 79 enrolled in the Health, Aging, and Body Composition Study from 1997 to 1998, 1,441 had complete data in the data set of all variables used, a dental examination within 6 months of baseline, and were eligible for this study. MEASUREMENTS: The primary outcome was pneumonia requiring hospitalization through 2008. RESULTS: Of 1,441 participants, 193 were hospitalized for pneumonia. In a multivariable model, male sex (hazard ratio (HR) = 2.07, 95% confidence interval (CI) = 1.51-2.83), white race (HR = 1.44, 95% CI = 1.03-2.01), history of pneumonia (HR = 3.09, 95% CI = 1.86-5.14), pack-years of smoking (HR = 1.006, 95% CI = 1.001-1.011), and percentage of predicted forced expiratory volume in 1 minute (moderate vs mild lung disease or normal lung function, HR = 1.78, 95% CI = 1.28-2.48; severe lung disease vs mild lung disease or normal lung function, HR = 2.90, 95% CI = 1.51-5.57) were nonmodifiable risk factors for pneumonia. Incident mobility limitation (HR = 1.77, 95% CI = 1.32-2.38) and higher mean oral plaque score (HR = 1.29, 95% CI = 1.02-1.64) were modifiable risk factors for pneumonia. Average attributable fractions revealed that 11.5% of cases of pneumonia were attributed to incident mobility limitation and 10.3% to a mean oral plaque score of 1 or greater. CONCLUSION: Incident mobility limitation and higher mean oral plaque score were two modifiable risk factors that 22% of pneumonia requiring hospitalization could be attributed to. These data suggest innovative opportunities for pneumonia prevention among community-dwelling older adults. C1 [Juthani-Mehta, Manisha; Quagliarello, Vincent] Yale Univ, Sch Med, Dept Internal Med, Infect Dis Sect, New Haven, CT 06520 USA. [De Rekeneire, Nathalie; Allore, Heather; Chen, Shu; O'Leary, John R.] Yale Univ, Sch Med, Dept Internal Med, Sect Geriatr, New Haven, CT 06520 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Yende, Sachin] Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA USA. [Weyant, Robert J.] Univ Pittsburgh, Sch Dent Med, Pittsburgh, PA USA. [Kritchevsky, Stephen] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. RP Juthani-Mehta, M (reprint author), Yale Univ, Sch Med, Dept Internal Med, Infect Dis Sect, POB 208022, New Haven, CT 06520 USA. EM manisha.juthani@yale.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781; Allore, Heather/0000-0001-7685-8175 FU National Institute on Aging (NIA) [R01 AG030575, K07 AG030093, K23 AG028691, R01-AG028050]; Claude D. Pepper Center Grant [P30 AG21342]; NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute of Nursing [R01-NR012459]; National Center for Research Resources [UL1 RR024139]; National Institutes of Health, NIA FX Funded by from the National Institute on Aging (NIA) Grants R01 AG030575 (VQ), K07 AG030093 (VQ), K23 AG028691 (MJM), R01-AG028050; Claude D. Pepper Center Grant P30 AG21342 (MJM, HGA); NIA Contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106; National Institute of Nursing Research Grant R01-NR012459; and Clinical and Translational Science Award Grant UL1 RR024139 from the National Center for Research Resources (MJM). This research was supported in part by the Intramural Research Program of the National Institutes of Health, NIA. NR 53 TC 13 Z9 13 U1 1 U2 5 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 2013 VL 61 IS 7 BP 1111 EP 1118 DI 10.1111/jgs.12325 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 297FT UT WOS:000330241800009 PM 23772872 ER PT J AU Rider, LG Shah, M Mamyrova, G Huber, AM Rice, MM Targoff, IN Miller, FW AF Rider, Lisa G. Shah, Mona Mamyrova, Gulnara Huber, Adam M. Rice, Madeline Murguia Targoff, Ira N. Miller, Frederick W. CA Childhood Myositis Heterogeneity C TI The Myositis Autoantibody Phenotypes of the Juvenile Idiopathic Inflammatory Myopathies SO MEDICINE LA English DT Article ID SIGNAL RECOGNITION PARTICLE; TRANSFER-RNA-SYNTHETASE; CLINICAL PHENOTYPES; JAPANESE PATIENTS; DERMATOMYOSITIS; ADULT; FEATURES; PROTEIN; PATHOGENESIS; ANTIBODIES AB The juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. In follow-up to our study defining the major clinical subgroup phenotypes of JIIM, we compared demographics, clinical features, laboratory measures, and outcomes among myositis-specific autoantibody (MSA) subgroups, as well as with published data on adult idiopathic inflammatory myopathy patients enrolled in a separate natural history study. In the present study, of 430 patients enrolled in a nationwide registry study who had serum tested for myositis autoantibodies, 374 had either a single specific MSA (n = 253) or no identified MSA (n = 121) and were the subject of the present report. Following univariate analysis, we used random forest classification and exact logistic regression modeling to compare autoantibody subgroups. Anti-p155/140 autoantibodies were the most frequent subgroup, present in 32% of patients with juvenile dermatomyositis (JDM) or overlap myositis with JDM, followed by anti-MJ autoantibodies, which were seen in 20% of JIIM patients, primarily in JDM. Other MSAs, including anti-synthetase, anti-signal recognition particle (SRP), and anti-Mi-2, were present in only 10% of JIIM patients. Features that characterized the anti-p155/140 autoantibody subgroup included Gottron papules, malar rash, "shawl-sign'' rash, photosensitivity, cuticular overgrowth, lowest creatine kinase (CK) levels, and a predominantly chronic illness course. The features that differed for patients with anti-MJ antibodies included muscle cramps, dysphonia, intermediate CK levels, a high frequency of hospitalization, and a monocyclic disease course. Patients with anti-synthetase antibodies had higher frequencies of interstitial lung disease, arthralgia, and "mechanic's hands,'' and had an older age at diagnosis. The anti-SRP group, which had exclusively juvenile polymyositis, was characterized by high frequencies of black race, severe onset, distal weakness, falling episodes, Raynaud phenomenon, cardiac involvement, high CK levels, chronic disease course, frequent hospitalization, and wheelchair use. Characteristic features of the anti-Mi-2 subgroup included Hispanic ethnicity, classic dermatomyositis and malar rashes, high CK levels, and very low mortality. Finally, the most common features of patients without any currently defined MSA or myositis-associated autoantibodies included linear extensor erythema, arthralgia, and a monocyclic disease course. Several demographic and clinical features were shared between juvenile and adult idiopathic inflammatory myopathy subgroups, but with several important differences. We conclude that juvenile myositis is a heterogeneous group of illnesses with distinct autoantibody phenotypes defined by varying clinical and demographic characteristics, laboratory features, and outcomes. C1 [Rider, Lisa G.; Shah, Mona; Mamyrova, Gulnara; Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, Program Clin Res, NIH,DHHS, Bethesda, MD 20892 USA. [Shah, Mona; Rice, Madeline Murguia] George Washington Univ, Sch Med, Dept Epidemiol & Biostat, Washington, DC USA. [Mamyrova, Gulnara] George Washington Univ, Sch Med, Dept Med, Div Rheumatol, Washington, DC USA. [Targoff, Ira N.] Univ Oklahoma, Hlth Sci Ctr, Vet Affairs Med Ctr, Oklahoma City, OK USA. Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Huber, Adam M.] IWK Hlth Ctr, Halifax, NS, Canada. [Huber, Adam M.] Dalhousie Univ, Halifax, NS, Canada. RP Rider, LG (reprint author), NIEHS, Environm Autoimmun Grp, NIH, DHHS, Clin Res Ctr Room 4-2352,10 Ctr Dr,MSC 1301, Bethesda, MD 20892 USA. EM riderl@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU NIEHS, NIH [ES101074]; NIAMS, NIH; CBER, Food and Drug Administration; Cure JM Foundation; Myositis Association FX This work was supported in part by the Intramural Research Programs of NIEHS, NIH (project number ES101074), NIAMS, NIH, and CBER, Food and Drug Administration. Gulnara Mamyrova was supported by the Cure JM Foundation and The Myositis Association. Ira Targoff is a consultant to the Oklahoma Medical Research Foundation Clinical Immunology Laboratory. NR 41 TC 40 Z9 43 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 EI 1536-5964 J9 MEDICINE JI Medicine (Baltimore) PD JUL PY 2013 VL 92 IS 4 BP 223 EP 243 DI 10.1097/MD.0b013e31829d08f9 PG 21 WC Medicine, General & Internal SC General & Internal Medicine GA 300KH UT WOS:000330462300005 PM 23877355 ER PT J AU Zusman, EE Heary, RF Stroink, AR Berger, MS Popp, AJ Friedlander, RM Martin, NA Lonser, RR Asthagiri, AR AF Zusman, Edie E. Heary, Robert F. Stroink, Ann R. Berger, Mitchel S. Popp, A. John Friedlander, Robert M. Martin, Neil A. Lonser, Russell R. Asthagiri, Ashok R. TI Philanthropy Funding for Neurosurgery Research and Program Development SO NEUROSURGERY LA English DT Article DE Donor; Fundraising; Philanthropy; Program development; Research funding ID WELLCOME-TRUST; PROJECTS; PEOPLE AB In times of fiscal and political uncertainty, philanthropy has become an increasingly important mechanism for building, maintaining, and expanding neurosurgical research programs. Although philanthropy has historically helped launch many hospital systems, scientists and clinicians have generally relied on government grants and industry investment to support research and program infrastructure. However, competition for funds from all sources has increased at the same time as the pipelines for those funds have eroded. Philanthropy can provide salary support to allow neurosurgeons to pursue research and, ultimately, advance the field to improve outcomes for patients. Funds raised can fill financial gaps to recruit and pay for needed research staff, equipment, and facilities. To foster charitable giving, institutions can develop both a culture and processes to promote and support philanthropy. Furthermore, it is essential to ensure that donor relationships are properly nurtured with ongoing stewardship. In addition to cultivating grateful patients, there are numerous creative models of fundraising for research that can be explored, including venture philanthropy, in which voluntary health organizations or individuals partner with academia and industry to invest in early-stage drug development and other innovations. Other approaches include formation of nonprofit foundations and partnerships with other entities to work jointly on shared development goals. C1 [Zusman, Edie E.] Sutter East Bay Neurosci Inst, Castro Valley, CA 94546 USA. [Heary, Robert F.] UMDNJ New Jersey Med Sch, Newark, NJ USA. [Stroink, Ann R.] Cent Illinois Neurohealth Sci, Bloomington, IL USA. [Berger, Mitchel S.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Popp, A. John] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA. [Friedlander, Robert M.] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15260 USA. [Martin, Neil A.] Univ Calif Los Angeles, Dept Neurol Surg, Los Angeles, CA USA. [Lonser, Russell R.; Asthagiri, Ashok R.] NIH, Bethesda, MD 20892 USA. RP Zusman, EE (reprint author), Sutter East Bay Neurosci Inst, 20055 Lake Chabot Rd,Suite 110, Castro Valley, CA 94546 USA. EM ZusmanE@sutterhealth.org RI Friedlander, Robert/A-2845-2016; OI Friedlander, Robert/0000-0003-4423-9219; Martin, Neil/0000-0002-6565-4131 NR 32 TC 1 Z9 1 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X EI 1524-4040 J9 NEUROSURGERY JI Neurosurgery PD JUL PY 2013 VL 73 IS 1 BP 177 EP 183 DI 10.1227/01.neu.0000429863.50018.f0 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 299FJ UT WOS:000330380900049 PM 23615103 ER PT J AU Arnone, JT Walters, AD Cohen-Fix, O AF Arnone, James T. Walters, Alison D. Cohen-Fix, Orna TI The dynamic nature of the nuclear envelope Lessons from closed mitosis SO NUCLEUS-AUSTIN LA English DT Article DE nuclear envelope; mitosis; nuclear membrane; checkpoint; nucleolus; nuclear envelope breakdown; nuclear morphology ID FISSION YEAST MEIOSIS; SPINDLE POLE BODY; PORE COMPLEX; ASPERGILLUS-NIDULANS; EMBRYO; SIZE AB In eukaryotes, chromosomes are encased by a dynamic nuclear envelope. In contrast to metazoans, where the nuclear envelope disassembles during mitosis, many fungi including budding yeast undergo "closed mitosis," where the nuclear envelope remains intact throughout the cell cycle. Consequently, during closed mitosis the nuclear envelope must expand to accommodate chromosome segregation to the two daughter cells. A recent study by Witkin et al. in budding yeast showed that if progression through mitosis is delayed, for example due to checkpoint activation, the nuclear envelope continues to expand despite the block to chromosome segregation. Moreover, this expansion occurs at a specific region of the nuclear envelope-adjacent to the nucleolus-forming an extension referred to as a "flare." These observations raise questions regarding the regulation of nuclear envelope expansion both in budding yeast and in higher eukaryotes, the mechanisms confining mitotic nuclear envelope expansion to a particular region and the possible consequences of failing to regulate nuclear envelope expansion during the cell cycle. C1 [Arnone, James T.; Walters, Alison D.; Cohen-Fix, Orna] Natl Inst Diabet & Digest & Kidney Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Cohen-Fix, O (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM ornac@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Rebecca Meseroll, John Hanover and Fred Chang for stimulating discussion and comments on the manuscript. The authors were supported by an intramural grant from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 28 TC 8 Z9 8 U1 1 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1949-1034 EI 1949-1042 J9 NUCLEUS-AUSTIN JI Nucleus-Austin PD JUL-AUG PY 2013 VL 4 IS 4 BP 261 EP 266 DI 10.4161/nucl.25341 PG 6 WC Cell Biology SC Cell Biology GA 299HF UT WOS:000330386100005 PM 23873576 ER PT J AU Thun, MJ Carter, BD Feskanich, D Freedman, ND Prentice, R Lopez, AD Hartge, P Gapstur, SM AF Thun, Michael J. Carter, Brian D. Feskanich, Diane Freedman, Neal D. Prentice, Ross Lopez, Alan D. Hartge, Patricia Gapstur, Susan M. TI 50-Year Trends in Smoking-Related Mortality in the United States EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material ID CESSATION C1 [Thun, Michael J.; Carter, Brian D.; Gapstur, Susan M.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [Feskanich, Diane] Harvard Univ, Brigham & Womens Hosp, Channing Div Network Med, Dept Med,Med Sch, Boston, MA 02115 USA. [Freedman, Neal D.; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Prentice, Ross] Fred Hutchison Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA USA. [Lopez, Alan D.] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. RP Thun, MJ (reprint author), Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. RI Freedman, Neal/B-9741-2015 OI Freedman, Neal/0000-0003-0074-1098 NR 3 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD JUL PY 2013 VL 68 IS 7 BP 516 EP 517 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 301DH UT WOS:000330512500011 ER PT J AU Boyle, A Reddy, UM Landy, HJ Huang, CC Driggers, RW Laughon, SK AF Boyle, Annelee Reddy, Uma M. Landy, Helain J. Huang, Chun-Chih Driggers, Rita W. Laughon, S. Katherine TI Primary Cesarean Delivery in the United States SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PATTERNS; BIRTH AB OBJECTIVES: To characterize the indications for primary cesarean delivery in a large national cohort and to identify opportunities to lower the U. S. primary cesarean delivery rate. METHODS: A retrospective cohort study of the 38,484 primary cesarean deliveries among the 228,562 deliveries at sites participating in the Consortium on Safe Labor from 2002 to 2008. RESULTS: The primary cesarean delivery rate was 30.8% for primiparous women and 11.5% for multiparous women. The most common indications for primary cesarean delivery were failure to progress (35.4%), non-reassuring fetal heart rate tracing (27.3%), and fetal malpresentation (18.5%), although frequencies for each indication varied by parity. Among women with failure to progress, 42.6% of primiparous women and 33.5% of multiparous women never progressed beyond 5 cm of dilation before delivery. Among women who reached the second stage of labor, 17.3% underwent cesarean delivery for arrest of descent before 2 hours and only 1.1% were given a trial of operative vaginal delivery. Of all primary cesarean deliveries, 45.6% were performed on primiparous women at term with a singleton fetus in cephalic presentation. CONCLUSION: Using 6 cm as the cut-off for active labor, allowing adequate time for the second stage of labor, and encouraging operative vaginal delivery, when appropriate, may be important strategies to reduce the primary cesarean delivery rate. These actions may be particularly important in the primiparous woman at term with a singleton fetus in cephalic presentation. C1 [Boyle, Annelee] MedStar Washington Hosp Ctr, Dept Obstet & Gynecol, Washington, DC 20010 USA. MedStar Georgetown Univ Hosp, Dept Obstet & Gynecol, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. MedStar Hlth Res Inst, Hyattsville, MD USA. RP Boyle, A (reprint author), MedStar Washington Hosp Ctr, Dept Obstet & Gynecol, 110 Irving St NW, Washington, DC 20010 USA. EM Annelee.C.Boyle@medstar.net OI Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C]; National Center for Research Resources [UL1RR031975]; National Center for Advancing Translational Science; National Institutes of Health, through the Clinical and Translational Science Awards Program, a trademark of the U.S. Department of Health and Human Services, part of the Roadmap Initiative, Reengineering the Clinical Research Enterprise FX From the Consortium on Safe Labor, which was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through contract number HHSN267200603425C. For a list of institutions involved in the Consortium on Safe Labor, see the Appendix online at http://links.lww.com/AOG/A396.; Funded in part with Federal funds (grant number UL1RR031975) from the National Center for Research Resources and the National Center for Advancing Translational Science, and the National Institutes of Health, through the Clinical and Translational Science Awards Program, a trademark of the U.S. Department of Health and Human Services, part of the Roadmap Initiative, Reengineering the Clinical Research Enterprise. NR 20 TC 34 Z9 34 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUL PY 2013 VL 122 IS 1 BP 33 EP 40 DI 10.1097/AOG.0b013e3182952242 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 301GC UT WOS:000330519800006 PM 23743454 ER PT J AU Bodnar, LM Rouse, DJ Momirova, V Peaceman, AM Sciscione, A Spong, CY Varner, MW Malone, FD Iams, JD Mercer, BM Thorp, JM Sorokin, Y Carpenter, MW Lo, J Ramin, SM Harper, M AF Bodnar, Lisa M. Rouse, Dwight J. Momirova, Valerija Peaceman, Alan M. Sciscione, Anthony Spong, Catherine Y. Varner, Michael W. Malone, Fergal D. Iams, Jay D. Mercer, Brian M. Thorp, John M., Jr. Sorokin, Yoram Carpenter, Marshall W. Lo, Julie Ramin, Susan M. Harper, Margaret CA Eunice Kennedy Shriver Natl Inst TI Maternal 25-Hydroxyvitamin D and Preterm Birth in Twin Gestations SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID VITAMIN-D DEFICIENCY; BACTERIAL VAGINOSIS; PREGNANCY OUTCOMES; HIGH-RISK; WOMEN; INSUFFICIENCY; ASSOCIATION; PREVALENCE AB OBJECTIVE: To assess whether there was an independent association between maternal 25-hydroxyvitamin D concentrations at 24-28 weeks of gestation and preterm birth in a multicenter U. S. cohort of twin pregnancies. METHODS: Serum samples from women who participated in a clinical trial of 17 alpha-hydroxyprogesterone caproate for the prevention of preterm birth in twin gestations (2004-2006) were assayed for 25-hydroxyvitamin D concentrations using liquid chromatography tandem mass spectrometry (n=211). Gestational age was determined early in pregnancy using a rigorous algorithm. Preterm birth was defined as delivery of the first twin or death of either twin at less than 35 weeks of gestation. RESULTS: The mean serum 25-hydroxyvitamin D concentration was 82.7 nmol/L (standard deviation 31.5); 40.3% of women had concentrations less than 75 nmol/L. Preterm birth at less than 35 weeks of gestation occurred in 49.4% of women with 25-hydroxyvitamin D concentrations less than 75 nmol/L compared with 26.2% among those with concentrations of 75 nmol/L or more (P<.001). After adjustment for maternal race and ethnicity, study site, parity, prepregnancy body mass index, season, marital status, education, gestational age at blood sampling, smoking status, and 17 alpha-hydroxyprogesterone caproate treatment, maternal 25-hydroxyvitamin D concentration of 75 nmol/L or more was associated with a 60% reduction in the odds of preterm birth compared with concentrations less than 75 nmol/L (adjusted odds ratio [OR] 0.4, 95% confidence interval [CI] 0.2-0.8). A similar protective association was observed when studying preterm birth at less than 32 weeks of gestation (OR 0.2, 95% CI 0.1-0.6) and after confounder adjustment. CONCLUSIONS: Late second-trimester maternal 25-hydroxyvitamin D concentrations less than 75 nmol/L are associated with an increase in the risk of preterm birth in this cohort of twin pregnancies. C1 Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA 15261 USA. Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. Northwestern Univ, Dept Epidemiol, Chicago, IL 60611 USA. Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Drexel Univ, Dept Epidemiol, Philadelphia, PA 19104 USA. Drexel Univ, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. Univ Utah, Dept Epidemiol, Salt Lake City, UT USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. Columbia Univ, Dept Epidemiol, New York, NY USA. Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. Ohio State Univ, Dept Epidemiol, Columbus, OH 43210 USA. Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Case Western Reserve Univ, Metrohlth Med Ctr, Dept Epidemiol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Metrohlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. Wayne State Univ, Dept Epidemiol, Detroit, MI USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. Univ Texas SW Med Ctr Dallas, Dept Epidemiol, Dallas, TX 75390 USA. Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol, Houston, TX 77030 USA. Univ Texas Hlth Sci Ctr Houston, Dept Obstet & Gynecol, Houston, TX 77030 USA. Wake Forest Univ Hlth Sci, Dept Epidemiol, Winston Salem, NC USA. Wake Forest Univ Hlth Sci, Dept Obstet & Gynecol, Winston Salem, NC USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Bodnar, LM (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, 130 DeSoto St,A742 Crabtree Hall, Pittsburgh, PA 15261 USA. EM bodnar@edc.pitt.edu RI Varner, Michael/K-9890-2013 OI Peaceman, Alan/0000-0002-4515-4850; Varner, Michael/0000-0001-9455-3973 FU National Institutes of Health [R01 HD056999]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD27869, HD21410, HD40512, HD34136, HD34208, HD40485, HD27915, HD40544, HD40560, HD27917, HD40500, HD34116, HD40545, HD27860, HD36801]; National Center for Research Resources [M01 RR00080, UL1 RR024989] FX Supported by National Institutes of Health grant R01 HD056999 (Principal Investigator: Bodnar) and by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD27869, HD21410, HD40512, HD34136, HD34208, HD40485, HD27915, HD40544, HD40560, HD27917, HD40500, HD34116, HD40545, HD27860, HD36801) and the National Center for Research Resources (M01 RR00080, UL1 RR024989), and its contents do not necessarily represent the official view of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Heart, Lung, and Blood Institute, National Center for Research Resources, or National Institutes of Health. NR 33 TC 16 Z9 17 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUL PY 2013 VL 122 IS 1 BP 91 EP 98 DI 10.1097/AOG.0b013e3182941d9a PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 301GC UT WOS:000330519800014 PM 23743453 ER PT J AU Cabarcas, SM Sun, L Mathews, L Thomas, S Zhang, XH Farrar, WL AF Cabarcas, Stephanie M. Sun, Lei Mathews, Lesley Thomas, Suneetha Zhang, Xiaohu Farrar, William L. TI The Differentiation of Pancreatic Tumor-Initiating Cells by Vitronectin Can Be Blocked by Cilengitide SO PANCREAS LA English DT Article DE pancreatic cancer; TICs; vitronectin; differentiation; Cilengitide ID CANCER STEM-CELLS; DUCTAL ADENOCARCINOMA; INTEGRIN ANTAGONISTS; SIGNALING NETWORK; PROGENITOR CELLS; IDENTIFICATION; CARCINOMA; EXPRESSION; ADHESION; TARGET AB Objective: Pancreatic cancer is a leading cancer type and its molecular pathology is poorly understood. The only potentially curative therapeutic option available is complete surgical resection; however, this is inadequate as most of the patients are diagnosed at an advanced or metastatic stage. Tumor-initiating cells (TICs) constitute a subpopulation of cells within a solid tumor that sustain tumor growth, metastasis, and chemo/radioresistance. Within pancreatic cancer, TICs have been identified based on the expression of specific cell surface markers. Methods: We use a sphere formation assay to enrich putative TICs and use human serum as a driver of differentiation. We demonstrate by using specific blocking reagents that we can inhibit the differentiation process and maintain TIC-associated markers and genes. Results: We can induce differentiation of pancreatospheres with the addition of human serum, and we identified vitronectin as an inducer of differentiation. We inhibit differentiation by human serum using an arginine-glycine-aspartate-specific peptide, which is Cilengitide; hence, demonstrating this differentiation is mediated via specific integrin receptors. Conclusions: Overall, our studies further the definition of pancreatic TICs and provide further insight into both the maintenance and differentiation of this lethal population. C1 [Cabarcas, Stephanie M.; Sun, Lei; Farrar, William L.] Frederick Natl Lab Canc Res, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD USA. [Mathews, Lesley] Natl Human Genome Res Inst, Natl Ctr Translat Therapeut, Natl Chem Genom Ctr, Rockville, MD USA. [Thomas, Suneetha] MedImmune, Gaithersburg, MD USA. [Zhang, Xiaohu] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Cabarcas, SM (reprint author), Gannon Univ, Dept Biol, 109 Univ Sq, Erie, PA 16541 USA. EM cabarcas002@gannon.edu RI Sun, Lei/J-9943-2015 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This study was supported in whole or in part with federal funds by the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E, and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views of 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 54 TC 1 Z9 1 U1 0 U2 3 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 2013 VL 42 IS 5 BP 861 EP 870 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 301IF UT WOS:000330525300016 PM 23462327 ER PT J AU Hazra, R Hance, LF Monteiro, JP Ruz, NP Machado, DM Saavedra, M Motta, F Harris, DR AF Hazra, Rohan Hance, Laura Freimanis Monteiro, Jacqueline Pontes Ruz, Noris Pavia Machado, Daisy Maria Saavedra, Mariza Motta, Fabrizio Harris, D. Robert CA NISDI Pediat Study Grp TI Insulin Resistance and Glucose and Lipid Concentrations in a Cohort of Perinatally HIV-infected Latin American Children SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE insulin resistance; pediatric; HIV; antiretroviral therapy ID METABOLIC ABNORMALITIES; ANTIRETROVIRAL THERAPY; YOUNG-ADULTS; ADOLESCENTS; LIPODYSTROPHY; YOUTH AB We measured glucose, insulin and lipids in 249 perinatally HIV-infected Latin American children. Only 1 subject had impaired fasting glucose; 6.8% had insulin resistance. Abnormalities in total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were reported for 13%, 13%, 21% and 34%, respectively. Continued follow-up of this population is necessary to characterize the evolution and clinical consequences of these findings. C1 [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Hance, Laura Freimanis; Harris, D. Robert] WESTAT Corp, Rockville, MD 20850 USA. [Monteiro, Jacqueline Pontes] Univ Sao Paulo, BR-14049 Ribeirao Preto, SP, Brazil. [Ruz, Noris Pavia] Hosp Infantil Mexico Dr Federico Gomez, Mexico City, DF, Mexico. [Machado, Daisy Maria] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Saavedra, Mariza] Hosp Fed Servidores Estado, Rio De Janeiro, Brazil. [Motta, Fabrizio] Irmandade Santa Casa Misericordia Porto Alegre, Porto Alegre, RS, Brazil. RP Hazra, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, 6100 Execut Blvd,Room 4B11, Bethesda, MD 20892 USA. EM hazrar@mail.nih.gov FU NICHD [HHSN267200800001C, N01-HD-8-0001] FX Supported by NICHD Contract # HHSN267200800001C (NICHD Control # N01-HD-8-0001). The authors have no other funding or conflicts of interest to disclose. NR 10 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JUL PY 2013 VL 32 IS 7 BP 757 EP 759 DI 10.1097/INF.0b013e318286c774 PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 300QO UT WOS:000330478800020 PM 23360832 ER PT J AU Shrivastava, S TrehanPati, N Kottilil, S Sarin, SK AF Shrivastava, Shikha TrehanPati, Nirupama Kottilil, Shyam Sarin, Shiv Kumar TI DECLINE IN IMMATURE TRANSITIONAL B CELLS AFTER HEPATITIS B VACCINATION IN HEPATITIS B POSITIVE NEWBORNS SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE transitional B cells; hepatitis B virus positive newborns; hepatitis B virus vaccine ID VIRUS-INFECTIONS; TRANSMISSION; PREVENTION; IMMUNITY; CHILDREN AB Humoral immune responses are protective against hepatitis B virus (HBV) infection. We characterized B-cell phenotypic changes in infants of hepatitis B surface antigen positive mothers compared with normal and hepatitis B surface antigen negative infants at birth and 1 year after HBV immunization. Hepatitis B surface antigen positive infants had higher immature transitional B cells at birth, which normalized a year after immunization. Immature B-cell response to neonatal HBV exposure is associated with maternal-child transmission of HBV. C1 [Shrivastava, Shikha; TrehanPati, Nirupama] Inst Liver & Biliary Sci, Dept Res, New Delhi 110070, India. [Shrivastava, Shikha; Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Sarin, Shiv Kumar] Inst Liver & Biliary Sci, Dept Hepatol, New Delhi 110070, India. RP Sarin, SK (reprint author), Inst Liver & Biliary Sci, Dept Hepatol, New Delhi 110070, India. EM shivsarin@gmail.com OI Sarin, Shiv Kumar/0000-0002-0544-5610 FU Department of Biotechnology [BT/PR7647/MED/14/1053/2006]; Reproductive Health and Nutrition Department, Indian Council of Medical Research, India [3/1/2/26/2010-RHN] FX This study was supported by the grant from Department of Biotechnology (sanction letter no. BT/PR7647/MED/14/1053/2006), and S.S. was awarded with Senior Research fellowship for 3/1/2/26/2010-RHN conducting this work from Reproductive Health and Nutrition Department, Indian Council of Medical Research, India. The authors have no other funding or conflicts of interest to disclose. NR 10 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JUL PY 2013 VL 32 IS 7 BP 792 EP 794 DI 10.1097/INF.0b013e31828df344 PG 4 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 300QO UT WOS:000330478800027 PM 23838779 ER PT J AU Lu, DY Lu, TR Zhu, PP AF Lu, Da-Yong Lu, Ting-Ren Zhu, Peng-Peng TI Pharmacogenetics in neural toxicities of drugs SO PHARMACOGENOMICS LA English DT Editorial Material ID INDUCED MANIA; SUICIDE; CHILD; RISK C1 [Lu, Da-Yong] Shanghai Univ, Sch Life Sci, Shanghai 200444, Peoples R China. [Lu, Ting-Ren] Shanghai Univ, Coll Sci, Shanghai 200444, Peoples R China. [Zhu, Peng-Peng] NINDS, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. RP Lu, DY (reprint author), Shanghai Univ, Sch Life Sci, Shanghai 200444, Peoples R China. EM ludayong@sh163.net NR 18 TC 0 Z9 2 U1 2 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 EI 1744-8042 J9 PHARMACOGENOMICS JI Pharmacogenomics PD JUL PY 2013 VL 14 IS 10 BP 1129 EP 1131 DI 10.2217/PGS.13.103 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 299DQ UT WOS:000330375800003 PM 23859566 ER PT J AU Eisenberger, NI AF Eisenberger, Naomi I. TI An Empirical Review of the Neural Underpinnings of Receiving and Giving Social Support: Implications for Health SO PSYCHOSOMATIC MEDICINE LA English DT Review DE social support; health; functional magnetic resonance imaging; social neuroscience; brain; neural; fMRI ID ANTERIOR CINGULATE CORTEX; SEPTAL-FOREBRAIN LESIONS; VENTRAL TEGMENTAL AREA; MATERNAL-BEHAVIOR; CARDIOVASCULAR REACTIVITY; CENTRAL NUCLEUS; PHYSIOLOGICAL PROCESSES; POSITIVE REINFORCEMENT; SUBJECTIVE RESPONSES; PSYCHOSOCIAL STRESS AB Decades of research have demonstrated strong links between social ties and health. Although considerable evidence has shown that social support can attenuate downstream physiological stress responses that are relevant to health, the neurocognitive mechanisms that translate perceptions of social ties into altered physiological responses are still not fully understood. This review integrates research from social and affective neuroscience to illuminate some of the neural mechanisms involved in social support processes, which may further our understanding of the ways in which social support influences health. This review focuses on two types of social support that have been shown to relate to health: receiving and giving social support. As the neural basis of receiving support, this article reviews the hypothesis that receiving support may benefit health through the activation of neural regions that respond to safety and inhibit threat-related neural and physiological responding. This article will then review neuroimaging studies in which participants were primed with or received support during a negative experience as well as studies in which self-reports of perceived support were correlated with neural responses to a negative experience. As the neural basis of giving support, this article reviews the hypothesis that neural regions involved in maternal caregiving behavior may be critical for the health benefits of support-giving through the inhibition of threat-related neural and physiological responding. Neuroimaging studies in which participants provided support to others or engaged in other related forms of prosocial behavior will then be reviewed. Implications of these findings for furthering our understanding of the relationships between social support and health are discussed. C1 [Eisenberger, Naomi I.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Eisenberger, Naomi I.] SAIC Frederick Inc, Clin Res Directorate, CMRP, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Eisenberger, NI (reprint author), UCLA Psych Soc, Box 951563,4444 Franz Hall, Los Angeles, CA 90095 USA. EM neisenbe@ucla.edu FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institutes of Mental Health [R01MH091352]; National Alliance for Research on Schizophrenia and Depression FX This project was funded, in part, with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This project was also supported by a grant from the National Institutes of Mental Health (R01MH091352) and a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression. The author has no financial gain related to the outcome of this research, and there are no potential conflicts of interest. NR 151 TC 22 Z9 24 U1 5 U2 45 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD JUL-AUG PY 2013 VL 75 IS 6 BP 545 EP 556 DI 10.1097/PSY.0b013e31829de2e7 PG 12 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 300MS UT WOS:000330468600005 PM 23804014 ER PT J AU Gangaputra, S Lovato, JF Hubbard, L Davis, MD Esser, BA Ambrosius, WT Chew, EY Greven, C Perdue, LH Wong, WT Condren, A Wilkinson, CP Agron, E Adler, S Danis, RP AF Gangaputra, Sapna Lovato, James F. Hubbard, Larry Davis, Matthew D. Esser, Barbara A. Ambrosius, Walter T. Chew, Emily Y. Greven, Craig Perdue, Letitia H. Wong, Wai T. Condren, Audree Wilkinson, Charles P. Agron, Elvira Adler, Sharon Danis, Ronald P. CA ACCORD Eye Res Grp TI COMPARISON OF STANDARDIZED CLINICAL CLASSIFICATION WITH FUNDUS PHOTOGRAPH GRADING FOR THE ASSESSMENT OF DIABETIC RETINOPATHY AND DIABETIC MACULAR EDEMA SEVERITY SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE ACCORD; FIND; diabetic retinopathy; fundus photography ID OPHTHALMOSCOPY; AGREEMENT; DISEASE AB Purpose: To compare evaluation by clinical examination with image grading at a reading center for the classification of diabetic retinopathy and diabetic macular edema. Methods: Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Family Investigations of Nephropathy in Diabetes (FIND) had similar methods of clinical and fundus photograph evaluation. For analysis purposes, the photographic grading scales were condensed to correspond to the clinical scales, and agreement between clinicians and reading center classification were compared. Results: Six thousand nine hundred and two eyes of ACCORD participants and 3,638 eyes of FIND participants were analyzed for agreement (percent, kappa) on diabetic retinopathy on a 5-level scale. Exact agreement between clinicians and reading center on diabetic retinopathy severity category was 69% in ACCORD and 74% in FIND (kappa 0.42 and 0.65). Sensitivities of the clinical grading to identify the presence of mild non-proliferative retinopathy or worse were 0.53 in ACCORD and 0.84 in FIND. Specificities were 0.97 and 0.96, respectively. Diabetic macular edema agreement in 6,649 eyes of ACCORD participants and 3,366 eyes of FIND participants was similar (kappa 0.35 and 0.41). Sensitivities of the clinical grading to identify diabetic macular edema were 0.44 and 0.53 and specificities were 0.99 and 0.94, respectively. Conclusion: The results support the use of clinical information for defining broad severity categories but not for documenting small-to-moderate changes in diabetic retinopathy over time. C1 [Gangaputra, Sapna; Hubbard, Larry; Davis, Matthew D.; Esser, Barbara A.; Danis, Ronald P.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Fundus Photograph Reading Ctr, Madison, WI 53717 USA. [Lovato, James F.; Ambrosius, Walter T.; Perdue, Letitia H.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Chew, Emily Y.; Wong, Wai T.; Condren, Audree; Agron, Elvira] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Greven, Craig] Wake Forest Sch Med, Dept Ophthalmol, Winston Salem, NC USA. [Wilkinson, Charles P.] Greater Baltimore Med Ctr, Baltimore, MD USA. [Wilkinson, Charles P.] Johns Hopkins Univ, Baltimore, MD USA. [Adler, Sharon] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, David Geffen Sch Med, Div Nephrol & Hypertens, Torrance, CA 90509 USA. RP Danis, RP (reprint author), Univ Wisconsin, Deptartment Ophthalmol & Visual Sci, Fundus Photograph Reading Ctr, 8010 Excelsior Dr,Suite 100, Madison, WI 53717 USA. EM rpdanis@wisc.edu RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute [M01-RR00425, R01-DK0069844, N01-HC-95178] FX Supported by the National Eye Institute Intramural Research Program, Sharon Adler: GCRC grant M01-RR00425. FIND grant R01-DK0069844, ACCORD grant N01-HC-95178. NR 19 TC 6 Z9 6 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD JUL-AUG PY 2013 VL 33 IS 7 BP 1393 EP 1399 PG 7 WC Ophthalmology SC Ophthalmology GA 300NN UT WOS:000330470700012 PM 23615341 ER PT J AU Holz, LE Yoon, JC Raghuraman, S Moir, S Sneller, MC Rehermann, B AF Holz, Lauren E. Yoon, Joo Chun Raghuraman, Sukanya Moir, Susan Sneller, Michael C. Rehermann, Barbara TI Reply: B-cell Frequency in HCV-Related Mixed Cryoglobulinemia SO HEPATOLOGY LA English DT Letter ID HEPATITIS-C VIRUS; HOMEOSTASIS; LYMPHOCYTES; NAIVE C1 [Holz, Lauren E.] NIDDKD, Liver Dis Branch, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, US Dept HHS, Bethesda, MD 20892 USA. RP Holz, LE (reprint author), NIDDKD, Liver Dis Branch, Bethesda, MD 20892 USA. RI Yoon, Joo Chun/D-3675-2012 OI Yoon, Joo Chun/0000-0001-9395-8418 NR 8 TC 0 Z9 0 U1 0 U2 2 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 2013 VL 58 IS 1 BP 448 EP 449 DI 10.1002/hep.26112 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 296IU UT WOS:000330179300048 PM 23111813 ER PT J AU Wilson, E Tanzosh, T Maldarelli, F AF Wilson, E. Tanzosh, T. Maldarelli, F. TI HIV diagnosis and testing: what every healthcare professional can do (and why they should) SO ORAL DISEASES LA English DT Review DE HIV; diagnosis; testing ID IMMUNODEFICIENCY-VIRUS TYPE-1; FOR-DISEASE-CONTROL; ACTIVE ANTIRETROVIRAL THERAPY; 2006 CDC RECOMMENDATIONS; UNITED-STATES; INFECTED INDIVIDUALS; SEXUAL TRANSMISSION; ANTIBODY TESTS; HIGH-RISK; GROUP-N AB Over the last thirty years, the human immunodeficiency virus (HIV) epidemic has matured. In the United States, HIV has changed from an explosive outbreak to an endemic disease; currently, an estimated 1.1 million people are infected with HIV, including a substantial number who are unaware of their status. With recent findings demonstrating the high transmissibility of HIV early in infection, and the potential benefit of early initiation of treatment, it is essential to identify as many infected individuals as possible. The Centers for Disease Control and Prevention (CDC) has expanded HIV testing to include any healthcare setting, including dental offices. Testing advances, including oral testing, have reduced the window period of HIV infection. Dental care represents a key, reliable, independent, and confidential link between the healthcare system and the general population that has been under-utilized in the effort to control the HIV epidemic. HIV testing is straightforward, and knowledge of the types of testing will afford dentists an important opportunity to help advance and preserve the health of their patients and to promote the public health of their community. Here, we review the basics of HIV testing and discuss new changes in the approach to HIV diagnostics. C1 [Wilson, E.; Tanzosh, T.; Maldarelli, F.] NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. RP Maldarelli, F (reprint author), NCI, HIV Drug Resistance Program, NIH, 9000 Rockville Pike,Bldg 10 Rm 5A06, Bethesda, MD 20892 USA. EM fmalli@mail.nih.gov OI Wilson, Eleanor/0000-0002-4855-514X NR 64 TC 2 Z9 3 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD JUL PY 2013 VL 19 IS 5 BP 431 EP 439 DI 10.1111/odi.12047 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 296LQ UT WOS:000330186900001 PM 23347510 ER PT J AU Kacker, S Frick, KD Quinn, TC Gray, RH Tobian, AAR AF Kacker, Seema Frick, Kevin D. Quinn, Thomas C. Gray, Ronald H. Tobian, Aaron A. R. TI Financial Implications of Male Circumcision Scale-Up for the Prevention of HIV and Other Sexually Transmitted Infections in a Sub-Saharan African Community SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; HUMAN-PAPILLOMAVIRUS; HPV-16,18 VACCINATION; YOUNG MEN; RISK; UGANDA; TRANSMISSION; RAKAI; METAANALYSIS; SYPHILIS AB Background: The financial implications of male circumcision ( MC) scale-up in sub-Saharan Africa associated with reduced HIV have been evaluated. However, no analysis has incorporated the expected reduction of a comprehensive set of other sexually transmitted infections including human papillomavirus, herpes simplex virus type 2, genital ulcer disease, bacterial vaginosis, and trichomoniasis. Methods: A Markov model tracked a dynamic population undergoing potential MC scale-up, as individuals experienced MC procedures, procedure-related adverse events, and MC-reduced sexually transmitted infections and accrued any associated costs. Rakai, Uganda, was used as a prototypical rural sub-Saharan African community. Monte Carlo microsimulations evaluated outcomes under 4 alternative scale-up strategies to reach 80% MC coverage among men aged 15 to 49 years, in addition to a baseline strategy defined by current MC rates in central Uganda. Financial outcomes included direct medical expenses only and were evaluated over 5 and 25 years. Costs were discounted to the beginning of each period, coinciding with the start of MC scale-up, and expressed in US$2012. Results: Cost savings from infections averted by MC vary from US$197,531 after 5 years of a scale-up program focusing on adolescent/adult procedures to more than US$13 million after 25 years, under a strategy incorporating increased infant MCs. Over a 5-year period, reduction in HIV contributes to 50% of cost savings, and for 25 years, this contribution rises to nearly 90%. Conclusions: Sexually transmitted infections other than HIV contribute to cost savings associated with MC scale-up. Previous analyses, focusing exclusively on the financial impact through averted HIV, may have underestimated true cost savings by 10% to 50%. C1 [Kacker, Seema; Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Frick, Kevin D.] Johns Hopkins Univ, Dept Hlth Policy & Management, Bloomberg Sch Publ Hlth, Baltimore, MD 21287 USA. [Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Gray, Ronald H.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21287 USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Carnegie 437,600 N Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU Doris Duke Charitable Foundation [22006.02]; National Institutes of Health [1K23AI093152-01A1] FX S.K. and A.A.R.T. were supported by the Doris Duke Charitable Foundation Clinician Scientist Development Award (No. 22006.02), and A. A. R. T was supported by the National Institutes of Health 1K23AI093152-01A1. NR 39 TC 5 Z9 5 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 EI 1537-4521 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD JUL PY 2013 VL 40 IS 7 BP 559 EP 568 DI 10.1097/OLQ.0b013e3182945e56 PG 10 WC Infectious Diseases SC Infectious Diseases GA 297FC UT WOS:000330240000009 PM 23965771 ER PT J AU Konda, KA Lescano, AG Celentano, DD Hall, E Montano, SM Kochel, TJ Coates, TJ Caceres, CF AF Konda, Kelika A. Lescano, Andres G. Celentano, David D. Hall, Eric Montano, Silvia M. Kochel, Tadeusz J. Coates, Thomas J. Caceres, Carlos F. CA NIMH Collaborative HIV STD TI In Peru, Reporting Male Sex Partners Imparts Significant Risk of Incident HIV/Sexually Transmitted Infection: All Men Engaging in Same-Sex Behavior Need Prevention Services SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID HETEROSEXUALLY-IDENTIFIED MEN; URBAN COASTAL PERU; BISEXUAL MEN; LOW-INCOME; HIV TRANSMISSION; LATINO MEN; WOMEN; GAY; SYPHILIS; HEALTH AB Background: Detailed information on the sexual behavior of bisexual, non-gay-identified men and the relationship between same-sex behavior and HIV/sexually transmitted infection (STI) incidence is limited. This study provides information on the sexual behavior with male partners of non-gay-identified men in urban, coastal Peru and the relationship of this behavior with HIV/STI incidence. Methods: We analyzed data from 2146 non-gay-identified men with a baseline and then 2 years of annual follow-up, including detailed information on sexual behavior with up to 5 sex partners, to determine the characteristics associated with bisexual behavior. Discrete time proportional hazards models were used to determine the effect of self-reported sex with men on subsequent HIV/STI incidence. Results: Over the 3 study visits, sex with a man was reported by 18.9% of men, 90% of whom also reported sex with a female partner. At baseline, reported bisexual behavior was associated with other sexual risk behaviors such as exchanging sex for money and increased risk of HIV, herpes simplex virus type 2, and gonorrhea. The number of study visits in which recent sex with men was reported was positively correlated with risk of other sexual risk behaviors and incident HIV, herpes simplex virus type 2, and gonorrhea. Recent sex with a man was associated with increased HIV/STI incidence (hazard ratio, 1.79; confidence interval, 1.19-2.70), after adjusting for sociodemographics and other sexual risk behaviors. Conclusions: Given the prevalence of recent sex with men and the relationship of this behavior with HIV/STI incidence, interventions with non-gay-identified men who have sex with men and their partners are warranted. C1 [Konda, Kelika A.; Celentano, David D.; Coates, Thomas J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Konda, Kelika A.] Univ Calif Los Angeles, David Geffen Sch Med, Div Infect Dis, Los Angeles, CA 90095 USA. [Lescano, Andres G.] US Naval Med Res Ctr Detachment, Dept Parasitol, Lima, Peru. [Lescano, Andres G.] Univ Peruana Cayetano Heredia, Fac Salud Publ & Adm, Lima, Peru. [Hall, Eric] Naval Med Res Ctr, Bethesda, MD USA. [Montano, Silvia M.] US Naval Med Res Ctr Detachment, Dept Bacteriol, Lima, Peru. [Kochel, Tadeusz J.] US Naval Med Res Ctr Detachment, Dept Virol, Lima, Peru. [Caceres, Carlos F.] Univ Peruana Cayetano Heredia, Fac Salud Publ, Lima, Peru. [NIMH Collaborative HIV STD] NIMH, Bethesda, MD 20892 USA. RP Konda, KA (reprint author), C Diez Canseco 333,Oficina 1, Lima 18, Peru. EM kkonda@jhsph.edu RI Lescano, Andres/B-8479-2008; OI Lescano, Andres/0000-0001-9779-633X; Caceres, Carlos/0000-0002-8101-0790 FU National Institutes of Health (NIH)/NIMH [U10 MH61536]; NIMH [F31 MH084765, T32MH080634]; Fogarty International Center of the US NIH [NIH/FIC 2D43 TW007393] FX This study was funded by National Institutes of Health (NIH)/NIMH Grant No. U10 MH61536, which was a 5-country Cooperative Agreement being conducted in China, India, Peru, Russia, and Zimbabwe. K. A. K. was supported by NIMH F31 MH084765 and NIMH T32MH080634. The participation of Dr Lescano in this project is sponsored by the Training Grant NIH/FIC 2D43 TW007393 awarded to NAMRU-6 by the Fogarty International Center of the US NIH. NR 31 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 EI 1537-4521 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD JUL PY 2013 VL 40 IS 7 BP 569 EP 574 DI 10.1097/OLQ.0b013e3182956eeb PG 6 WC Infectious Diseases SC Infectious Diseases GA 297FC UT WOS:000330240000010 PM 23965772 ER PT J AU Post, MJD Thurnher, MM Clifford, DB Nath, A Gonzalez, RG Gupta, RK Post, KK AF Post, M. J. D. Thurnher, M. M. Clifford, D. B. Nath, A. Gonzalez, R. G. Gupta, R. K. Post, K. K. TI CNS-Immune Reconstitution Inflammatory Syndrome in the Setting of HIV Infection, Part 1: Overview and Discussion of Progressive Multifocal Leukoencephalopathy-Immune Reconstitution Inflammatory Syndrome and Cryptococcal-Immune Reconstitution Inflammatory Syndrome SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Review ID ACTIVE ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS-INFECTION; CENTRAL-NERVOUS-SYSTEM; OF-THE-LITERATURE; RISK-FACTORS; AIDS PATIENTS; CLINICAL-MANIFESTATIONS; MULTIPLE-SCLEROSIS; PROLONGED SURVIVAL; FOLLOW-UP AB While uncommon, CNS-IRIS developing after the initiation of HAART in the setting of HIV-related severe immunosuppression is characterized by an intense inflammatory reaction to dead or latent organisms or to self-antigens due to a heightened but dysregulated immune response. While this reaction can range from mild to fulminating, encompassing a very wide clinical spectrum, it is important to recognize because changes in medical management may be necessary to prevent neurologic decline and even death. Once contained, however, this inflammatory response can be associated with improved patient outcome as immune function is restored. Among the infectious organisms that are most commonly associated with CNS-IRIS are the JC virus and Cryptococcus organisms, which will be the subject of this review. CD8 cell infiltration in the leptomeninges, perivascular spaces, blood vessels, and even parenchyma seems to be the pathologic hallmark of CNS-IRIS. While recognition of CNS-IRIS may be difficult, the onset of new or progressive clinical symptoms, despite medical therapy and despite improved laboratory data, and the appearance on neuroimaging studies of contrast enhancement, interstitial edema, mass effect, and restricted diffusion in infections not typically characterized by these findings in the untreated HIV-infected patient should raise the strong suspicion for CNS-IRIS. While CNS-IRIS is a diagnosis of exclusion, the neuroradiologist can play a critical role in alerting the clinician to the possibility of this syndrome. C1 [Post, M. J. D.] Univ Miami, Miller Sch Med, Jackson Mem Med Ctr, Sect Neuroradiol,Dept Radiol, Miami, FL 33136 USA. [Thurnher, M. M.] Univ Vienna, Dept Radiol, Univ Hosp Vienna, Vienna, Austria. [Clifford, D. B.] Washington Univ, Dept Neurol, St Louis, MO USA. [Nath, A.] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Gonzalez, R. G.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Gonzalez, R. G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gupta, R. K.] Sanjay Gandhi Postgrad Inst Med Sci, Dept Radiol, Lucknow, Uttar Pradesh, India. [Post, K. K.] UMass Mem Med Ctr, Dept Internal Med, Worcester, MA USA. RP Post, MJD (reprint author), Univ Miami, Miller Sch Med, Jackson Mem Med Ctr, Sect Neuroradiol,Dept Radiol, West Wing 279,1611 NW 12th Ave, Miami, FL 33136 USA. EM jpost@med.miami.edu FU Millennium; Genentech FX Majda Thurnher-UNRELATED: Royalties: Amirsys. David Clifford-UNRELATED: Consultancy: All <$10,000 annually: Biogen Idec, Genentech, Millennium, Genzyme, Bristol Myers Squibb, Pfizer, Janssen, Expert Testimony: Biogen Idec, Comments: European Medicines Agency (EMA) discussion of natalizumab, Payment for Development of Educational Presentations: Millennium, payment for teaching video on exam for PML; Genentech, payment for teaching video on PML diagnosis, Other: Millennium, Independent Adjudication Committee, Genzyme, Data Monitoring Committee, Chair; Genentech, Panel of Experts, Translational Immunology Consultant; Pfizer, Data Safety Monitoring Committee (DSMB). NR 99 TC 12 Z9 12 U1 0 U2 3 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JUL PY 2013 VL 34 IS 7 BP 1297 EP 1307 DI 10.3174/ajnr.A3183 PG 11 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 290DZ UT WOS:000329734800007 PM 22790246 ER PT J AU Post, MJD Thurnher, MM Clifford, DB Nath, A Gonzalez, RG Gupta, RK Post, KK AF Post, M. J. D. Thurnher, M. M. Clifford, D. B. Nath, A. Gonzalez, R. G. Gupta, R. K. Post, K. K. TI CNS-Immune Reconstitution Inflammatory Syndrome in the Setting of HIV Infection, Part 2: Discussion of Neuro-Immune Reconstitution Inflammatory Syndrome with and without Other Pathogens SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Review ID ACTIVE ANTIRETROVIRAL THERAPY; CENTRAL-NERVOUS-SYSTEM; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; OF-THE-LITERATURE; RISK-FACTORS; VIRUS-INFECTION; CYTOMEGALOVIRUS ENCEPHALITIS; CLINICAL-MANIFESTATIONS; IMAGING FINDINGS; HAART ERA AB While the previous review of CNS-IRIS in the HIV-infected patient on highly active antiretroviral therapy (Part 1) dealt with an overview of the biology, pathology, and neurologic presentation of this condition and a discussion of the atypical imaging findings in PML-IRIS and cryptococcal meningitis-IRIS due to the robust inflammatory response, the current review (Part 2) discusses the imaging findings in other commonly encountered organisms seen in association with CNS-IRIS, namely, VZV, CMV, HIV, Candida organisms, Mycobacterium tuberculosis, and Toxoplasma gondii. Also described is the imaging appearance of CNS-IRIS when not associated with a particular organism. Recognition of these imaging findings will give credence to the diagnosis of CNS-IRIS and will allow the clinician to institute changes in medical management, if necessary, so that immune reconstitution and improved patient outcome can occur with time. C1 [Post, M. J. D.] Univ Miami, Miller Sch Med, Jackson Mem Med Ctr, Sect Neuroradiol,Dept Radiol, Miami, FL 33136 USA. [Thurnher, M. M.] Univ Vienna, Univ Hosp Vienna, Dept Radiol, Vienna, Austria. [Clifford, D. B.] Washington Univ, Dept Neurol, St Louis, MO USA. [Nath, A.] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Gonzalez, R. G.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Gonzalez, R. G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gupta, R. K.] Sanjay Gandhi Postgrad Inst Med Sci, Dept Radiol, Lucknow, Uttar Pradesh, India. [Post, K. K.] UMass Mem Med Ctr, Dept Internal Med, Worcester, MA USA. RP Post, MJD (reprint author), Univ Miami, Miller Sch Med, Jackson Mem Med Ctr, Sect Neuroradiol,Dept Radiol, West Wing 279,1611 NW 12th Ave, Miami, FL 33136 USA. EM jpost@med.miami.edu FU Millennium; Genentech FX Majda Thurnher-UNRELATED: Royalties: Amirsys. David Clifford-UNRELATED: Consultancy: All <$10,000 annually: Biogen Idec, Genentech, Millennium, Genzyme, Bristol Myers Squibb, Pfizer, Janssen, Expert Testimony: Biogen Idec, Comments: European Medicines Agency (EMA) discussion of natalizumab, Payment for Development of Educational Presentations: Millennium, payment for the teaching video on the examination for PML; Genentech, payment for the teaching video on PML diagnosis, Other: Millennium, Independent Adjudication Committee, Genzyme, Data Monitoring Committee, Chair; Genentech, Panel of Experts, Translational Immunology Consultant; Pfizer, Data Safety Monitoring Committee (DSMB). NR 79 TC 5 Z9 6 U1 0 U2 2 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JUL PY 2013 VL 34 IS 7 BP 1308 EP 1318 DI 10.3174/ajnr.A3184 PG 11 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 290DZ UT WOS:000329734800008 PM 22790252 ER PT J AU Garcia, I Kuska, R Somerman, MJ AF Garcia, I. Kuska, R. Somerman, M. J. TI Expanding the Foundation for Personalized Medicine: Implications and Challenges for Dentistry SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE targeted therapies; genomics; diagnostics; pharmacogenomics; biomarkers; oral diseases ID SQUAMOUS-CELL CARCINOMA; GENOMIC MEDICINE; HEAD; BIOMARKERS; CANCER; IDENTIFICATION; INFORMATION; PATTERNS; ELEMENTS; NETWORK AB Personalized medicine aims to individualize care based on a person's unique genetic, environmental, and clinical profile. Dentists and physicians have long recognized variations between and among patients, and have customized care based on each individual's health history, environment, and behavior. However, the sequencing of the human genome in 2003 and breakthroughs in regenerative medicine, imaging, and computer science redefined personalized medicine as clinical care that takes advantage of new molecular tools to facilitate highly precise health care based on an individual's unique genomic and molecular characteristics. Major investments in science bring a new urgency toward realizing the promise of personalized medicine; yet, many challenges stand in the way. In this article, we present an overview of the opportunities and challenges that influence the oral health community's full participation in personalized medicine. We highlight selected research advances that are solidifying the foundation of personalized oral health care, elaborate on their impact on dentistry, and explore obstacles toward their adoption into practice. It is our view that now is the time for oral health professionals, educators, students, researchers, and patients to engage fully in preparations for the arrival of personalized medicine as a means to provide quality, customized, and effective oral health care for all. C1 [Garcia, I.; Kuska, R.; Somerman, M. J.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Somerman, MJ (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bldg 31,Room 2C39,31 Ctr Dr,MSC 2290, Bethesda, MD 20892 USA. EM Martha.Somerman@nih.gov NR 53 TC 8 Z9 8 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD JUL PY 2013 VL 92 IS S7 SU 7 BP S3 EP S10 DI 10.1177/0022034513487209 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 287LC UT WOS:000329542300001 PM 23690361 ER PT J AU Ramos-Murguialday, A Broetz, D Rea, M Laer, L Yilmaz, O Brasil, FL Liberati, G Curado, MR Garcia-Cossio, E Vyziotis, A Cho, W Agostini, M Soares, E Soekadar, S Caria, A Cohen, LG Birbaumer, N AF Ramos-Murguialday, Ander Broetz, Doris Rea, Massimiliano Laeer, Leonhard Yilmaz, Oezge Brasil, Fabricio L. Liberati, Giulia Curado, Marco R. Garcia-Cossio, Eliana Vyziotis, Alexandros Cho, Woosang Agostini, Manuel Soares, Ernesto Soekadar, Surjo Caria, Andrea Cohen, Leonardo G. Birbaumer, Niels TI Brain-Machine Interface in Chronic Stroke Rehabilitation: A Controlled Study SO ANNALS OF NEUROLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; MOTOR FUNCTION; COMPUTER INTERFACES; MENTAL PRACTICE; RECOVERY; PLASTICITY; STIMULATION; IMAGERY; ARM; THERAPY AB ObjectiveChronic stroke patients with severe hand weakness respond poorly to rehabilitation efforts. Here, we evaluated efficacy of daily brain-machine interface (BMI) training to increase the hypothesized beneficial effects of physiotherapy alone in patients with severe paresis in a double-blind sham-controlled design proof of concept study. MethodsThirty-two chronic stroke patients with severe hand weakness were randomly assigned to 2 matched groups and participated in 17.81.4 days of training rewarding desynchronization of ipsilesional oscillatory sensorimotor rhythms with contingent online movements of hand and arm orthoses (experimental group, n=16). In the control group (sham group, n=16), movements of the orthoses occurred randomly. Both groups received identical behavioral physiotherapy immediately following BMI training or the control intervention. Upper limb motor function scores, electromyography from arm and hand muscles, placebo-expectancy effects, and functional magnetic resonance imaging (fMRI) blood oxygenation level-dependent activity were assessed before and after intervention. ResultsA significant group x time interaction in upper limb (combined hand and modified arm) Fugl-Meyer assessment (cFMA) motor scores was found. cFMA scores improved more in the experimental than in the control group, presenting a significant improvement of cFMA scores (3.41 +/- 0.563-point difference, p=0.018) reflecting a clinically meaningful change from no activity to some in paretic muscles. cFMA improvements in the experimental group correlated with changes in fMRI laterality index and with paretic hand electromyography activity. Placebo-expectancy scores were comparable for both groups. InterpretationThe addition of BMI training to behaviorally oriented physiotherapy can be used to induce functional improvements in motor function in chronic stroke patients without residual finger movements and may open a new door in stroke neurorehabilitation. ANN NEUROL 2013;74:100-108 C1 [Ramos-Murguialday, Ander; Broetz, Doris; Rea, Massimiliano; Laeer, Leonhard; Yilmaz, Oezge; Brasil, Fabricio L.; Liberati, Giulia; Curado, Marco R.; Garcia-Cossio, Eliana; Vyziotis, Alexandros; Cho, Woosang; Agostini, Manuel; Soares, Ernesto; Caria, Andrea; Birbaumer, Niels] Univ Tubingen, Inst Med Psychol & Behav Neurobiol, D-72074 Tubingen, Germany. [Ramos-Murguialday, Ander; Broetz, Doris; Rea, Massimiliano; Laeer, Leonhard; Yilmaz, Oezge; Brasil, Fabricio L.; Liberati, Giulia; Curado, Marco R.; Garcia-Cossio, Eliana; Vyziotis, Alexandros; Cho, Woosang; Agostini, Manuel; Soares, Ernesto; Caria, Andrea; Birbaumer, Niels] Univ Tubingen, Magnetoencephalog Ctr, D-72074 Tubingen, Germany. [Ramos-Murguialday, Ander] Tecnalia, Hlth Technol Dept, San Sebastian, Spain. [Soekadar, Surjo; Cohen, Leonardo G.] NINDS, Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. [Soekadar, Surjo] Univ Tubingen Hosp, Dept Psychiat & Psychotherapy, Tubingen, Germany. [Birbaumer, Niels] San Camillo Hosp, Inst Hospitalizat & Sci Care, Venice Lido, Italy. RP Ramos-Murguialday, A (reprint author), Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Garten Str 29, D-72074 Tubingen, Germany. EM ander.ramos@med.uni-tuebingen.de; niels.birbaumer@uni-tuebingen.de RI Lima Brasil, Fabricio/I-7529-2015; OI Lima Brasil, Fabricio/0000-0002-9984-1007; Ramos-Murguialday, Ander/0000-0002-1549-4029 FU German Federal Ministry of Education and Research [01GQ0831]; Deutsche Forschungsgemeinschaft; European Research Council [ERC 227632]; European Union Information and Communication Technologies [HUMOUR 231724]; NIH National Institute of Neurological Disorders and Stroke (Bethesda, MD); Center for Neuroscience and Regenerative Medicine; Uniformed Services University of Health Sciences (Bethesda, MD); Werner Reichardt Center for Integrative Neuroscience; University of Tubingen; Tecnalia; Deutscher Akademischer Austauschdienst; Brazilian National Counsel of Technological and Scientific Development; Coordination for the Improvement of Higher Education Personnel (Brazil); Humbolt Award FX This work was supported by the German Federal Ministry of Education and Research (Forderzeichen 01GQ0831) as well as the Deutsche Forschungsgemeinschaft, European Research Council (ERC 227632), European Union Information and Communication Technologies Framework Program 7 (HUMOUR 231724), Intramural Research Program of the NIH National Institute of Neurological Disorders and Stroke (Bethesda, MD), Center for Neuroscience and Regenerative Medicine, Uniformed Services University of Health Sciences (Bethesda, MD), Werner Reichardt Center for Integrative Neuroscience, University of Tubingen, and Tecnalia. Several authors were supported by the Deutscher Akademischer Austauschdienst (O.Y., E.G., F.L.B., and M.R.C.), Brazilian National Counsel of Technological and Scientific Development (F.L.B.), and Coordination for the Improvement of Higher Education Personnel (Brazil) (M.R.C.), and a Humbolt Award to L.G.C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 147 Z9 153 U1 22 U2 66 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 2013 VL 74 IS 1 BP 100 EP 108 DI 10.1002/ana.23879 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 282UH UT WOS:000329198600013 PM 23494615 ER PT J AU Barsoum, IB Kaur, J Ge, RS Cooke, PS Yao, HHC AF Barsoum, Ivraym B. Kaur, Jaspreet Ge, Renshan S. Cooke, Paul S. Yao, Humphrey Hung-Chang TI Dynamic changes in fetal Leydig cell populations influence adult Leydig cell populations in mice SO FASEB JOURNAL LA English DT Article DE hedgehog pathway; spermatogenesis; steroidogenic factor 1; testis ID HEDGEHOG DHH GENE; DESERT-HEDGEHOG; MOUSE TESTIS; GONADAL-DYSGENESIS; PROGENITOR CELLS; SERTOLI-CELLS; DIFFERENTIATION; IDENTIFICATION; MUTATION; PROLIFERATION AB Testes contain two distinct Leydig cell populations during development: fetal and adult Leydig cells (FLCs and ALCs, respectively). ALCs are not derived from FLCs, and it is unknown whether these two populations share common progenitors. We discovered that hedgehog (Hh) signaling is responsible for transforming steroidogenic factor 1-positive (SF1(+)) progenitors into FLCs. However, not all SF1(+) progenitors become FLCs, and some remain undifferentiated through fetal development. We therefore hypothesized that if FLCs and ALCs share SF1(+) progenitors, increased Hh pathway activation in SF1(+) progenitor cells could change the dynamics and distribution of SF1(+) progenitors, FLCs, and ALCs. Using a genetic model involving constitutive activation of Hh pathway in SF1(+) cells, we observed reduced numbers of SF1(+) progenitor cells and increased FLCs. Conversely, increased Hh activation led to decreased ALC populations prepubertally, while adult ALC numbers were comparable to control testes. Hence, reduction in SF1(+) progenitors temporarily affects ALC numbers, suggesting that SF1(+) progenitors in fetal testes are a potential source of both FLCs and ALCs. Besides transient ALC defects, adult animals with Hh activation in SF1(+) progenitors had reduced testicular weight, oligospermia, and decreased sperm mobility. These defects highlight the importance of properly regulated Hh signaling in Leydig cell development and testicular functions.Barsoum, I. B., Kaur, J. Ge, R. S., Cooke, P. S., Yao, H. H.-C. Dynamic changes in fetal Leydig cell populations influence adult Leydig cell populations in mice. C1 [Barsoum, Ivraym B.; Kaur, Jaspreet; Cooke, Paul S.; Yao, Humphrey Hung-Chang] Univ Illinois, Coll Vet Med, Dept Comparat Biosci, Urbana, IL USA. [Ge, Renshan S.] Populat Council, New York, NY 10021 USA. [Cooke, Paul S.] Univ Florida, Coll Vet Med, Dept Physiol Sci, Gainesville, FL 32610 USA. [Yao, Humphrey Hung-Chang] NIEHS, Dev Reprod Biol Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Yao, HHC (reprint author), NIEHS, 111 TW Alexander Dr,Maildrop C4-10, Res Triangle Pk, NC 27709 USA. EM humphrey.yao@nih.gov RI Yao, Humphrey Hung-Chang/B-4795-2010 OI Yao, Humphrey Hung-Chang/0000-0003-2944-8469 FU U.S. National Institutes of Health [HD-059961]; U.S. National Institutes of Health (National Institute of Environmental Health Sciences) [ES-102965]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH [U54-HD28934] FX The authors are grateful for the assistance and support of H.H.-C.Y. laboratory members. This study was funded by the U.S. National Institutes of Health (grant HD-059961 to H.H.-C.Y. and P. S. C., and National Institute of Environmental Health Sciences Intramural Research Fund ES-102965 to H.H.-C.Y.). The authors dedicate this study to their collaborator and friend, Dr. Keith Parker, who passed away on December 13, 2008. The authors also thank the University of Virginia (UVA) Center for Research and Reproduction Ligand Assay and Analysis Core (Charlottesville, VA, USA) for hormone measurement. The UVA Center is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (Specialized Cooperative Centers Program in Reproduction and Infertility Research) grant U54-HD28934. NR 39 TC 14 Z9 14 U1 0 U2 3 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 2013 VL 27 IS 7 BP 2657 EP 2666 DI 10.1096/fj.12-225060 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 277TA UT WOS:000328841000015 PM 23568777 ER PT J AU Bernhardt, ML Bustamante-Marin, X AF Bernhardt, Miranda L. Bustamante-Marin, Ximena TI Triangle Consortium for Reproductive Biology 22nd Annual Meeting SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Article ID PLANARIAN REGENERATION; DIFFERENTIATION; EXPRESSION; PROTEINS; EXPOSURE; IDENTITY; MEIOSIS; OOCYTES; GENES; MOUSE AB Mol. Reprod. Dev. 80: 504-507, 2013. (c) 2013 Wiley Periodicals, Inc. This article is a US government work and, as such, is in the public domain in the United States of America. C1 [Bernhardt, Miranda L.] NIEHS, Reprod Med Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Bustamante-Marin, Ximena] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. [Bustamante-Marin, Ximena] Univ Antofagasta, Dept Biomed, Antofagasta, Chile. RP Bernhardt, ML (reprint author), NIEHS, NIH, DHHS, POB 12233,MD E4-02, Res Triangle Pk, NC 27709 USA. EM miranda.bernhardt@nih.gov OI Bernhardt, Miranda/0000-0001-5424-5685 FU Wiley; National Institute of Environmental Health Sciences/National Institutes of Health, Duke University School of Medicine; Campion Fund of the Mark and Phyllis Leppert Foundation FX We thank the TCRB and Duke Organizing Committees, particularly Phyllis Leppert, Friederike Jayes, and Carmen Williams, for organizing the event. We are grateful for the support provided by Wiley (especially Dr. Mark Paalman and Allyn Molina for their continued interest in supporting the research community), National Institute of Environmental Health Sciences/National Institutes of Health, Duke University School of Medicine, and the Campion Fund of the Mark and Phyllis Leppert Foundation that made the meeting possible. We also thank meeting participants and audience members for sharing their data and for strengthening the discourse with interesting questions and lively discussion. NR 22 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1040-452X EI 1098-2795 J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD JUL PY 2013 VL 80 IS 7 BP 504 EP 507 DI 10.1002/mrd.22203 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 267WA UT WOS:000328127800001 PM 23757113 ER PT J AU Safaeian, M Kemp, TJ Pan, DY Porras, C Rodriguez, AC Schiffman, M Cortes, B Katki, H Wacholder, S Schiller, JT Gonzalez, P Penrose, K Lowy, DR Quint, W van Doorn, LJ Herrero, R Hildesheim, A Pinto, LA AF Safaeian, Mahboobeh Kemp, Troy J. Pan, David Yuanji Porras, Carolina Cecilia Rodriguez, Ana Schiffman, Mark Cortes, Bernal Katki, Hormuzd Wacholder, Sholom Schiller, John T. Gonzalez, Paula Penrose, Kerri Lowy, Douglas R. Quint, Wim van Doorn, Leen-Jan Herrero, Rolando Hildesheim, Allan Pinto, Ligia A. TI Cross-protective vaccine efficacy of the bivalent HPV vaccine against HPV31 is associated with humoral immune responses Results from the Costa Rica vaccine trial SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article; Proceedings Paper CT 23rd National Immunisation Conference for Health Care Workers (NIC) CY DEC 07, 2012 CL Manchester, ENGLAND DE HPV vaccine; humoral; immune response; cross-protection; mechanisms for protection ID HUMAN-PAPILLOMAVIRUS HPV; NEUTRALIZATION ASSAY; ANTIBODY-RESPONSES; PARTICLE VACCINE; DOUBLE-BLIND; WOMEN; INFECTION; IMMUNIZATION; SPECTRUM; ELISA AB Background:We investigated the role of antibody responses as potential mechanism for the cross-protective vaccine-efficacies (VE) observed from randomized clinical trials of the HPV16/18 bivalent vaccine. Results:HPV31 cases had lower HPV16 antibody levels than controls (OR4th quartile compared with 1st quartile = 0.63; 95%CI: 0.36-1.08; p-trend = 0.03). HPV31 cases were also less likely to have detectable HPV31 neutralization, and HPV16 avidity than controls. No statistically significant differences by HPV18 antibody or HPV45 neutralization were observed among HPV45 cases and controls. Protection against HPV58 was not associated with any of the markers, confirming the specificity of our findings. Methods:Samples are from three-dose HPV vaccine recipients from the Costa Rica HPV16/18 vaccine trial. Women with a new HPV31, HPV45, or HPV58 infections over four years of follow-up were compared with randomly selected control womenwith no new infection with HPV31/45/58with respect to HPV16 and HPV18 antibody, HPV31, HPV45, and HPV58 neutralization, and HPV16 avidity. Conclusions:High HPV16 levels and avidity, and the ability to neutralize HPV31 were associated with protection against newly detected HPV31 infections, suggesting that the partial VE demonstrated for HPV31 is likely to be mediated at least in part through antibodies induced by HPV16/18 vaccination. C1 [Safaeian, Mahboobeh; Schiffman, Mark; Katki, Hormuzd; Wacholder, Sholom; Schiller, John T.; Lowy, Douglas R.; Hildesheim, Allan] NCI, NIH, Bethesda, MD 20892 USA. [Kemp, Troy J.; Pan, David Yuanji; Penrose, Kerri; Pinto, Ligia A.] SAIC Frederick Inc, HPV Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Porras, Carolina; Cecilia Rodriguez, Ana; Cortes, Bernal; Gonzalez, Paula; Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Gonzalez, Paula; Herrero, Rolando] Int Agcy Res Canc, Prevent & Implementat Grp, F-69372 Lyon, France. [Quint, Wim; van Doorn, Leen-Jan] DDL Diagnost Lab, Voorburg, Netherlands. RP Safaeian, M (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM Safaeianm@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU Intramural Research Program of the National Institute of Health; National Cancer Institute; intramural National Cancer Institute; National Institute of Health's Office of Research on Women's Health FX This work was supported by the Intramural Research Program of the National Institute of Health and the National Cancer Institute. The Costa Rica HPV16/18 Vaccine Trial is funded by intramural National Cancer Institute and the National Institute of Health's Office of Research on Women's Health and is conducted in agreement with the Ministry of Health of Costa Rica. NR 23 TC 16 Z9 16 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD JUL 1 PY 2013 VL 9 IS 7 BP 1399 EP 1406 DI 10.4161/hv.24340 PG 8 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 273YR UT WOS:000328572700010 PM 23571174 ER PT J AU Rosenberg, HF AF Rosenberg, Helene F. TI Mouse eosinophils expressing Cre recombinase: endless "flox"ibilities SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material DE peroxidase; cytokines; leukocytes ID DISEASE; HEALTH AB Discussion of innovative murine models based on eosinophils expressing Cre-recombinase. C1 NIAID, Inflammat Immunobiol Sect, NIH, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, Inflammat Immunobiol Sect, NIH, Bldg 10,Rm 11C215,MSC 1883,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU Intramural NIH HHS; NIAID NIH HHS [AI000941, Z01 AI000941] NR 8 TC 1 Z9 1 U1 1 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 2013 VL 94 IS 1 BP 3 EP 4 DI 10.1189/jlb.0413191 PG 2 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 277SY UT WOS:000328840800002 PM 23818016 ER PT J AU Bouma, HR Mandl, JN Strijkstra, AM Boerema, AS Kok, JW van Dam, A IJzerman, A Kroese, FGM Henning, RH AF Bouma, Hjalmar R. Mandl, Judith N. Strijkstra, Arjen M. Boerema, Ate S. Kok, Jan-Willem van Dam, Annie IJzerman, Ad Kroese, Frans G. M. Henning, Robert H. TI 5 '-AMP impacts lymphocyte recirculation through activation of A(2B) receptors SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE hibernation; anesthesiology; inflammation; suspended animation; metabolism ID TANDEM MASS-SPECTROMETRY; REGULATORY T-CELLS; ORGAN PRESERVATION; GROUND-SQUIRREL; DAILY TORPOR; COLD ISCHEMIA; IN-VIVO; HIBERNATION; ADENOSINE; TEMPERATURE AB Natural hibernation consists of torpid phases with metabolic suppression alternating with euthermic periods. Induction of torpor holds substantial promise in various medical conditions, including trauma, major surgery, and transplantation. Torpor in mice can be induced pharmacologically by 5-AMP. Previously, we showed that during natural torpor, the reduction in body temperature results in lymphopenia via a reduction in plasma S1P. Here, we show that during torpor induced by 5-AMP, there is a similar reduction in the number of circulating lymphocytes that is a result of their retention in secondary lymphoid organs. This lymphopenia could be mimicked by engagement of A(2B)Rs by a selective A(2B)R agonist (LUF6210) in the absence of changes in temperature and prevented by A(2B)R antagonists during 5-AMP-induced torpor. In addition, forced cooling of mice led to peripheral blood lymphopenia, independent of A(2B)R signaling. The induction of torpor using 5-AMP impacted the migration of lymphocytes within and between secondary lymphoid organs. During torpor, the homing into LNs was impaired, and two-photon intravital microscopy revealed that cell motility was decreased significantly and rapidly upon 5-AMP administration. Furthermore, the S1P plasma concentration was reduced by 5-AMP but not by LUF6210. S1P plasma levels restored upon arousal. Likely, the reduced migration in LNs combined with the reduced S1P plasma level substantially reduces lymphocyte egress after injection of 5-AMP. In conclusion, 5-AMP induces a state of pharmacological torpor in mice, during which, lymphopenia is governed primarily by body temperature-independent suppression of lymphocyte egress from LNs. C1 [Bouma, Hjalmar R.; Henning, Robert H.] Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharmacol, NL-9713 AV Groningen, Netherlands. [Kok, Jan-Willem] Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, NL-9713 AV Groningen, Netherlands. [Kroese, Frans G. M.] Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, NL-9713 AV Groningen, Netherlands. [Strijkstra, Arjen M.; Boerema, Ate S.] Univ Groningen, Dept Chronobiol, NL-9700 AB Groningen, Netherlands. [van Dam, Annie] Univ Groningen, Ctr Pharm, Mass Spectrometry Core Facil, NL-9700 AB Groningen, Netherlands. [Mandl, Judith N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [IJzerman, Ad] Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Med Chem, Leiden, Netherlands. RP Bouma, HR (reprint author), Univ Med Ctr Groningen, Dept Clin Pharmacol FB20, Antonius Deusinglaan 1, NL-9713 AV Groningen, Netherlands. EM h.r.bouma@umcg.nl RI Bouma, Hjalmar/F-9737-2015; OI Bouma, Hjalmar/0000-0003-1032-321X; Henning, Robert/0000-0002-5135-4621; IJzerman, Ad/0000-0002-1182-2259 NR 62 TC 2 Z9 2 U1 0 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUL PY 2013 VL 94 IS 1 BP 89 EP 98 DI 10.1189/jlb.1212613 PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 277SY UT WOS:000328840800010 PM 23682128 ER PT J AU De Wever, O De Boeck, A Maynard, D Bracke, M Hendrix, A AF De Wever, Olivier De Boeck, Astrid Maynard, Dawn Bracke, Marc Hendrix, An TI Protein Secretome Analysis of Evolving and Responding Tumor Ecosystems SO CURRENT PROTEOMICS LA English DT Article DE CAF; exosome; proteomics; stroma; TIF ID CANCER BIOMARKER DISCOVERY; NIPPLE ASPIRATE FLUID; PANCREATIC DUCTAL ADENOCARCINOMA; MALIGNANT PLEURAL EFFUSIONS; TANDEM MASS-SPECTROMETRY; HUMAN COLON-CANCER; PROTEOMIC ANALYSIS; BREAST-CANCER; INTERSTITIAL FLUID; IDENTIFICATION TECHNOLOGY AB In the tumor ecosystem, we recognize local and distant environments, and the circulation through which the exchange of messages occurs. Communication is largely mediated through secretory protein signals and non-conventional secretory mechanisms such as the release of extracellular vesicles containing protein and RNA payloads. A plethora of antibody microarrays and mass spectrometry platforms are available to perform protein secretome analysis. Further application of nanomaterials will improve sensitivity and robustness to detect low-abundance proteins. The term tumor secretome is very broad; by using the ecosystem concept we introduce different in vivo and ex vivo sample types that can be employed for proteomics. These include tumor interstitial fluid (TIF), tumor proximal body fluids, organotypic tissue slices and exposure of a fresh surgical specimen to biotinylation, followed by streptavidin precipitation. In vitro models may mimic the tumor ecosystem or can be simplified by incorporating one cell type from the tumor ecosystem. We believe that models allowing the study of secretomes from tumor ecosystems will provide us insights in tumor biology, biomarkers (prognostic/predictive) and novel therapeutic targets. C1 [De Wever, Olivier; Bracke, Marc; Hendrix, An] Ghent Univ Hosp, Lab Expt Canc Res, Dept Radiat Oncol & Expt Canc Res, B-9000 Ghent, Belgium. [De Boeck, Astrid] Univ Calgary, Dept Oncol, Calgary, AB, Canada. [Maynard, Dawn] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. RP De Wever, O (reprint author), UZ Gent, Lab Expt Canc Res, 1P7,De Pintelaan 185, B-9000 Ghent, Belgium. EM Olivier.DeWever@ugent.be RI de wever, olivier/J-3094-2013 OI de wever, olivier/0000-0002-5453-760X FU National Human Genome Research Institute; Vlaamse Liga tegen Kanker; Stichting tegen Kanker; a krediet a anna vorsers; Fund for Scientific Research-Flanders FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute, Vlaamse Liga tegen Kanker, Stichting tegen Kanker and a krediet a anna vorsers (O.D.W.) and a postdoctoral grant (A.H.) from Fund for Scientific Research-Flanders. NR 100 TC 1 Z9 1 U1 1 U2 10 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-1646 EI 1875-6247 J9 CURR PROTEOMICS JI Curr. Proteomics PD JUL PY 2013 VL 10 IS 2 BP 120 EP 135 PG 16 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 267TK UT WOS:000328120800005 ER PT J AU Vargas-Inchaustegui, DA Robert-Guroff, M AF Vargas-Inchaustegui, Diego A. Robert-Guroff, Marjorie TI Fc Receptor-Mediated Immune Responses: New Tools But Increased Complexity in HIV Prevention SO CURRENT HIV RESEARCH LA English DT Article DE Antibody-dependent cell-mediated viral inhibition; antibody-dependent cellular cytotoxicity; antibody-dependent cellular phagocytosis; avidity; B cell memory; Fc glycosylation; FcR polymorphisms; transcytosis inhibition ID DEPENDENT CELLULAR CYTOTOXICITY; HUMAN-IMMUNODEFICIENCY-VIRUS; NATURAL-KILLER-CELLS; DELTA T-CELLS; VACCINE-INDUCED ANTIBODIES; IMMATURE DENDRITIC CELLS; HIV-1/SIV CHIMERIC VIRUS; HUMAN EPITHELIAL BARRIER; SIV-INFECTED MACAQUES; MUCOSAL NK CELLS AB The modest success of the RV144 HIV vaccine trial in Thailand and the ensuing suggestion that a Fc-receptor-mediated antibody activity might have played a role in the protection observed have intensified investigations on Fc-related immune responses. HIV neutralizing antibodies have been and continue to be the focal point of research into humoral immune protection. However, recent knowledge that their protective efficacy can be augmented by Fc-FcR interactions has increased the complexity of identifying immune correlates of protection. If anything, continued studies of both humoral and cellular immune mechanisms point to the lack of a single protective anti-HIV immune response. Here we focus on humoral immunity, analyzing the role played by Fc receptor-related responses and discussing how new knowledge of their interactions requires further investigation, but may also spur novel vaccination approaches. We initially address classical Fc-receptor mediated anti-viral mechanisms including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell mediated viral inhibition (ADCVI), and antibody-dependent cellular phagocytosis (ADCP), as well as the effector cells that mediate these functions. Next, we summarize key aspects of FcR-Fc interactions that are important for potential control of HIV/SIV such as FcR polymorphisms and post-transcriptional modifications. Finally we discuss less commonly studied non-mechanistic anti-HIV immune functions: antibody avidity and envelope-specific B cell memory. Overall, a spectrum of immune responses, reflecting the immune system's redundancy, will likely be needed to prevent HIV infection and/or disease progression. Aside from elicitation of critical immune mechanisms, a successful vaccine will need to induce mature B cell responses and long-lasting immune memory. C1 [Vargas-Inchaustegui, Diego A.; Robert-Guroff, Marjorie] NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20192 USA. EM guroffm@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 185 TC 12 Z9 12 U1 0 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-162X EI 1873-4251 J9 CURR HIV RES JI Curr. HIV Res. PD JUL PY 2013 VL 11 IS 5 BP 407 EP 420 PG 14 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 262XR UT WOS:000327771700007 PM 24191937 ER PT J AU Weinberger, DM Givon-Lavi, N Shemer-Avni, Y Bar-Ziv, J Alonso, WJ Greenberg, D Dagan, R AF Weinberger, Daniel M. Givon-Lavi, Noga Shemer-Avni, Yonat Bar-Ziv, Jacob Alonso, Wladimir J. Greenberg, David Dagan, Ron TI Influence of Pneumococcal Vaccines and Respiratory Syncytial Virus on Alveolar Pneumonia, Israel SO EMERGING INFECTIOUS DISEASES LA English DT Article ID STREPTOCOCCUS-PNEUMONIAE; CONJUGATE VACCINE; SEROTYPE REPLACEMENT; SOUTHERN ISRAEL; RISK-FACTORS; CHILDREN; DISEASE; IMPACT; HOSPITALIZATIONS; BACTERIAL AB Postlicensure surveillance of pneumonia incidence can be used to estimate whether pneumococcal conjugate vaccines (PCVs) affect incidence. We used Poisson regression models that control for baseline seasonality to determine the impact of PCVs and the possible effects of variations in virus activity in Israel on these surveillance estimates. PCV was associated with significant declines in radiologically confirmed alveolar pneumonia (CA) among patients <6 months, 6-17 months, and 18-35 months of age (-31% [95% Cl -51% to -15%], -41% [-95% Cl -52 to -32%], and -34% [95% Cl -42% to -25%], respectively). Respiratory syncytial virus (RSV) activity was associated with strong increases in RCAP incidence, with up to 44% of cases attributable to RSV among infants <6 months' of age and lower but significant impacts in older children. Seasonal variations, particularly in RSV activity, masked the impact of 7-valent PCVs,,especially for young children in the first 2 years after vaccine introduction. C1 [Weinberger, Daniel M.] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT 06520 USA. [Weinberger, Daniel M.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Alonso, Wladimir J.] NIH, Bethesda, MD 20892 USA. [Givon-Lavi, Noga; Shemer-Avni, Yonat; Greenberg, David] Soroka Univ, Med Ctr, Beer Sheva, Israel. [Givon-Lavi, Noga; Shemer-Avni, Yonat; Greenberg, David; Dagan, Ron] Ben Gurion Univ Negev, IL-84105 Beer Sheva, Israel. [Bar-Ziv, Jacob] Hadassah Univ, Med Ctr, Jerusalem, Israel. RP Weinberger, DM (reprint author), Yale Univ, Sch Publ Hlth, POB 208034,Rm 720, New Haven, CT 06520 USA. EM daniel.weinberger@yale.edu OI Weinberger, Daniel/0000-0003-1178-8086 FU IsraNIP; Pfizer [ISRANIP 0887X1-4603]; Multinational Influenza Seasonal Mortality Study; Office of Global Health Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services; Berna/Crucell; Wyeth/Pfizer; Merck; Sharp; Dohme (MSD); Abbott; MSD FX This Work was supported by IsraNIP, the Israeli study on the impact of vaccination on morbidity outcomes. This work is sponsored in part by grant ISRANIP 0887X1-4603 from Pfizer. This work was also supported by the Multinational Influenza Seasonal Mortality Study, with funding from the Office of Global Health Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services.; D.M.W. has received research support from Pfizer. In the last 5 years, R.D. has received grants and research support from Berna/Crucell; Wyeth/Pfizer; Merck, Sharp and Dohme (MSD); and Protea and has been a scientific consultant for Berna/Crucell, GlaxoSmithKline, Novartis, Wyeth/Pfizer, Protea, and MSD and a speaker for Berna/Crucell, GlaxoSmithKline, Wyeth/Pfizer; he is a shareholder of Protea/NasVax. D.G. has received grants and research support from Abbott and MSD and has been a scientific consultant MSD and a speaker for Abbott, MSD, GlaxoSmithKline, and Wyeth/Pfizer. NR 26 TC 14 Z9 15 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 2013 VL 19 IS 7 BP 1084 EP 1091 DI 10.3201/eid1907.121625 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 268LZ UT WOS:000328173600006 PM 23763864 ER PT J AU Lu, SH Zheng, YF Li, T Hu, YW Liu, XN Xi, XH Chen, QG Wang, QL Cao, Y Wang, YB Zhou, LJ Lowrie, D Bao, J AF Lu, Shuihua Zheng, Yufang Li, Tao Hu, Yunwen Liu, Xinian Xi, Xiuhong Chen, Qingguo Wang, Qingle Cao, Ye Wang, Yanbing Zhou, Lijun Lowrie, Douglas Bao, Jing TI Clinical Findings for Early Human Cases of Influenza A(H7N9) Virus Infection, Shanghai, China SO EMERGING INFECTIOUS DISEASES LA English DT Article AB A novel strain of influenza A(H7N9) virus has emerged in China and is causing mild to severe clinical symptoms in infected humans. Some case-patients have died. To further knowledge of this virus, we report the characteristics and clinical histories of 4 early case-patients. C1 [Lu, Shuihua; Zheng, Yufang; Li, Tao; Hu, Yunwen; Liu, Xinian; Xi, Xiuhong; Chen, Qingguo; Wang, Qingle; Cao, Ye; Wang, Yanbing; Zhou, Lijun; Lowrie, Douglas] Shanghai Publ Hlth Clin Ctr, Shanghai 201508, Peoples R China. [Bao, Jing] NIAID, Henry M Jackson Fdn Div AIDS, NIH, Bethesda, MD 20892 USA. RP Lu, SH (reprint author), Shanghai Publ Hlth Clin Ctr, 2901 Caolong Rd, Shanghai 201508, Peoples R China. EM tubercle@shaphc.org FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HH-SN272200800014C] FX This study was funded in part by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services (contract no. HH-SN272200800014C). NR 9 TC 11 Z9 15 U1 3 U2 7 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 2013 VL 19 IS 7 BP 1142 EP 1146 DI 10.3201/eid1907.130612 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 268LZ UT WOS:000328173600022 PM 23769184 ER PT J AU Smrz, D Bandara, G Beaven, MA Metcalfe, DD Gilfillan, AM AF Smrz, Daniel Bandara, Geethani Beaven, Michael A. Metcalfe, Dean D. Gilfillan, Alasdair M. TI Prevention of F-actin assembly switches the response to SCF from chemotaxis to degranulation in human mast cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Chemotaxis; Degranulation; F-actin; Mast Cell; SCF ID EPSILON-RI AGGREGATION; SIGNALING PATHWAYS; FILAMENTOUS ACTIN; MEDIATOR RELEASE; ACTIVATION; CALCIUM; IGE; KIT; PHOSPHORYLATION; REARRANGEMENT AB Following antigen/IgE-mediated aggregation of high affinity IgE-receptors (Fc epsilon RI), mast cells (MCs) degranulate and release inflammatory mediators leading to the induction of allergic reactions including anaphylaxis. Migration of MCs to resident tissues and sites of inflammation is regulated by tissue chemotactic factors such as stem cell factor (SCF (KIT ligand)). Despite inducing similar early signaling events to antigen, chemotactic factors, including SCF, produce minimal degranulation in the absence of other stimuli. We therefore investigated whether processes regulating MC chemotaxis are rate limiting for MC mediator release. To investigate this issue, we disrupted actin polymerization, a requirement for MC chemotaxis, with latrunculin B and cytochalasin B, then examined chemotaxis and mediator release in human (hu)MCs induced by antigen or SCF. As expected, such disruption minimally affected early signaling pathways, but attenuated SCF-induced human mast cell chemotaxis. In contrast, SCF, in the absence of other stimuli, induced substantial degranulation in a concentration-dependent manner following actin disassembly. It also moderately enhanced antigen-mediated human mast cell degranulation which was further enhanced in the presence of SCF. These observations suggest that processes regulating cell migration limit MC degranulation as a consequence of cytoskeletal reorganization. C1 [Smrz, Daniel; Bandara, Geethani; Metcalfe, Dean D.; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Smrz, D (reprint author), Charles Univ Prague, Inst Immunol, Sch Med 2, V Uvalu 84, Prague 15006 5, Czech Republic. EM daniel.smrz@lfmotol.cuni.cz RI Smrz, Daniel/D-4853-2014 OI Smrz, Daniel/0000-0003-0143-8744 FU Intramural Research programs within NIAID; NHLBI FX Research in the authors' laboratories was supported by funding from the Intramural Research programs within NIAID (DS, DDM, and AMG) and NHLBI (MAB). We would like to thank Biological Imaging Facility (RTB/NIAID/NIH) for technical support in confocal image acquisition including Juraj Kabat for assistance in image post processing and analysis. NR 51 TC 9 Z9 9 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2013 VL 43 IS 7 BP 1873 EP 1882 DI 10.1002/eji.201243214 PG 10 WC Immunology SC Immunology GA 261WO UT WOS:000327695500022 PM 23616175 ER PT J AU Steinhagen, F McFarland, AP Rodriguez, LG Tewary, P Jarret, A Savan, R Klinman, DM AF Steinhagen, Folkert McFarland, Adelle P. Rodriguez, Luis G. Tewary, Poonam Jarret, Abigail Savan, Ram Klinman, Dennis M. TI IRF-5 and NF-kappa B p50 co-regulate IFN-beta and IL-6 expression in TLR9-stimulated human plasmacytoid dendritic cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CpG oligonucleotide; Dendritic cell; IRF-5; NF-kappa B; TLR9 ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; TOLL-LIKE RECEPTORS; SEQUENCE BINDING-PROTEIN; I INTERFERON INDUCTION; CPG-DNA; TRANSCRIPTION FACTORS; REGULATORY FACTOR; IMMUNE-COMPLEXES; GENE-EXPRESSION; ACTIVATION AB Synthetic oligonucleotides (ODN) expressing CpG motifs mimic the ability of bacterial DNA to trigger the innate immune system via TLR9. Plasmacytoid dendritic cells (pDCs) make a critical contribution to the ensuing immune response. This work examines the induction of antiviral (IFN-) and pro-inflammatory (IL-6) cytokines by CpG-stimulated human pDCs and the human CAL-1 pDC cell line. Results show that interferon regulatory factor-5 (IRF-5) and NF-B p50 are key co-regulators of IFN- and IL-6 expression following TLR9-mediated activation of human pDCs. The nuclear accumulation of IRF-1 was also observed, but this was a late event that was dependant on type 1 IFN and unrelated to the initiation of gene expression. IRF-8 was identified as a novel negative regulator of gene activation in CpG-stimulated pDCs. As variants of IRF-5 and IRF-8 were recently found to correlate with susceptibility to certain autoimmune diseases, these findings are relevant to our understanding of the pharmacologic effects of K ODN and the role of TLR9 ligation under physiologic, pathologic, and therapeutic conditions. C1 [Steinhagen, Folkert; McFarland, Adelle P.; Savan, Ram; Klinman, Dennis M.] Frederick Natl Lab Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. [Rodriguez, Luis G.] SAIC Frederick Inc, Lab Prote & Analyt Technol, Frederick, MD USA. [Tewary, Poonam] FNLCR, Mol Immunoregulat Lab, CIP, Frederick, MD USA. [Steinhagen, Folkert] Univ Hosp Bonn, Dept Anaesthesiol & Intens Care Med, Bonn, Germany. [McFarland, Adelle P.; Jarret, Abigail; Savan, Ram] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. RP Klinman, DM (reprint author), Frederick Natl Lab Canc Res, Canc & Inflammat Program, Bldg 567 Rm 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU Intramural Research Program of the NIH, NCI [HHSN261200800001E]; Department of Immunology, University of Washington FX The authors would like to thank Debra Tross-Currie for technical assistance; Bruce Beutler for providing the HA-MyD88 plasmid; and Hide Shirota, Stefan Sauer, Lyudmila A. Lyakh, and Dan McVicar for discussions and advice. This research was supported by the Intramural Research Program of the NIH, NCI, and partly funded with Contract No. HHSN261200800001E and by the Department of Immunology, University of Washington. 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 27 Z9 28 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2013 VL 43 IS 7 BP 1896 EP 1906 DI 10.1002/eji.201242792 PG 11 WC Immunology SC Immunology GA 261WO UT WOS:000327695500024 PM 23616277 ER PT J AU Striebel, JF Race, B Chesebro, B AF Striebel, James F. Race, Brent Chesebro, Bruce TI Prion protein and susceptibility to kainate-induced seizures Genetic pitfalls in the use of PrP knockout mice SO PRION LA English DT Editorial Material DE kainate; seizures; Prnp deletion; Prnp knockout; flanking genes ID HAMSTER SCRAPIE; TRANSGENIC MICE; SCHWANN-CELLS; EXPRESSION; MOUSE; LEVEL; REPLICATION; DEFICIENT; RESISTANT; STRAINS AB Prion protein (PrP) is a cell surface glycoprotein which is required for susceptibility to prion infection and disease. However, PrP is expressed in many different cell types located in numerous organs. Therefore, in addition to its role in prion diseases, PrP may have a large variety of other biological functions involving the nervous system and other systems. We recently showed that susceptibility to kainate-induced seizures differed in Prnp(-/-) and Prnp(+/+) mice on the C57BL/10SnJ background. However, in a genetic complementation experiment a PrP expressing transgene was not able to rescue the Prnp(+/+) phenotype. Thus the apparent effect of PrP on seizures was actually due to genes flanking the Prnp(-/-) gene rather that the Prnp deletion itself. We discuss here several pitfalls in the use of Prnp(-/-) genotypes expressed in various mouse genetic backgrounds to determine the functions of PrP. In particular, the use of Prnp(-/-) mice with heterogeneous mixed genetic backgrounds may have weakened the conclusions of many previous experiments. Use of either co-isogenic mice or congenic mice with more homogeneous genetic backgrounds is now feasible. For congenic mice, the potential problem of flanking genes can be mitigated by the use of appropriate transgene rescue experiments to confirm the conclusions. C1 [Striebel, James F.; Race, Brent; Chesebro, Bruce] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MO USA. RP Chesebro, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MO USA. EM bchesebro@nih.gov NR 31 TC 8 Z9 8 U1 2 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6896 EI 1933-690X J9 PRION JI Prion PD JUL 1 PY 2013 VL 7 IS 4 BP 280 EP 285 DI 10.4161/pri.25738 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 259SA UT WOS:000327545400005 PM 23851597 ER PT J AU Kim, YJ Serpe, M AF Kim, Young-Jun Serpe, Mihaela TI Building a synapse A complex matter SO FLY LA English DT Article ID DROSOPHILA NEUROMUSCULAR-JUNCTION; IONOTROPIC GLUTAMATE RECEPTORS; FORMATION IN-VIVO; KAINATE RECEPTORS; AUXILIARY SUBUNITS; KINASE MUSK; PROTEIN; CORNICHON; NETO1; AGRIN C1 [Kim, Young-Jun; Serpe, Mihaela] NICHHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. RP Serpe, M (reprint author), NICHHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. EM serpemih@mail.nih.gov FU Intramural Research Program at NIH, NICHD FX We are grateful to Kendal Broadie for Drosophila stocks. We thank Mik Sulkowski and members of the Serpe lab for help and suggestions. This work was supported by the Intramural Research Program at NIH, NICHD. NR 57 TC 4 Z9 4 U1 1 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6934 EI 1933-6942 J9 FLY JI Fly PD JUL 1 PY 2013 VL 7 IS 3 BP 146 EP 152 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 260OF UT WOS:000327603500004 PM 23680998 ER PT J AU Puri, V Streaker, E Prabakaran, P Zhu, ZY Dimitrov, DS AF Puri, Vinita Streaker, Emily Prabakaran, Ponraj Zhu, Zhongyu Dimitrov, Dimiter S. TI Highly efficient selection of epitope specific antibody through competitive yeast display library sorting SO MABS LA English DT Article DE yeast display antibody library; competitive sorting; epitope specific targeting; dengue virus; human antibody library ID MONOCLONAL-ANTIBODIES; DENGUE VIRUS; ENVELOPE PROTEIN; DOMAIN-III; VACCINE; GLYCOPROTEINS; TRENDS AB Combinatory antibody library display technologies have been invented and successfully implemented for the selection and engineering of therapeutic antibodies. Precise targeting of important epitopes on the protein of interest is essential for such isolated antibodies to serve as effective modulators of molecular interactions. We developed a strategy to efficiently isolate antibodies against a specific epitope on a target protein from a yeast display antibody library using dengue virus envelope protein domain III as a model target. A domain III mutant protein with a key mutation inside a cross-reactive neutralizing epitope was designed, expressed, and used in the competitive panning of a yeast display naive antibody library. All the yeast display antibodies that bound to the wild type domain III but not to the mutant were selectively sorted and characterized. Two unique clones were identified and showed cross-reactive binding to envelope protein domain IIIs from different serotypes. Epitope mapping of one of the antibodies confirmed that its epitope overlapped with the intended neutralizing epitope. This novel approach has implications for many areas of research where the isolation of epitope-specific antibodies is desired, such as selecting antibodies against conserved epitope(s) of viral envelope proteins from a library containing high titer, high affinity non-neutralizing antibodies, and targeting unique epitopes on cancer-related proteins. C1 [Puri, Vinita; Streaker, Emily; Prabakaran, Ponraj; Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, Protein Interact Grp, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. [Streaker, Emily; Prabakaran, Ponraj] Sci Applicat Int Corp Frederick Inc, Basic Res Program, Frederick, MD USA. RP Zhu, ZY (reprint author), NCI, Protein Interact Grp, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21701 USA. EM zhongyu.zhu@nih.gov FU Intramural Research Program of the National Institute of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research; NCI, NIH [N01-CO-12400]; NIAID Biodefense Program FX We thank Professor Dane Wittrup, Massachusetts Institute of Technology, for providing the yeast display vector and yeast strain. We also thank members of our groups for helpful discussions. This project was supported by the Intramural Research Program of the National Institute of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research, and by federal funds from the NCI, NIH, under contract N01-CO-12400, as well as by the NIAID Biodefense Program to DSD. NR 28 TC 3 Z9 3 U1 1 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1942-0862 EI 1942-0870 J9 MABS-AUSTIN JI mAbs PD JUL 1 PY 2013 VL 5 IS 4 BP 533 EP 539 DI 10.4161/mabs.25211 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 259SS UT WOS:000327547200004 PM 23765162 ER PT J AU Gaitan, MI Sati, P Inati, SJ Reich, DS AF Gaitan, Maria I. Sati, Pascal Inati, Souheil J. Reich, Daniel S. TI Initial investigation of the blood-brain barrier in MS lesions at 7 tesla SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE Veins; contrast-enhancing lesions; blood-brain barrier; magnetic resonance imaging; 7 tesla; susceptibility weighted imaging ID MULTIPLE-SCLEROSIS LESIONS; NATURAL-HISTORY; ENHANCEMENT; HETEROGENEITY; DEMYELINATION; PATHOLOGY; SERIAL; RING; MRI AB Background: We previously described two dynamics of contrast enhancement in scans of active multiple sclerosis lesions: Medium-sized, early lesions enhance centrifugally, whereas larger, slightly older lesions enhance centripetally. Due to technical limitations, our previous study did not characterize lesions < 5 mm in diameter, cortical enhancement, and anatomical structures within lesions. Objective: The objective of this paper is to obtain initial observations of these important aspects of lesion development on a 7 tesla scanner at high spatial resolution. Methods: We scanned eight patients, acquiring precontrast T2*-weighted scans, T1-weighted scans before and after contrast, and high-resolution dynamic contrast-enhanced scans during and up to 30 min after contrast. Results: We detected 15 enhancing lesions, obtaining dynamic data in 10: Five lesions < 4 mm enhanced centrifugally (initial central enhancement expanded outward), and five lesions > 4 mm enhanced centripetally (initial peripheral enhancement gradually filled the lesion). A leukocortical lesion initially showed enhancement in its white matter portion, which gradually spread into the cortex. Seventy-three percent of lesions were clearly perivenular. Conclusion: Most active lesions are perivenular, and the smallest lesions enhance centrifugally. This supports the idea that lesions grow outward from a central vein. C1 [Gaitan, Maria I.; Sati, Pascal; Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Inati, Souheil J.] NIMH, NIH, Bethesda, MD USA. RP Reich, DS (reprint author), NIH, 10 Ctr Dr MSC 1400,Bldg 10 Room 5C103, Bethesda, MD 20892 USA. EM daniel.reich@nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU Intramural Research Program of NINDS FX This study was supported by the Intramural Research Program of NINDS. NR 18 TC 14 Z9 14 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD JUL PY 2013 VL 19 IS 8 BP 1068 EP 1073 DI 10.1177/1352458512471093 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 257HD UT WOS:000327373300014 PM 23246799 ER PT J AU Ferreira, JN Hoffman, MP AF Ferreira, Joao N. Hoffman, Matthew P. TI Interactions between developing nerves and salivary glands SO ORGANOGENESIS LA English DT Review DE parasympathetic innervation; salivary gland; innervation; neurturin; epithelial progenitors; cholinergic signaling ID INTESTINAL POLYPEPTIDE VIP; SYMPATHETIC-NERVOUS-SYSTEM; MOUSE SUBMANDIBULAR-GLAND; MICE LACKING GFR-ALPHA-2; PARKINSONS-DISEASE; COMPLEMENTARY ROLE; DISTINCT ROLES; PAROTID-GLAND; BLOOD-FLOW; IN-VIVO AB Our aim is to provide a summary of the field of salivary gland development and regeneration from the perspective of what is known about the function of nerves during these processes. The primary function of adult salivary glands is to produce and secrete saliva. Neuronal control of adult salivary gland function has been a focus of research ever since Pavlov's seminal experiments on salivation in dogs. Less is known about salivary gland innervation during development and how the developing nerves influence gland organogenesis and regeneration. Here, we will review what is known about the communication between the autonomic nervous system and the epithelium of the salivary glands during organogenesis. An important emerging theme is the instructive role of the nervous system on the epithelial stem/progenitor cells during development as well as regeneration after damage. We will provide a brief overview of the neuroanatomy of the salivary glands and discuss recent literature that begins to integrate neurobiology with epithelial organogenesis, which may provide paradigms for exploring these interactions in other organ systems. C1 [Ferreira, Joao N.; Hoffman, Matthew P.] Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Ferreira, Joao N.] Mahidol Univ, Fac Dent, Rajthevi, Thailand. RP Hoffman, MP (reprint author), Natl Inst Dent & Craniofacial Res, Matrix & Morphogenesis Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. EM mhoffman@mail.nih.gov RI Ferreira, Joao/M-1517-2016 OI Ferreira, Joao/0000-0002-4230-4593 FU Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, DHHS FX The authors would like to thank Vaishali Patel, Isabelle Lombaert, Wendy Knosp, Toru Hayashi and Kyle Holmberg for helpful discussions and critical reading of this manuscript. The study was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, NIH, DHHS. NR 59 TC 11 Z9 11 U1 2 U2 15 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1547-6278 EI 1555-8592 J9 ORGANOGENESIS JI Organogenesis PD JUL 1 PY 2013 VL 9 IS 3 BP 199 EP 205 DI 10.4161/org.25224 PG 7 WC Biochemistry & Molecular Biology; Developmental Biology; Engineering, Biomedical SC Biochemistry & Molecular Biology; Developmental Biology; Engineering GA 258DB UT WOS:000327438300011 PM 23974175 ER PT J AU Feng, ZM Dubyak, GR Jia, X Lubkowski, JT Weinberg, A AF Feng, Zhimin Dubyak, George R. Jia, Xun Lubkowski, Jacek T. Weinberg, Aaron TI Human beta-defensin-3 structure motifs that are important in CXCR4 antagonism SO FEBS JOURNAL LA English DT Article DE antagonism; CXCR4; defensin; human -defensin-3; structure ID CHEMOTAXIS AB Previously, we reported that human -defensin (hBD)-3 can both antagonize CXCR4 function on Tcells and promote receptor internalization in the absence of activation. In the present study, we explored the important structural elements of hBD-3 that are involved in blocking CXCR4 activation by its natural ligand, stromal-derived factor1 (SDF-1; CXCL12). Results from site-directed mutagenesis studies suggest that the ability of hBD-3 to inhibit SDF-1-CXCR4 interaction, as assayed either by blocking SDF-1 binding to CXCR4 or antagonizing SDF-1-induced Ca2+ mobilization, is correlated with the presence of hBD-3 cysteine residues, specific surface-distributed cationic residues, and the electrostatic properties and availability of both hBD-3 termini. Specifically, hBD-3 activity against CXCR4 is reduced by: (a) replacing all six cysteines; (b) replacing the cationic residues with acidic ones in the N-terminus and C- terminus; (c) removal of the first 10N-terminal residues; and (d) replacing the surface-exposed basic residues Lys8, Lys32 and Arg36 with neutral ones. The hBD-3-CXCR4 interaction has potentially wide-ranging implications for HIV-related biology, as well as for a host of CXCR4-dependent activities, including hematopoiesis, neurogenesis, angiogenesis, carcinogenesis, and immune cell trafficking. CXCR4 is highly expressed on Tcells, monocytes, and epithelial cells. Therefore, understanding the structure-function relationship between hBD-3 and CXCR4 that accounts for the antagonistic interaction between the two molecules may provide new insights into HIV/highly active antiretroviral therapy-related pathology, as well as novel insights into the interaction between innate and adaptive immunity at mucosal sites. C1 [Feng, Zhimin; Jia, Xun; Weinberg, Aaron] Case Western Reserve Univ, Sch Dent Med, Dept Biol Sci, Cleveland, OH 44106 USA. [Dubyak, George R.] Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Lubkowski, Jacek T.] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick Natl Lab, Frederick, MD 21701 USA. RP Weinberg, A (reprint author), Case Western Reserve Univ, Sch Dent Med, 10900 Euclid Ave, Cleveland, OH 44106 USA. EM aaron.weinberg@case.edu FU NIH/NIDCR [PO1DE019759]; Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX This study was supported by NIH/NIDCR PO1DE019759 (A. Weinberg) and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (J. T. Lubkowski). NR 20 TC 3 Z9 3 U1 0 U2 2 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 2013 VL 280 IS 14 BP 3365 EP 3375 DI 10.1111/febs.12328 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 253ZG UT WOS:000327128700017 PM 23659571 ER PT J AU Morens, DM Taubenberger, JK Fauci, AS AF Morens, David M. Taubenberger, Jeffery K. Fauci, Anthony S. TI H7N9 Avian Influenza A Virus and the Perpetual Challenge of Potential Human Pandemicity SO MBIO LA English DT Review ID OCULAR TROPISM; HUMAN CONJUNCTIVITIS; HUMAN-BEINGS; POULTRY; H5N1; TRANSMISSIBILITY; EPIDEMIC; DISEASES; RISK AB The ongoing H7N9 influenza epizootic in China once again presents us questions about the origin of pandemics and how to recognize them in early stages of development. Over the past similar to 135 years, H7 influenza viruses have neither caused pandemics nor been recognized as having undergone human adaptation. Yet several unusual properties of these viruses, including their poultry epizootic potential, mammalian adaptation, and atypical clinical syndromes in rarely infected humans, suggest that they may be different from other avian influenza viruses, thus questioning any assurance that the likelihood of human adaptation is low. At the same time, the H7N9 epizootic provides an opportunity to learn more about the mammalian/human adaptational capabilities of avian influenza viruses and challenges us to integrate virologic and public health research and surveillance at the animal-human interface. C1 [Morens, David M.; Fauci, Anthony S.] NIAID, Off Director, NIH, Bethesda, MD 20892 USA. [Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, Off Director, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dmorens@niaid.nih.gov FU NIAID FX This work was supported by the Intramural Research Program of NIAID. NR 39 TC 15 Z9 18 U1 3 U2 15 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 2013 VL 4 IS 4 AR e00445-13 DI 10.1128/mBio.00445-13 PG 4 WC Microbiology SC Microbiology GA 250UK UT WOS:000326881100041 ER PT J AU Taubenberger, JK Morens, DM AF Taubenberger, Jeffery K. Morens, David M. TI Reply to "'But Nature Started It': Examining Taubenberger and Morens' View on Influenza A Virus and Dual-Use Research of Concern" SO MBIO LA English DT Editorial Material C1 [Taubenberger, Jeffery K.; Morens, David M.] NIAID, NIH, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov NR 6 TC 0 Z9 0 U1 1 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 2013 VL 4 IS 4 AR e00579-13 DI 10.1128/mBio.00579-13 PG 1 WC Microbiology SC Microbiology GA 250UK UT WOS:000326881100059 ER PT J AU Taubenberger, JK Morens, DM AF Taubenberger, Jeffery K. Morens, David M. TI Influenza Viruses: Breaking All the Rules SO MBIO LA English DT Article ID NORTH-AMERICAN SWINE; A H7N9 VIRUS; AVIAN INFLUENZA; PANDEMIC INFLUENZA; OSELTAMIVIR RESISTANCE; RESPIRATORY-DROPLET; H5N1 INFLUENZA; UNITED-STATES; NS1 PROTEIN; STAPHYLOCOCCUS-AUREUS AB Influenza A viruses (IAV) are significant pathogens able to repeatedly switch hosts to infect multiple avian and mammalian species, including humans. The unpredictability of IAV evolution and interspecies movement creates continual public health challenges, such as the emergence of the 2009 pandemic H1N1 virus from swine, as well as pandemic threats from the ongoing H5N1 and the recent H7N9 epizootics. In the last decade there has been increased concern about the "dual use" nature of microbiology, and a set of guidelines covering "dual use research of concern" includes seven categories of potentially problematic scientific experiments. In this Perspective, we consider how in nature IAV continually undergo "dual use experiments" as a matter of evolution and selection, and we conclude that studying these properties of IAV is critical for mitigating and preventing future epidemics and pandemics. C1 [Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Morens, David M.] NIAID, Off Director, NIH, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU NIAID FX This work was supported by the Intramural Research Program of NIAID. NR 99 TC 1 Z9 1 U1 3 U2 15 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 2013 VL 4 IS 4 AR e00365-13 DI 10.1128/mBio.00365-13 PG 6 WC Microbiology SC Microbiology GA 250UK UT WOS:000326881100019 ER PT J AU Del Prete, GQ Lifson, JD AF Del Prete, Gregory Q. Lifson, Jeffrey D. TI Considerations in the development of nonhuman primate models of combination antiretroviral therapy for studies of AIDS virus suppression, residual virus, and curative strategies SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE antiretroviral therapy; cure; nonhuman primate; simian immunodeficiency viruses ID SIMIAN-IMMUNODEFICIENCY-VIRUS; SIV-INFECTED MACAQUES; CD4(+) T-CELLS; REVERSE-TRANSCRIPTASE INHIBITORS; SIVMAC239-INFECTED RHESUS MACAQUES; CENTRAL-NERVOUS-SYSTEM; IMMUNE-RESPONSES; VIRAL RESERVOIRS; HIV-1 INFECTION; M184V MUTATION AB Purpose of reviewAnimal models will be critical for preclinical evaluations of novel HIV eradication and/or functional cure strategies in the setting of suppressive combination antiretroviral therapy (cART). Here, the strengths, limitations, and challenges of recent efforts to develop nonhuman primate (NHP) models of cART-mediated suppression for use in studies of persistent virus and curative approaches are discussed.Recent findingsSeveral combinations of NHP species and viruses that recapitulate key aspects of human HIV infection have been adapted for cART-mediated suppression studies. Different cART regimens incorporating drugs targeting multiple different steps of the viral replication cycle have provided varying levels of virologic suppression, dependent in part upon the host species, virus, drug regimen and timing, and virologic monitoring assay sensitivity. New, increasingly sensitive virologic monitoring approaches for measurements of plasma viral RNA, cell-associated and tissue-associated viral RNA and DNA, and the replication-competent residual viral pool in the setting of cART in NHP models are being developed to allow for the assessment of persistent virus on cART and to evaluate the impact of viral induction/eradication strategies in vivo.SummaryGiven the vagaries of each specific virus and host species, and cART regimen, each model will require further development and analysis to determine their appropriate application for addressing specific experimental questions. C1 [Del Prete, Gregory Q.; Lifson, Jeffrey D.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. RP Lifson, JD (reprint author), SAIC Frederick Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, POB B, Frederick, MD 21702 USA. EM lifsonj@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported with federal funds from the National Cancer Institute, National Institutes of Health under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 85 TC 13 Z9 13 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD JUL PY 2013 VL 8 IS 4 BP 262 EP 272 DI 10.1097/COH.0b013e328361cf40 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 248UP UT WOS:000326730100002 PM 23698559 ER PT J AU Lynch, RM Yamamoto, T McDermott, AB AF Lynch, Rebecca M. Yamamoto, Takuya McDermott, Adrian B. TI HIV vaccine research and discovery in the nonhuman primates model: a unified theory in acquisition prevention and control of SIV infection SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE nonhuman primates model; SIV; vaccines ID T-CELL RESPONSES; IMMUNODEFICIENCY VIRUS CHALLENGE; NEUTRALIZATION IN-VITRO; MUCOSAL SHIV CHALLENGE; ENVELOPE PROTEIN; RHESUS MACAQUES; GERMINAL CENTER; GAG/POL/NEF VACCINE; IMMUNE-RESPONSES; ENV VACCINE AB Purpose of reviewHere we highlight the latest advances in HIV vaccine concepts that will expand our knowledge on how to elicit effective acquisition-prevention and/or control of simian immunodeficiency virus (SIV) replication in the nonhuman primate (NHP) model.Recent findingsIn the context of the promising analyses from the RV144 Thai Trial and the effective control of SIV replication exerted by rhCMV-(SIV) elicited EM CD8 T cells, the HIV field has recently shifted toward vaccine concepts that combine protection from acquisition with effective control of SIV replication. Current studies in the NHP model have demonstrated the efficacy of HIV-neutralizing antibodies via passive transfer, the potential importance of the CD4 Tfh subset, the ability to effectively model the RV144 vaccine trial and the capacity of an Ad26 prime and modified vaccinia Ankara virus boost to elicit Env-specific antibody and cellular responses that both limit acquisition and control heterologous SIVmac251 challenge.SummaryThe latest work in the NHP model suggests that the next generation HIV-1 vaccines should aim to provoke a comprehensive adaptive immune response for both prevention of SIV acquisition as well as control of replication in breakthrough infection. C1 [Lynch, Rebecca M.; Yamamoto, Takuya; McDermott, Adrian B.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP McDermott, AB (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Rm 3508, Bethesda, MD 20892 USA. EM adrian.mcdermott@nih.gov RI Yamamoto, Takuya/L-2642-2013 OI Yamamoto, Takuya/0000-0003-3753-1211 FU Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [T32 AI007610] NR 68 TC 6 Z9 6 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD JUL PY 2013 VL 8 IS 4 BP 288 EP 294 DI 10.1097/COH.0b013e328361cfe8 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 248UP UT WOS:000326730100005 PM 23666390 ER PT J AU Malekzadeh, MM Etemadi, A Kamangar, F Khademi, H Golozar, A Islami, F Pourshams, A Poustchi, H Navabakhsh, B Naemi, M Pharoah, PD Abnet, CC Brennan, P Boffetta, P Dawsey, SM Esteghamati, A Malekzadeh, R AF Malekzadeh, Masoud M. Etemadi, Arash Kamangar, Farin Khademi, Hooman Golozar, Asieh Islami, Farhad Pourshams, Akram Poustchi, Hossein Navabakhsh, Behrouz Naemi, Mohammad Pharoah, Paul D. Abnet, Christian C. Brennan, Paul Boffetta, Paolo Dawsey, Sanford M. Esteghamati, Alireza Malekzadeh, Reza TI Prevalence, awareness and risk factors of hypertension in a large cohort of Iranian adult population SO JOURNAL OF HYPERTENSION LA English DT Article DE awareness; hypertension; obesity; smoking; socioeconomic status ID CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; NONCOMMUNICABLE DISEASES; PHYSICAL-ACTIVITY; ENDOTHELIAL DYSFUNCTION; NATIONAL SURVEILLANCE; INCIDENT HYPERTENSION; ARTERIAL STIFFNESS; CIGARETTE-SMOKING; GOLESTAN COHORT AB Background:There is considerable variation in hypertension prevalence and awareness, and their correlates, across different geographic locations and ethnic groups. We performed this cross-sectional analysis on data from the Golestan Cohort Study (GCS).Methods:Enrollment in this study occurred in 2004-2008, and included 50045 healthy individuals from Golestan Province in northeastern Iran. Hypertension was defined as a SBP at least 140mmHg, a DBP at least 90mmHg, a prior diagnosis of hypertension, or the use of antihypertensive drugs. Potential correlates of hypertension and its awareness were analyzed by logistic regression adjusted for sex, age, BMI, place of residence, literacy, ethnicity, physical activity, smoking, black and green tea consumption and wealth score.Results:Of the total cohort participants, 21350 (42.7%) were hypertensive. Age-standardized prevalence of hypertension, using the 2001 WHO standard world population, was 41.8% (95% confidence interval: 38.3-45.2%). Hypertension was directly associated with female sex, increased BMI, Turkmen ethnicity, and lack of physical activity, and inversely associated with drinking black tea and wealth score. Among hypertensive patients, 46.2% were aware of their disease, 17.6% were receiving antihypertensive medication, and 32.1% of the treated patients had controlled hypertension. Hypertension awareness was greater among women, the elderly, overweight and obese patients, and those with a higher wealth score.Conclusion:Hypertension is highly prevalent in rural Iran, many of the affected individuals are unaware of their disease, and the rate of control by antihypertensive medications is low. Increasing hypertension awareness and access to health services, especially among less privileged residents are recommended. C1 [Malekzadeh, Masoud M.; Etemadi, Arash; Kamangar, Farin; Khademi, Hooman; Golozar, Asieh; Islami, Farhad; Pourshams, Akram; Poustchi, Hossein; Navabakhsh, Behrouz; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Etemadi, Arash; Golozar, Asieh; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Kamangar, Farin; Brennan, Paul] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. [Khademi, Hooman] Int Agcy Res Canc, F-69372 Lyon, France. [Islami, Farhad; Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Islami, Farhad; Boffetta, Paolo] Inst Translat Epidemiol, New York, NY USA. [Naemi, Mohammad] Gorgan Univ Med Sci, Sch Med, Dept Internal Med, Gorgan, Iran. [Pharoah, Paul D.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul D.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Esteghamati, Alireza] Univ Tehran Med Sci, Vali Asr Hosp, Endocrinol & Metab Res Ctr, Tehran, Iran. RP Etemadi, A (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. EM arash.etemadi@nih.gov RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016; OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072; Malekzadeh, Reza/0000-0003-1043-3814 FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH; Digestive Disease Research Center of Tehran University of Medical Sciences [82-603]; Cancer Research UK (CRUK); International Agency for Research on Cancer FX This study was supported in part by the intramural research program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, NIH, by the Digestive Disease Research Center of Tehran University of Medical Sciences (grant No 82-603), by Cancer Research UK (CRUK), and by the International Agency for Research on Cancer. NR 72 TC 22 Z9 22 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD JUL PY 2013 VL 31 IS 7 BP 1364 EP 1371 DI 10.1097/HJH.0b013e3283613053 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 247DR UT WOS:000326595500005 PM 23673348 ER PT J AU Ho, JE Larson, MG Ghorbani, A Cheng, S Vasan, RS Wang, TJ Januzzi, JL AF Ho, Jennifer E. Larson, Martin G. Ghorbani, Anahita Cheng, Susan Vasan, Ramachandran S. Wang, Thomas J. Januzzi, James L., Jr. TI Soluble ST2 predicts elevated SBP in the community SO JOURNAL OF HYPERTENSION LA English DT Article DE biological markers; blood pressure; epidemiology; hypertension; immune system; risk factors ID FAMILY-MEMBER ST2; DECOMPENSATED HEART-FAILURE; MYOCARDIAL-INFARCTION; ENDOTHELIAL-CELLS; NATRIURETIC PEPTIDE; CARDIAC STRUCTURE; ACUTE DYSPNEA; SERUM-LEVELS; T-CELLS; IL-33 AB Background:Soluble ST2 (sST2) is an emerging prognostic biomarker in patients with existing cardiovascular disease. ST2 and its ligand, interleukin-33 (IL-33), are expressed in endothelial cells, and may play an important role in the development of early atherosclerosis and vascular biology. We sought to investigate the association of sST2 and progression of blood pressure (BP), as well as the development of hypertension.Methods:Circulating sST2 concentrations were measured in 1834 participants (mean age 56 years, 57% women) of the community-based Framingham Offspring study. Participants were free of hypertension at baseline. Multivariable linear and logistic regression models were used to evaluate the association of sST2 concentrations and subsequent BP outcomes.Results:Higher sST2 concentrations were associated with incident hypertension over 3 years of follow-up [multivariable-adjusted odds ratio per 1 standard deviation increase in sST2 1.22, 95% confidence interval 1.05-1.42, P=0.01]. Individuals in the upper sST2 quartile had a 2.6mmHg greater increase in SBP compared with those in the lowest quartile (P for trend across quartiles 0.002) and a 1.8mmHg greater increase in pulse pressure (P for trend 0.005). In contrast, sST2 concentrations were not associated with changes in DBP (P=0.27).Conclusion:These findings suggest that sST2 concentrations predict changes in BP physiology typically seen with aging and progressive arterial stiffness. Further studies are needed to elucidate underlying mechanisms by which the ST2/IL-33 pathway may contribute to BP physiology. C1 [Ho, Jennifer E.; Larson, Martin G.; Cheng, Susan; Vasan, Ramachandran S.; Wang, Thomas J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ho, Jennifer E.; Larson, Martin G.; Cheng, Susan; Vasan, Ramachandran S.; Wang, Thomas J.] Boston Univ, Sch Med, Framingham, MA USA. [Ho, Jennifer E.] Boston Univ, Dept Med, Cardiovasc Med Sect, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Ghorbani, Anahita; Wang, Thomas J.; Januzzi, James L., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA USA. [Cheng, Susan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Cardiol, Boston, MA USA. [Vasan, Ramachandran S.; Januzzi, James L., Jr.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovascu Res Ctr,Dept Med, Boston, MA 02115 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey 5984,32 Fruit St, Boston, MA 02114 USA. EM jjanuzzi@partners.org OI Larson, Martin/0000-0002-9631-1254; Ho, Jennifer/0000-0002-7987-4768; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Heart Association; Ellison Foundation FX This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195). J.E.H. is supported by an American Heart Association Clinical Research Program award. S.C. is supported by an award from the Ellison Foundation. NR 40 TC 10 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD JUL PY 2013 VL 31 IS 7 BP 1431 EP 1436 DI 10.1097/HJH.0b013e3283611bdf PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 247DR UT WOS:000326595500013 PM 23615326 ER PT J AU Reed, LT Knapp, DW Miller, MA AF Reed, L. T. Knapp, D. W. Miller, M. A. TI Cutaneous Metastasis of Transitional Cell Carcinoma in 12 Dogs SO VETERINARY PATHOLOGY LA English DT Article DE bladder cancer; dog diseases; immunohistochemistry; neoplasm metastasis; Prox1; transitional cell carcinoma; urinary tract; uroplakin III ID URINARY-BLADDER; CYCLOOXYGENASE-2; EXPRESSION; CANCER; PROX1 AB In humans, cutaneous metastasis of transitional cell carcinoma (TCC) has been attributed to direct extension, lymphatic or hematogenous dissemination, or surgical implantation. The purpose of this study was to characterize the clinical and histologic features of cutaneous TCC metastasis, confirmed by uroplakin-III immunohistochemistry, in dogs. The 12 cases were 9 spayed female and 3 neutered male dogs, 6 to 14 years old (mean, 11 years). Four dogs had a history of urinary incontinence. Three had undergone abdominal surgery for TCC diagnosis or treatment. The primary neoplasms were 7 papillary infiltrating and 5 nonpapillary infiltrating TCC. Cutaneous lesions were detected at a mean of 123 days (median, 38 days) after diagnosis of the primary TCC and appeared as plaques, papules, or nodules in, with 1 exception, perineal, inguinal, or ventral abdominal dermis or subcutis. Of 8 dogs with dermal TCC, 5 had epidermal erosion or ulceration. In 10 dogs, TCC was detected in cutaneous lymphatic vessels, identified by endothelial immunoreactivity for Prox1. Metastases were also detected in lymph nodes in all dogs and at distant noncutaneous sites, usually the lungs, in 10 dogs. Mean survival after diagnosis was 162 days (median, 90 days). Despite medical treatment of 10 dogs after the development of cutaneous metastasis, remission was not achieved; 4 dogs had stable disease. Although TCC could have spread to skin by direct extension or lymphatic or vascular dissemination, the proximity of most cutaneous metastases to the vulva or prepuce raises the additional possibility of transepidermal spread through urine-scalded skin. C1 [Reed, L. T.; Miller, M. A.] Purdue Univ, Dept Comparat Pathobiol, W Lafayette, IN 47907 USA. [Reed, L. T.; Miller, M. A.] Purdue Univ, Indiana Anim Dis Diagnost Lab, W Lafayette, IN 47907 USA. [Reed, L. T.] NCI, NIH, Comparat Biomed Scientist Training Program, Bethesda, MD 20892 USA. [Knapp, D. W.] Purdue Univ, Dept Vet Clin Sci, W Lafayette, IN 47907 USA. [Knapp, D. W.] Purdue Univ, Ctr Canc Res, W Lafayette, IN 47907 USA. RP Miller, MA (reprint author), Purdue Univ, Anim Dis Diagnost Lab, 406 S Univ St, W Lafayette, IN 47907 USA. EM pegmiller@purdue.edu NR 15 TC 3 Z9 3 U1 1 U2 19 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD JUL PY 2013 VL 50 IS 4 BP 676 EP 681 DI 10.1177/0300985812465326 PG 6 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 248MX UT WOS:000326705600017 PM 23136183 ER PT J AU Kassim, SH Jordan, J Schreiter, J Adhikarakunnathu, S Baribaud, F Mateo, LS AF Kassim, Sadik H. Jordan, Jarrat Schreiter, Jessica Adhikarakunnathu, Sreedevi Baribaud, Fred Mateo, Lani San TI Systematic identification of novel SLE related autoantibodies responsible for type I IFN production in human plasmacytoid dendritic cells SO CELLULAR IMMUNOLOGY LA English DT Article DE Protein array; Autoimmune; Innate immunity; SLE; Plasmacytoid dendritic cells; Type I interferons ID CUTANEOUS LUPUS-ERYTHEMATOSUS; ANTI-CCP ANTIBODIES; 3 ETHNIC-GROUPS; INTERFERON-ALPHA; IMMUNE-COMPLEXES; RHEUMATOID-ARTHRITIS; ALZHEIMERS-DISEASE; NUCLEIC-ACID; ACTIVATION; PROTEIN AB Plasmacytoid dendritic cells [pDC], also known as type I interferon [IFN] producing cells, play a significant role in the pathogenesis of systemic lupus erythematosus ISLE]. The current study was undertaken to identify novel SLE autoantibody specificities associated with interferon-inducing activity in human pDCs. We found that immune complex mixtures from some Interferon signature negative [IFN-] and all interferon signature positive [IFN+] SLE patients could trigger type I IFN production by pDCs. IgGs from IFN- and IFN+ SLE patients were subsequently screened via a high throughput protein microarray to identify novel auto-antibody specifities that mediate type I IFN production by pDCs. ThiS approach identified five novel autoantibodies that may contribute to type I IFN production by pDCs via a nucleic acid dependent mechanism. The newly identified autoantibody specificities function in a myriad of cell processess and, to date, have not been implicated in SLE pathogenesis. Published by Elsevier Inc. C1 [Kassim, Sadik H.; Jordan, Jarrat; Schreiter, Jessica; Adhikarakunnathu, Sreedevi; Baribaud, Fred; Mateo, Lani San] Janssen Pharmaceut Res & Dev LLC, Innate Immun, Spring House, PA 19477 USA. RP Kassim, SH (reprint author), NCI, NIH, Surg Branch, Bldg 10-CRC,Room 3W3808, Bethesda, MD 20892 USA. EM sadik.kassim@nih.gov FU Janssen Pharmaceutical Research and Development, L.L.C FX Janssen Pharmaceutical Research and Development, L.L.C funded the research described in this manuscript. The authors declare that they have no financial interests that could create a potential conflict of interest or the appearance of a conflict of interest with regard to the work. NR 51 TC 3 Z9 4 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 EI 1090-2163 J9 CELL IMMUNOL JI Cell. Immunol. PD JUL-AUG PY 2013 VL 284 IS 1-2 BP 119 EP 128 DI 10.1016/j.cellimm.2013.07.017 PG 10 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 244YL UT WOS:000326426000016 PM 23973875 ER PT J AU Verma, M AF Verma, Mukesh TI Cancer control and prevention: nutrition and epigenetics SO CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE LA English DT Review DE bioactive food components; biomarker; cancer; epigenetics; prevention ID DETECT GASTROINTESTINAL NEOPLASIA; GENE PROMOTER HYPERMETHYLATION; HISTONE DEACETYLASE ACTIVITY; BIOACTIVE FOOD COMPONENTS; SQUAMOUS-CELL CARCINOMA; TUMOR-SUPPRESSOR GENES; FECAL DNA METHYLATION; TRANS-RETINOIC ACID; COLORECTAL-CANCER; LUNG-CANCER AB Purpose of reviewTo evaluate recent developments in nutritional epigenomics and related challenges, opportunities, and implications for cancer control and prevention.Recent findingsCancer is one of the leading causes of death worldwide, and understanding the factors that contribute to cancer development may facilitate the development of strategies for cancer prevention and control. Cancer development involves genetic and epigenetic alterations. Genetic marks are permanent, whereas epigenetic marks are dynamic, change with age, and are influenced by the external environment. Thus, epigenetics provides a link between the environment, diet, and cancer development. Proper food selection is imperative for better health and to avoid cancer and other diseases. Nutrients either contribute directly to cancer prevention or support the repair of genomic and epigenomic damage caused by exposure to cancer-causing agents such as toxins, free radicals, radiation, and infectious agents. Nutritional epigenomics provides an opportunity for cancer prevention because selected nutrients have the potential to reverse cancer-associated epigenetic marks in different tumor types. A number of natural foods and their bioactive components have been shown to have methylation-inhibitory and deacetylation-inhibitory properties.SummaryNatural foods and bioactive food components have characteristics and functions that are similar to epigenetic inhibitors and therefore have potential in cancer control and prevention. C1 [Verma, Mukesh] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Verma, M (reprint author), NCI, Methods & Technol Branch, Div Canc Control & Populat Sci, NIH, 6130 Execut Blvd,Suite 5100, Bethesda, MD 20892 USA. EM vermam@mail.nih.gov NR 134 TC 11 Z9 12 U1 5 U2 37 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1363-1950 EI 1473-6519 J9 CURR OPIN CLIN NUTR JI Curr. Opin. Clin. Nutr. Metab. Care PD JUL PY 2013 VL 16 IS 4 BP 376 EP 384 DI 10.1097/MCO.0b013e328361dc70 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 247AZ UT WOS:000326586600002 PM 23676683 ER PT J AU Tarlykov, P Shoaib, M Kulyyassov, A Robin, C Ramanculov, E Ogryzko, V AF Tarlykov, P. Shoaib, M. Kulyyassov, A. Robin, C. Ramanculov, E. Ogryzko, V. TI A novel proteomic approach to study epigenetic changes in chromatin SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Tarlykov, P.] LN Gumilyov Eurasian Natl Univ, Astana, Kazakhstan. [Shoaib, M.; Robin, C.; Ogryzko, V.] Univ Paris 11, CNRS UMR 8126, Inst Cancerol Gustave Roussy, Villejuif, France. [Kulyyassov, A.; Ramanculov, E.] Natl Biotechnol Ctr, Astana, Kazakhstan. RI Tarlykov, Pavel/C-2587-2012 OI Tarlykov, Pavel/0000-0003-2075-307X 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 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 9 EP 9 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919200028 ER PT J AU Stranecky, V Hoischen, A Hartmannova, H Zaki, MS Chaudhary, A Zudaire, E Noskova, L Baresova, V Pristoupilova, A Hodanova, K Sovova, J AF Stranecky, V. Hoischen, A. Hartmannova, H. Zaki, M. S. Chaudhary, A. Zudaire, E. Noskova, L. Baresova, V. Pristoupilova, A. Hodanova, K. Sovova, J. TI Mutations in ANTXR1 cause GAPO syndrome inherited disorders SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Stranecky, V.; Hartmannova, H.; Noskova, L.; Baresova, V.; Pristoupilova, A.; Hodanova, K.; Sovova, J.] Charles Univ Prague, Inst Inherited Metab Disorders, Fac Med 1, Prague, Czech Republic. [Hoischen, A.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen Ctr Mol Life Sci,Inst Genet & Metab Dis, NL-6525 ED Nijmegen, Netherlands. [Zaki, M. S.] Natl Res Ctr, Dept Clin Genet, Cairo, Egypt. [Chaudhary, A.; Zudaire, E.] Frederick Natl Lab Canc Res, Tumor Angiogenesis Sect, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 22 EP 22 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919200071 ER PT J AU Wilson, SH AF Wilson, S. H. TI Understanding base lesion DNA repair SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Wilson, S. H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 53 EP 53 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919200177 ER PT J AU Pizzi, S Lazzaro, F Novarina, D Carnevali, S Watt, D Stone, J Burgers, PM Kunkel, T Muzi-Falconi, M Plevani, P AF Pizzi, S. Lazzaro, F. Novarina, D. Carnevali, S. Watt, D. Stone, J. Burgers, P. M. Kunkel, T. Muzi-Falconi, M. Plevani, P. TI RNase H and post-replication repair protect cells from ribonucleotides incorporated in DNA SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Pizzi, S.; Lazzaro, F.; Novarina, D.; Carnevali, S.; Muzi-Falconi, M.; Plevani, P.] Univ Milan, Dipartimento Biosci, I-20122 Milan, Italy. [Watt, D.; Stone, J.; Kunkel, T.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Watt, D.; Stone, J.; Kunkel, T.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Burgers, P. M.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RI Lazzaro, Federico/J-3585-2013 OI Lazzaro, Federico/0000-0001-6415-2925 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 55 EP 55 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919200183 ER PT J AU Muftuoglu, M Aamann, MD Stevnsner, T Bohr, VA AF Muftuoglu, M. Aamann, M. D. Stevnsner, T. Bohr, V. A. TI The involvement of Cockayne syndrome B protein in base excision repair SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Muftuoglu, M.] Koc Univ, Dept Biochem, Sch Med, Istanbul, Turkey. [Aamann, M. D.; Stevnsner, T.] Aarhus Univ, Dept Mol Biol & Genet, Danish Ctr Mol Gerontol, Aarhus, Denmark. [Aamann, M. D.; Stevnsner, T.] Aarhus Univ, Danish Aging Res Ctr, Aarhus, Denmark. [Bohr, V. A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 62 EP 62 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919200205 ER PT J AU Rosta, E Yang, W Hummer, G AF Rosta, E. Yang, W. Hummer, G. TI Complementary role of the two metal ions in the catalytic reaction of RNase H SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Yang, W.; Hummer, G.] NIDDK, NIH, Bethesda, MD USA. RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 93 EP 93 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919200296 ER PT J AU Rotanova, TV Wlodawer, A Gustchina, A AF Rotanova, T. V. Wlodawer, A. Gustchina, A. TI Unique alpha-helical insert between the N-terminal domain and AAA(+) module of LonA proteases SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Rotanova, T. V.] Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. [Wlodawer, A.; Gustchina, A.] NCI, Frederick, MD 21701 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 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 136 EP 136 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919200422 ER PT J AU Kasikci, F Niamh, CX Yanik, T Loh, PY AF Kasikci, F. Niamh, C. X. Yanik, T. Loh, P. Y. TI Investigation of the cellular mechanisms underlying the carboxypeptidase E mutation SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Kasikci, F.; Yanik, T.; Loh, P. Y.] Middle E Tech Univ, Dept Biol Sci, TR-06531 Ankara, Turkey. [Niamh, C. X.] NICHHD, Cellular Neurobiol Sect, Dev Neurobiol 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 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 203 EP 203 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919201132 ER PT J AU Lyanguzova, M Arnaoutov, A Dasso, M AF Lyanguzova, M. Arnaoutov, A. Dasso, M. TI Divergent mechanisms of Ran pathway organization in metazoan species SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Lyanguzova, M.; Arnaoutov, A.; Dasso, M.] NICHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 271 EP 272 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919201339 ER PT J AU Bruton, P Huidobro, C Larionov, V Kagansky, A AF Bruton, P. Huidobro, C. Larionov, V. Kagansky, A. TI Screening for small molecules that disrupt epigenetic silencing in mammalian cells SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Bruton, P.; Huidobro, C.; Larionov, V.] Univ Edinburgh, Human Genet Unit, MRC, Edinburgh EH8 9YL, Midlothian, Scotland. [Kagansky, A.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 276 EP 276 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919201349 ER PT J AU Wlodawer, A AF Wlodawer, A. TI Fighting HIV: enzyme inhibitors, lectins, and antibodies SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Wlodawer, A.] NCI, Frederick, MD 21701 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 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 354 EP 354 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919202125 ER PT J AU Khandazhinskaya, A Karpenko, I Frolova, S Kukhanova, M Jasko, M Yanvarev, D Shirokova, E Margolis, L Kochetkov, S AF Khandazhinskaya, A. Karpenko, I. Frolova, S. Kukhanova, M. Jasko, M. Yanvarev, D. Shirokova, E. Margolis, L. Kochetkov, S. TI AZT prodrugs: achievements and trends in the treatment and prevention of HIV infection SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Khandazhinskaya, A.; Karpenko, I.; Frolova, S.; Kukhanova, M.; Jasko, M.; Yanvarev, D.; Shirokova, E.; Kochetkov, S.] Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow, Russia. [Margolis, L.] NICHHD, NICHD, NIH, Bethesda, MD 20892 USA. RI Kochetkov, Sergey /O-1065-2013; Karpenko, Inna/F-5879-2015 OI Karpenko, Inna/0000-0001-9849-0447 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 365 EP 365 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919202158 ER PT J AU Staudt, LM AF Staudt, L. M. TI Therapeutic efficacy of B cell receptor signaling inhibitors in lymphoma SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Staudt, L. M.] NCI, Metab Branch, 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 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 375 EP 375 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919202186 ER PT J AU Aitkulova, A Tarlykov, P Dzholdasbekova, A Taizhanova, D Karabaeva, R Zholdybaeva, E AF Aitkulova, A. Tarlykov, P. Dzholdasbekova, A. Taizhanova, D. Karabaeva, R. Zholdybaeva, E. TI Genetic variations associated with coronary restenosis in Kazakh population SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Aitkulova, A.; Tarlykov, P.; Zholdybaeva, E.] Natl Biotechnol Ctr, Astana, Kazakhstan. [Dzholdasbekova, A.] Natl Sci Med Res Ctr, Astana, Kazakhstan. [Taizhanova, D.] Karaganda State Med Univ, Karaganda, Kazakhstan. RI Akhmadyarova, Bota/R-4730-2016; Tarlykov, Pavel/C-2587-2012 OI Tarlykov, Pavel/0000-0003-2075-307X 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 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 385 EP 386 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919202218 ER PT J AU Crane-Robinson, C Hu, GQ Cui, K Zhao, K AF Crane-Robinson, C. Hu, G. -Q. Cui, K. Zhao, K. TI The variant histone H2A.Z is a general facilitator of chromatin remodeling SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Crane-Robinson, C.] Univ Portsmouth, Portsmouth, Hants, England. [Hu, G. -Q.; Cui, K.; Zhao, K.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 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 2013 VL 280 SU 1 SI SI BP 445 EP 445 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919202395 ER PT J AU Liskovykh, M Larionov, V Kouprina, N Bader, M Alenina, N Tomilin, A AF Liskovykh, M. Larionov, V. Kouprina, N. Bader, M. Alenina, N. Tomilin, A. TI Mouse embryonic stem cells carrying human artificial chromosome SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Liskovykh, M.; Tomilin, A.] Russian Acad Sci, Inst Cytol, St Petersburg 194064, Russia. [Larionov, V.; Kouprina, N.] NCI, NIH, Bethesda, MD 20892 USA. [Bader, M.; Alenina, N.] Max Delbruck Ctr Mol Med, Berlin, Germany. RI Tomilin, Alexey/C-3361-2014 OI Tomilin, Alexey/0000-0002-1137-7167 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 448 EP 448 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919202406 ER PT J AU Chashchina, AA Drutskaya, MS Kruglov, AA Kozlov, SV Nedospasov, SA AF Chashchina, A. A. Drutskaya, M. S. Kruglov, A. A. Kozlov, S. V. Nedospasov, S. A. TI Evaluation of the immune functions in novel humanized TNF knock-in mice SO FEBS JOURNAL LA English DT Meeting Abstract CT 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS) CY JUL 06-11, 2013 CL Saint Petersburg, RUSSIA SP Federat European Biochemical Soc C1 [Chashchina, A. A.; Drutskaya, M. S.; Kruglov, A. A.; Nedospasov, S. A.] Moscow MV Lomonosov State Univ, Fac Biol, Moscow, Russia. [Chashchina, A. A.; Drutskaya, M. S.; Kruglov, A. A.; Nedospasov, S. A.] Moscow MV Lomonosov State Univ, AN Belozersky Res Inst Physicochem Biol, Moscow, Russia. [Chashchina, A. A.; Drutskaya, M. S.; Nedospasov, S. A.] Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow, Russia. [Kruglov, A. A.] Leibniz Inst, German Rheumatism Res Ctr DRFZ, Berlin, Germany. [Kozlov, S. V.] Ctr Adv Preclin Res, Frederick Natl Lab Canc Res, Frederick, MD USA. RI Nedospasov, Sergei/L-1990-2015; Nedospasov, Sergei/Q-7319-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD JUL PY 2013 VL 280 SU 1 SI SI BP 462 EP 462 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 238CV UT WOS:000325919203015 ER PT J AU Simon, R Polley, E AF Simon, Richard Polley, Eric TI Clinical trials for precision oncology using next-generation sequencing SO PERSONALIZED MEDICINE LA English DT Article DE cancer biomarker; cancer clinical trial; next-generation sequencing; personalized medicine; precision medicine ID LUNG-CANCER; MEDICINE; DESIGN; DISCOVERY; SURVIVAL; THERAPY; GENOME AB The demonstrated genomic heterogeneity of human cancers is having major impacts on the development and evaluation of cancer therapeutics and molecular diagnostics. Many new cancer drugs target somatic alterations in tumors and are being developed with companion diagnostics. Oncology drug development and practice are likely to become increasingly stratified and utilize the enrichment Phase III trial paradigm. Although this paradigm includes an increasing number of successes, single-agent molecularly targeted treatment of metastatic disease will generally provide limited patient benefit. More substantial gains will require better understanding of crosstalk among signaling pathways, ability to combine drugs and use of drugs at initial diagnosis. Early phase discovery clinical trials in which patients will have genome-wide tumor characterization at diagnosis and at critical retreatment points will provide data sets for learning how to effectively match therapeutics to genomic alterations. However, moving tumor genomics to clinical oncology entails many practical challenges. We review some of these challenges and the clinical studies that are being undertaken to translate genomics to clinical oncology. C1 [Simon, Richard; Polley, Eric] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, 9609 Med Ctr Dr,Room 5W110,MSC 9735, Bethesda, MD 20892 USA. EM rsimon@nih.gov NR 27 TC 8 Z9 8 U1 1 U2 7 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 EI 1744-828X J9 PERS MED JI Pers. Med. PD JUL PY 2013 VL 10 IS 5 BP 485 EP 495 DI 10.2217/pme.13.36 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 244KX UT WOS:000326388300013 ER PT J AU Grant, K Lindenberg, ML Shebel, H Pang, YX Agarwal, HK Bernardo, M Kurdziel, KA Turkbey, B Choyke, PL AF Grant, Kinzya Lindenberg, Maria L. Shebel, Haytham Pang, Yuxi Agarwal, Harsh K. Bernardo, Marcelino Kurdziel, Karen A. Turkbey, Baris Choyke, Peter L. TI Functional and molecular imaging of localized and recurrent prostate cancer SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Review DE Prostate cancer; MRI; PET/CT ID DIFFUSION-WEIGHTED MRI; CONTRAST-ENHANCED MRI; BEAM RADIATION-THERAPY; RADICAL PROSTATECTOMY; ENDORECTAL MR; C-11-ACETATE PET/CT; ANTI-1-AMINO-3-F-18-FLUOROCYCLOBUTANE-1-CARBOXYLIC ACID; HISTOPATHOLOGIC CORRELATION; EXTRACAPSULAR EXTENSION; PATHOLOGICAL FINDINGS AB Prostate cancer is the most common malignancy among American men. Imaging of localized and recurrent prostate cancer is challenging since conventional imaging techniques are limited. New imaging techniques such as multiparametric MRI and PET with targeted tracers have been investigated extensively in the last decade. As a result, the role of novel imaging techniques for the detection of localized and recurrent prostate cancer has recently expanded. In this review, novel functional and molecular imaging techniques used in the management of localized and recurrent prostate cancer are discussed. C1 [Grant, Kinzya; Lindenberg, Maria L.; Bernardo, Marcelino; Kurdziel, Karen A.; Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Shebel, Haytham] Mansoura Univ, Dept Radiol, Urol & Nephrol Ctr, Mansoura, Egypt. [Pang, Yuxi] Philips Healthcare, Cleveland, OH USA. [Agarwal, Harsh K.] Philips Res North Amer, Briarcliff Manor, NY USA. [Bernardo, Marcelino] NCI, SAIC Frederick, Frederick, MD 21702 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr,MSC 1182 Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov NR 74 TC 5 Z9 5 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD JUL PY 2013 VL 40 SU 1 BP S48 EP S59 DI 10.1007/s00259-013-2419-6 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 237CU UT WOS:000325846600008 PM 23649462 ER PT J AU Park, JY Jeon, HJ Kim, TY Lee, KY Park, K Lee, ES Choi, JM Park, CG Jeon, SH AF Park, Joo-Young Jeon, Ho-Jin Kim, Tae Yun Lee, Kyeong-Yeoll Park, Kyoungsook Lee, Eui Seok Choi, Je-Min Park, Chung-Gyu Jeon, Soung-Hoo TI Comparative analysis of mesenchymal stem cell surface marker expression for human dental mesenchymal stem cells SO REGENERATIVE MEDICINE LA English DT Article DE CD71; human dental mesenchymal stem cells; stem cell marker; transferrin receptor ID HUMAN BONE-MARROW; HUMAN PERIODONTAL-LIGAMENT; THERAPY POSITION STATEMENT; STROMAL CELLS; INTERNATIONAL-SOCIETY; PROGENITOR CELLS; NEURAL CREST; SELF-RENEWAL; DIFFERENTIATION; PULP AB Aim: Human dental mesenchymal stem cells (hDMSCs) have been isolated from extracted human teeth and proven to have different proliferation and differentiation abilities among the subtypes. Despite increasing interest in the clinical use of hDMSCs, a well-defined specific marker has been absent for these stem cells. In this study, a comparative analysis with known mesenchymal stem cell surface markers such as STRO-1, CD90, CD146, CD34 and TfR (CD71) was performed. Materials & methods: Four subtypes of the hDMSCs were obtained and cultured. The hDMSCs were processed by flow cytometric analysis, fluorescence immunocytostaining for in vitro study and in situ immunohistochemical staining for in vivo study. Results & conclusion: The previously known positive and negative MSC markers, such as STRO-1, CD90, CD146 and CD34 showed comparative expression profiles of hDMSC subtypes. TfR was highly positive in hDMSCs compared with the control cells; therefore, TfR was suggested as a new marker for hDMSCs in this study. C1 [Park, Joo-Young] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Park, Joo-Young; Park, Chung-Gyu; Jeon, Soung-Hoo] Seoul Natl Univ, Coll Med, Xenotransplantat Res Ctr, Seoul Natl Univ Hosp,Dept Microbiol & Immunol,Can, Seoul 110799, South Korea. [Park, Joo-Young; Park, Chung-Gyu; Jeon, Soung-Hoo] Seoul Natl Univ, Coll Med, Xenotransplantat Res Ctr, Seoul Natl Univ Hosp,Transplantat Res Inst SNUMRC, Seoul 110799, South Korea. [Jeon, Ho-Jin] Seoul Natl Univ, Dept Civil & Environm Engn, Seoul 151744, South Korea. [Kim, Tae Yun] Yonsei Univ, Coll Med, Dept Environm Med Biol, Seoul 120749, South Korea. [Lee, Kyeong-Yeoll] Kyungpook Natl Univ, Coll Agr & Life Sci, Taegu 702701, South Korea. [Park, Kyoungsook] Sungkyunkwan Univ, Mol Therapy Res Ctr, Seoul 135710, South Korea. [Park, Kyoungsook] Samsung Biomed Res Inst, Clin Res Ctr, Seoul 135710, South Korea. [Lee, Eui Seok] Korea Univ, Grad Sch Clin Dent, Seoul 136705, South Korea. [Choi, Je-Min] Hanyang Univ, Res Inst Nat Sci, Dept Life Sci, Seoul 133791, South Korea. RP Jeon, SH (reprint author), Seoul Natl Univ, Coll Med, Xenotransplantat Res Ctr, Seoul Natl Univ Hosp,Dept Microbiol & Immunol,Can, 103 Daehak Ro, Seoul 110799, South Korea. EM shjeon1201@snu.ac.kr OI Park, Chung-Gyu/0000-0003-4083-8791 FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2012-0002779]; Korea Health 21 RD Project; Ministry of Health & Welfare, Republic of Korea [A040004] FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012-0002779) to S-H Jeon. This work was also supported in part by the grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A040004). 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 41 TC 5 Z9 5 U1 0 U2 7 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0751 EI 1746-076X J9 REGEN MED JI Regen. Med. PD JUL PY 2013 VL 8 IS 4 BP 453 EP 466 DI 10.2217/rme.13.23 PG 14 WC Cell & Tissue Engineering; Engineering, Biomedical SC Cell Biology; Engineering GA 236TX UT WOS:000325823400015 PM 23826699 ER PT J AU Wiener, L Pao, M Battles, H Zadeh, S Patenaude, AF Madan-Swain, A Friebert, S Elkin, D Kupst, MJ AF Wiener, Lori Pao, Maryland Battles, Haven Zadeh, Sima Patenaude, Andrea Farkas Madan-Swain, Avi Friebert, Sarah Elkin, David Kupst, Mary Jo CA Lone-Parent Study Grp TI Socio-Environmental Factors Associated With Lone Parenting Chronically Ill Children SO CHILDRENS HEALTH CARE LA English DT Article ID NEWLY-DIAGNOSED CANCER; DISTRESS THERMOMETER; CHILDHOOD-CANCER; CHRONIC ILLNESS; HEALTH-PROBLEMS; MOTHERS; DEPRESSION; SUPPORT; SINGLE; CAREGIVERS AB This article reports findings from 2 studies assessing the relation between parental perception of "lone" parenting and socioeconomic factors, including low income, perception of child health, and parental emotional distress among parents of chronically ill children. In both studies, parents who considered themselves a lone parent when caring for their ill child had significantly lower incomes and greater distress (i.e., were more likely to score at or above clinical or "case" cutoffs on the Brief Symptom Inventory) than those who considered themselves to be married or partnered. Longitudinal research is needed to determine the impact of lone parenting and low income on parental and child health outcomes over time. C1 [Wiener, Lori] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pao, Maryland] NIMH, NIH, Bethesda, MD 20892 USA. [Battles, Haven; Zadeh, Sima] NCI, NIH, Bethesda, MD 20892 USA. [Patenaude, Andrea Farkas] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Madan-Swain, Avi] Univ Alabama Birmingham, Div Hematol Oncol, Birmingham, AL 35294 USA. [Friebert, Sarah] Akron Childrens Hosp, Div Pediat Palliat Care, Akron, OH USA. [Elkin, David] Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA. [Kupst, Mary Jo] Med Coll Wisconsin, Milwaukee, WI 53226 USA. RP Wiener, L (reprint author), NCI, Behav Sci Core, Psychosocial Support & Res Program, Pediat Oncol Branch,Ctr Canc Res, 10 Ctr Dr, Bethesda, MD 20892 USA. EM wienerl@mail.nih.gov OI Kearney, Julia/0000-0003-1113-9617 NR 37 TC 2 Z9 2 U1 0 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0273-9615 EI 1532-6888 J9 CHILD HEALTH CARE JI Child. Health Care PD JUL 1 PY 2013 VL 42 IS 3 SI SI BP 264 EP 280 DI 10.1080/02739615.2013.816612 PG 17 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 218UN UT WOS:000324458100007 ER PT J AU Adams-Chapman, I Hansen, NI Shankaran, S Bell, EF Boghossian, NS Murray, JC Laptook, AR Walsh, MC Carlo, WA Sanchez, PJ Van Meurs, KP Das, A Hale, EC Newman, NS Ball, MB Higgins, RD Stoll, BJ AF Adams-Chapman, Ira Hansen, Nellie I. Shankaran, Seetha Bell, Edward F. Boghossian, Nansi S. Murray, Jeffrey C. Laptook, Abbot R. Walsh, Michele C. Carlo, Waldemar A. Sanchez, Pablo J. Van Meurs, Krisa P. Das, Abhik Hale, Ellen C. Newman, Nancy S. Ball, M. Bethany Higgins, Rosemary D. Stoll, Barbara J. CA Eunice Kennedy Shriver Natl Inst C TI Ten-Year Review of Major Birth Defects in VLBW Infants SO PEDIATRICS LA English DT Article DE birth defects; prematurity; Neonatal Research Network; low birth weight ID EXTREMELY PRETERM INFANTS; NEONATAL RESEARCH NETWORK; CONGENITAL HEART-DEFECTS; VERMONT-OXFORD NETWORK; WEIGHT INFANTS; UNITED-STATES; NECROTIZING ENTEROCOLITIS; MORTALITY; OUTCOMES; MALFORMATIONS AB OBJECTIVE: Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care. METHODS: Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics. RESULTS: A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41-3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001). CONCLUSIONS: Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants. C1 [Adams-Chapman, Ira; Hale, Ellen C.; Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30303 USA. [Adams-Chapman, Ira; Hale, Ellen C.; Stoll, Barbara J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Hansen, Nellie I.] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Bell, Edward F.; Boghossian, Nansi S.; Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Walsh, Michele C.; Newman, Nancy S.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Sanchez, Pablo J.; Ball, M. Bethany] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Van Meurs, Krisa P.] Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Van Meurs, Krisa P.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Adams-Chapman, I (reprint author), Emory Univ, Sch Med, Dept Pediat, Dev Progress Clin, 46 Jesse Hill Jr Dr SE, Atlanta, GA 30303 USA. EM iadamsc@emory.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health (NIH) FX The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development provided grant support for the Neonatal Research Network's VLBW registry study. Funded by the National Institutes of Health (NIH). NR 22 TC 10 Z9 10 U1 0 U2 12 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2013 VL 132 IS 1 BP 49 EP 61 DI 10.1542/peds.2012-3111 PG 13 WC Pediatrics SC Pediatrics GA 197HW UT WOS:000322841900045 PM 23733791 ER PT J AU Seward, SL Gahl, WA AF Seward, Samuel L., Jr. Gahl, William A. TI Hermansky-Pudlak Syndrome: Health Care Throughout Life SO PEDIATRICS LA English DT Review DE Hermansky-Pudlak; albinism; platelet storage pool deficiency; standard of care ID IDIOPATHIC PULMONARY-FIBROSIS; DISEASE; PIRFENIDONE; MUTATIONS; PATIENT; GENE; FORM; SKIN AB Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease that displays genetic heterogeneity; there are 9 known subtypes. HPS is characterized by oculocutaneous albinism, a platelet storage pool deficiency and resultant bleeding diathesis, and lysosomal accumulation of ceroid lipofuscin. Patients with HPS, specifically those with the genotypes HPS-1, HPS-2, or HPS-4, are predisposed to interstitial lung disease. In addition, some patients with HPS develop granulomatous colitis. Optimal health care requires a thorough knowledge of the unique health risks and functional limitations associated with this syndrome. C1 [Seward, Samuel L., Jr.] Columbia Univ, Dept Med, Med Ctr, New York, NY USA. [Gahl, William A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Seward, SL (reprint author), Columbia Hlth, MC 3601,519 West 114th St, New York, NY 10027 USA. EM sls2109@columbia.edu NR 30 TC 20 Z9 20 U1 1 U2 6 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2013 VL 132 IS 1 BP 153 EP 160 DI 10.1542/peds.2012-4003 PG 8 WC Pediatrics SC Pediatrics GA 197HW UT WOS:000322841900057 PM 23753089 ER PT J AU Alleman, BW Bell, EF Li, L Dagle, JM Smith, PB Ambalavanan, N Laughon, MM Stoll, BJ Goldberg, RN Carlo, WA Murray, JC Cotten, CM Shankaran, S Walsh, MC Laptook, AR Ellsbury, DL Hale, EC Newman, NS Wallace, DD Das, A Higgins, RD AF Alleman, Brandon W. Bell, Edward F. Li, Lei Dagle, John M. Smith, P. Brian Ambalavanan, Namasivayam Laughon, Matthew M. Stoll, Barbara J. Goldberg, Ronald N. Carlo, Waldemar A. Murray, Jeffrey C. Cotten, C. Michael Shankaran, Seetha Walsh, Michele C. Laptook, Abbot R. Ellsbury, Dan L. Hale, Ellen C. Newman, Nancy S. Wallace, Dennis D. Das, Abhik Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Ins Human Dev Neonatal Res Network TI Individual and Center- Level Factors Affecting Mortality Among Extremely Low Birth Weight Infants SO PEDIATRICS LA English DT Article DE mortality rates; outcome; NICU; preterm infants; extremely preterm infants ID NEONATAL RESEARCH NETWORK; GESTATIONAL-AGE; INTENSIVE-CARE; OUTCOMES; INDEX; SCORE; BORN; RISK AB OBJECTIVE: To examine factors affecting center differences in mortality for extremely low birth weight (ELBW) infants. METHODS: We analyzed data for 5418 ELBW infants born at 16 Neonatal Research Network centers during 2006-2009. The primary outcomes of early mortality (<= 12 hours after birth) and in-hospital mortality were assessed by using multilevel hierarchical models. Models were developed to investigate associations of center rates of selected interventions with mortality while adjusting for patient-level risk factors. These analyses were performed for all gestational ages (GAs) and separately for GAs <25 weeks and >= 25 weeks. RESULTS: Early and in-hospital mortality rates among centers were 5% to 36% and 11% to 53% for all GAs, 13% to 73% and 28% to 90% for GAs <25 weeks, and 1% to 11% and 7% to 26% for GAs >= 25 weeks, respectively. Center intervention rates significantly predicted both early and in-hospital mortality for infants <25 weeks. For infants >= 25 weeks, intervention rates did not predict mortality. The variance in mortality among centers was significant for all GAs and outcomes. Center use of interventions and patient risk factors explained some but not all of the center variation in mortality rates. CONCLUSIONS: Center intervention rates explain a portion of the center variation in mortality, especially for infants born at <25 weeks' GA. This finding suggests that deaths may be prevented by standardizing care for very early GA infants. However, differences in patient characteristics and center intervention rates do not account for all of the observed variability in mortality; and for infants with GA >= 25 weeks these differences account for only a small part of the variation in mortality. C1 [Alleman, Brandon W.; Bell, Edward F.; Dagle, John M.; Laughon, Matthew M.; Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Li, Lei; Wallace, Dennis D.] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Smith, P. Brian; Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Ambalavanan, Namasivayam; Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Laughon, Matthew M.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Shankaran, Seetha] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Walsh, Michele C.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Laptook, Abbot R.] Brown Univ, Dept Pediat, Women & Infants Hosp, Providence, RI 02912 USA. [Ellsbury, Dan L.] Pediatrix Med Grp, Ctr Res Educ & Qual, Sunrise, FL USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Bell, EF (reprint author), Univ Iowa, Dept Pediat, 200 Hawkins Dr, Iowa City, IA 52242 USA. EM edward-bell@uiowa.edu RI Smith, Phillip/I-5565-2014; OI Ambalavanan, Namasivayam/0000-0003-0731-9092 FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); NICHD; National Institutes for Health FX The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided grant support for the Neonatal Research Network's Generic Database Study. Dr Higgins is employed by the NICHD. The institutions of the other authors (except for Dr Ellsbury) received grant funding from the NICHD in support of this study. Funded by the National Institutes for Health. NR 19 TC 21 Z9 23 U1 0 U2 10 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2013 VL 132 IS 1 BP E175 EP E184 DI 10.1542/peds.2012-3707 PG 10 WC Pediatrics SC Pediatrics GA 197HW UT WOS:000322841900022 PM 23753096 ER PT J AU Carpenter, MA Hoberman, A Mattoo, TK Mathews, R Keren, R Chesney, RW Moxey-Mims, M Greenfield, SP AF Carpenter, Myra A. Hoberman, Alejandro Mattoo, Tej K. Mathews, Ranjiv Keren, Ron Chesney, Russell W. Moxey-Mims, Marva Greenfield, Saul P. CA RIVUR Trial Investigators TI The RIVUR Trial: Profile and Baseline Clinical Associations of Children With Vesicoureteral Reflux SO PEDIATRICS LA English DT Article DE vesicoureteral reflux (VUR); urinary tract infections; renal scarring; clinical research/trials ID URINARY-TRACT-INFECTION; YOUNG-CHILDREN; VOIDING CYSTOURETHROGRAPHY; ANTIBIOTIC-PROPHYLAXIS; FEBRILE INFANTS; RENAL SCARS; INITIAL UTI; FOLLOW-UP; DIAGNOSIS; MANAGEMENT AB BACKGROUND AND OBJECTIVE: Vesicoureteral reflux (VUR) is diagnosed in similar to 30% to 40% of children who have imaging studies after urinary tract infections (UTIs). Our goal is to characterize children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial and to compare our study cohort with those from previously published studies. METHODS: RIVUR investigators from 19 pediatric sites in the United States recruited 607 children with grade I through IV VUR. Children were enrolled after a first or second UTI. This cross-sectional report of baseline data includes extensive clinical, parental report, and imaging study results. RESULTS: RIVUR recruited 607 children (558 girls, 49 boys) with grade I (11%), II (42%), III (38%), or IV (8%) reflux. The median age was 12 months, and most children (91%) were enrolled after their first UTI. The UTI leading to enrollment was both febrile and symptomatic for 323 children, febrile only in 197 children, and symptomatic only in 86. Renal involvement at baseline as documented by a Tc-99m dimercaptosuccinic acid scan was uncommon with cortical defects identified in 89 (15%) children. Bladder and bowel dysfunction was identified in 71 (56%) of 126 toilet-trained subjects assessed. CONCLUSIONS: RIVUR is the largest prospective, randomized trial for children with primary VUR to date, comparing prophylaxis with placebo. The study sample comprises patients from 19 pediatric clinical sites in the United States, whose demographic and clinical characteristics may differ from those of children enrolled in previous trials from other countries. C1 [Carpenter, Myra A.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Hoberman, Alejandro] Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15213 USA. [Mattoo, Tej K.] Childrens Hosp Michigan, Dept Pediat, Detroit, MI 48201 USA. [Mathews, Ranjiv] Johns Hopkins Sch Med, Dept Urol, Baltimore, MD USA. [Keren, Ron] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Chesney, Russell W.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA. [Moxey-Mims, Marva] NIDDK, NIH, Bethesda, MD USA. [Greenfield, Saul P.] Women & Childrens Hosp Buffalo, Dept Pediat Urol, Buffalo, NY USA. RP Carpenter, MA (reprint author), Univ N Carolina, Collaborat Studies Coordinating Ctr, Dept Biostat, CB 8030,137 E Franklin St,Suite 203, Chapel Hill, NC 27599 USA. EM myra.carpenter@unc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services [U01 DK074059, U01 DK074053, U01 DK074082, U01 DK074064, U01 DK074062, U01 DK074063]; Children's Hospital of Philadelphia Clinical and Translational Science Award [UL1TR000003]; National Center for Research Resources at the National Center for Advancing Translational Sciences, National Institutes of Health; National Institutes of Health (NIH) FX Supported by grants U01 DK074059, U01 DK074053, U01 DK074082, U01 DK074064, U01 DK074062, and U01 DK074063 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services. The trial was also supported by the Children's Hospital of Philadelphia Clinical and Translational Science Award (grant UL1TR000003) from the National Center for Research Resources, now at the National Center for Advancing Translational Sciences, National Institutes of Health. Funded by the National Institutes of Health (NIH). NR 59 TC 20 Z9 20 U1 0 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2013 VL 132 IS 1 BP E34 EP E45 DI 10.1542/peds.2012-2301 PG 12 WC Pediatrics SC Pediatrics GA 197HW UT WOS:000322841900005 PM 23753091 ER PT J AU Martin, GR Beekman, RH Mikula, EB Fasules, J Garg, LF Kemper, AR Morrow, WR Pearson, GD Mahle, WT AF Martin, Gerard R. Beekman, Robert H. Mikula, Elizabeth Bradshaw Fasules, James Garg, Lorraine F. Kemper, Alex R. Morrow, W. Robert Pearson, Gail D. Mahle, William T. TI Implementing Recommended Screening for Critical Congenital Heart Disease SO PEDIATRICS LA English DT Article DE newborn screening; congenital heart defects ID PULSE OXIMETRY AB BACKGROUND AND OBJECTIVE: Critical congenital heart disease (CCHD) is endorsed by the US Secretary of Health and Human Services as part of the recommended uniform screening panel for newborns. Although initial recommendations for implementation exist, as states and hospitals have moved forward with implementation of screening, new challenges and areas for additional focus have been identified. The objective of this study was to develop recommendations to address current challenges and areas of focus surrounding CCHD newborn screening. METHODS: A workgroup of experts and stakeholders was convened in Washington, District of Columbia, for a 1-day meeting in February 2012. At the beginning of the meeting, the stakeholders held a brainstorming session to identify areas of main priority based on their experience. After this, stakeholders broke into small groups to refine recommendations, which were then finalized by consensus. RESULTS: Recommendations to address selection of screening equipment, standards for reporting of screening outcomes to stakeholders, training of health care providers and educating families, future research priorities, payment for screening, follow-up diagnostic testing, and public health oversight, and advocacy to facilitate effective and comprehensive screening were proposed. Suggestions for future work were developed. CONCLUSIONS: Screening for CCHD presents novel challenges and opportunities; however, addressing these will strengthen newborn screening and newborn care networks, and ultimately improve health outcomes. C1 [Martin, Gerard R.; Mikula, Elizabeth Bradshaw] George Washington Univ, Sch Med, Childrens Natl Med Ctr, Washington, DC USA. [Beekman, Robert H.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Fasules, James] Amer Coll Cardiol, Washington, DC USA. [Garg, Lorraine F.] New Jersey Dept Hlth, Trenton, NJ USA. [Kemper, Alex R.] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. [Kemper, Alex R.] Univ Arkansas Med Sci, Coll Med, Arkansas Childrens Hosp, Little Rock, AR 72205 USA. [Pearson, Gail D.] NHLBI, NIH, Bethesda, MD 20892 USA. [Mahle, William T.] Emory Univ, Sch Med, Childrens Healthcare Atlanta, Atlanta, GA USA. RP Martin, GR (reprint author), 111 Michigan Ave NW, Washington, DC 20010 USA. EM gmartin@childrensnational.org NR 8 TC 12 Z9 13 U1 1 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2013 VL 132 IS 1 BP E185 EP E192 DI 10.1542/peds.2012-3926 PG 8 WC Pediatrics SC Pediatrics GA 197HW UT WOS:000322841900023 PM 23776113 ER PT J AU Lo-Ciganic, WH Boudreau, RM Gray, SL Zgibor, JC Donohue, JM Perera, S Newman, AB Simonsick, EM Bauer, DC Satterfield, S Hanlon, JT AF Lo-Ciganic, Wei-Hsuan Boudreau, Robert M. Gray, Shelly L. Zgibor, Janice C. Donohue, Julie M. Perera, Subashan Newman, Anne B. Simonsick, Eleanor M. Bauer, Douglas C. Satterfield, Suzanne Hanlon, Joseph T. TI Changes in Cholesterol-Lowering Medications Use Over a Decade in Community-Dwelling Older Adults SO ANNALS OF PHARMACOTHERAPY LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-HEART-DISEASE; HIGH BLOOD CHOLESTEROL; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; ELDERLY-PATIENTS; BODY-COMPOSITION; SECONDARY PREVENTION; CONTROLLED TRIAL; UNITED-STATES AB BACKGROUND: The impact of evidence-based guidelines and controlled trial data on use of cholesterol-lowering medications in older adults is unclear. OBJECTIVE: To examine whether utilization patterns of cholesterol-lowering medications in community-dwelling older adults changed following the release of the National Cholesterol Education Program Adult Treatment Panel III guidelines and results from the Prospective Study of Pravastatin in the Elderly at Risk in 2002. METHODS: Community-dwelling elderly individuals who were enrolled in the Health, Aging and Body Composition Study in 1997-1998 were followed for up to 11 years. An interrupted time series analysis with multivariable generalized estimating equations (GEEs) was used to examine changes in level and trend in cholesterol-lowering medication use before and after 2002, adjusting for sociodemographics, health-related behaviors, and health status. RESULTS: Cholesterol-lowering medication use increased nearly 3-fold from 14.9% in 1997-1998 to 42.6% in 2007-2008, with statins representing the most common class used (87-94%). Multivariable GEE results revealed no significant difference in the level of cholesterol-lowering medication use after 2002 (adjusted OR 0.95; 95% CI 0.89-1.02). Multivariable GEE results revealed that trend changes in the rate of increase in cholesterol-lowering medication declined after 2002 (adjusted ratio of ORs 0.92; 95% CI 0.89-0.95). CONCLUSIONS: The use of cholesterol-lowering medication increased substantially over a decade in community-dwelling elderly individuals but was not related to a change in level or trend following the release of the guidelines and evidence-based data. C1 [Lo-Ciganic, Wei-Hsuan] Univ Pittsburgh, Sch Publ Hlth, Pittsburgh, PA 15260 USA. [Boudreau, Robert M.; Zgibor, Janice C.; Newman, Anne B.] Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Gray, Shelly L.] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. [Donohue, Julie M.] Univ Pittsburgh, Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA 15260 USA. [Perera, Subashan; Hanlon, Joseph T.] Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr, Pittsburgh, PA 15213 USA. [Simonsick, Eleanor M.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Sch Med, Dept Med, Div Gen Med, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Hanlon, Joseph T.] Pittsburgh Vet Affairs Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Hanlon, Joseph T.] Pittsburgh Vet Affairs Hlth Care Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. RP Hanlon, JT (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr, Pittsburgh, PA 15213 USA. EM jth14@pitt.edu RI Perera, Subashan/D-7603-2014; Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging [R01-AG 027017, P30-AG024827, T32-AG021885, K07-AG033174, R01-AG034056, R01-AG028050, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute of Nursing Research grants [R01-NR010135, R01-NR012459]; Agency for Healthcare Research and Quality [R01-HS017695, K12-HS019461, R01-HS018721]; National Institutes of Health, National Institute on Aging FX This study was supported in part by National Institute on Aging grants and contracts (R01-AG 027017, P30-AG024827, T32-AG021885, K07-AG033174, R01-AG034056, R01-AG028050, N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106), National Institute of Nursing Research grants (R01-NR010135, R01-NR012459), and Agency for Healthcare Research and Quality grants (R01-HS017695, K12-HS019461, R01-HS018721). This research was also supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 59 TC 5 Z9 5 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JUL-AUG PY 2013 VL 47 IS 7-8 BP 984 EP 992 DI 10.1345/aph.1S050 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 225UP UT WOS:000324989500016 PM 23780807 ER PT J AU Pandey, S AF Pandey, Sanjay TI Deep brain stimulation: Lessons learned in 25 years and future ahead SO NEUROLOGY INDIA LA English DT Review DE Deep brain stimulation; essential tremor; functional neurosurgery; movement disorder; Parkinson's disease ID ADVANCED PARKINSONS-DISEASE; SUBTHALAMIC NUCLEUS; ESSENTIAL TREMOR; FOLLOW-UP; DISORDERS; DYSTONIA; OUTCOMES; TRIAL AB Deep brain stimulation (DBS) is a major advancement in the field of functional neurosurgery in the last century. This treatment option is now utilized for many hyperkinetic and hypokinetic movement disorders and certain disorders in the field of psychiatry. The basis of treatment is a by-product of excellent advancement made in the field of basic neuroscience and technology. Due to the improvement in the field of neuroimaging, brain structures are now better localized leading to a better outcome. Newer sites of stimulations are being recognized, which may further improve the clinical outcome in patients. However, it is very important to stick to stringent inclusion and exclusion criteria while selecting patients for DBS to get the best results. C1 [Pandey, Sanjay] GB Pant Hosp, Dept Neurol, New Delhi, India. [Pandey, Sanjay] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Pandey, S (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM sanjaysgpgi2002@yahoo.co.in FU Indo-US Science Technology Forum (IUSTTF) FX Indo-US Science Technology Forum (IUSTTF), which has awarded the fellowship to the author to be conducted at Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, MD, USA in the field of Parkinson's disease and movement disorder. NR 20 TC 1 Z9 1 U1 6 U2 20 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0028-3886 J9 NEUROL INDIA JI Neurol. India PD JUL-AUG PY 2013 VL 61 IS 4 BP 345 EP 348 DI 10.4103/0028-3886.117581 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 223BZ UT WOS:000324780000002 PM 24005722 ER PT J AU Metti, AL Cauley, JA Ayonayon, HN Harris, TB Rosano, C Williamson, JD Yaffe, K AF Metti, Andrea L. Cauley, Jane A. Ayonayon, Hilsa N. Harris, Tamara B. Rosano, Caterina Williamson, Jeff D. Yaffe, Kristine CA Hlth Aging & Body Composition Stud TI The Demographic and Medical Correlates of Plasma A beta 40 and A beta 42 SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE plasma amyloid beta; dementia; cognitive decline; biomarker; epidemiology ID MILD COGNITIVE IMPAIRMENT; INSULIN-DEGRADING ENZYME; ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; BODY-COMPOSITION; INFLAMMATORY MARKERS; AFRICAN-AMERICAN; APOLIPOPROTEIN-E; AMYLOID-BETA; RISK AB Plasma amyloid -42 (A42) and A42/A40 are increasingly recognized as biomarkers for dementia, with low levels indicating increased risk. Little is known about the demographic and medical correlates of plasma A40 or A42. In 997 community-dwelling, nondemented older adults from the Health, Aging, and Body Composition Study, we determined the cross-sectional association between a wide range of demographic and medical variables with A40 and A42. In multivariate stepwise linear regression models, A40 was significantly associated with race (=-14.70, F=22.01, P<0.0001), age (=1.34, F=6.39, P=0.01), creatinine (=52.91, F=151.77, P<0.0001), and the serum brain-derived neurotrophic factor (=-0.0004, F=7.34, P=0.007); A42 was significantly associated with race (=-3.72, F=30.83, P<0.0001), sex (=1.39, F=4.32, P=0.04), education (=1.50, F=4.78, P=0.03), apolipoprotein E e4 genotype (=-2.82, F=16.57, P<0.0001), and creatinine (=9.32, F=120.09, P<0.0001). These correlates should be considered as potential confounders in future studies investigating plasma A as a biomarker of dementia. Understanding fully how these correlates mediate or modify the association between plasma A and dementia will be a fundamental step in determining the biological pathways through which plasma A40 and A42 are associated with dementia, and in determining their full potential as biomarkers. C1 [Metti, Andrea L.; Cauley, Jane A.; Rosano, Caterina] Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Aging & Populat Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Ayonayon, Hilsa N.; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Harris, Tamara B.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Williamson, Jeff D.] Wake Forest Univ, Med Ctr, Dept Geriatr & Gerontol, Winston Salem, NC USA. RP Metti, AL (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Aging & Populat Hlth, Dept Epidemiol, 130 N Bellefield,4th Floor,Room 456, Pittsburgh, PA 15213 USA. EM alw111@pitt.edu OI Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, K24 AG031155]; NINR [R01-NR012459]; NIH, National Institute on Aging; National Institutes of Health [2T32AG000181] FX The Health, Aging and Body Composition Study is supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A. L. M. is supported by the National Institutes of Health Training Grant (2T32AG000181). K.Y. is supported in part by NIA Grant K24 AG031155. The remaining authors declare no conflicts of interest. NR 34 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2013 VL 27 IS 3 BP 244 EP 249 DI 10.1097/WAD.0b013e318260a8cb PG 6 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 210FM UT WOS:000323814700008 PM 22732677 ER PT J AU Keil, MF AF Keil, Margaret F. TI Quality of Life and Other Outcomes in Children Treated for Cushing Syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Review ID BONE-MINERAL DENSITY; TERM-FOLLOW-UP; PITUITARY-ADRENAL AXIS; LONG-TERM; TRANSSPHENOIDAL SURGERY; SURGICAL CURE; BILATERAL ADRENALECTOMY; CONSENSUS STATEMENT; CARDIOVASCULAR RISK; METABOLIC SYNDROME AB Context: Cushing syndrome (CS) in children is associated with residual impairment in measures of health-related quality of life, even after successful resolution of hypercortisolemia, highlighting the need for early identification of morbidities and improvements in long-term management of these patients. Evidence Acquisition and Synthesis: A PubMed, Scopus, and Web of Science search of articles from 1900 onward identified available studies related to quality of life and complications of pediatric CS as well as important historical articles. This review summarizes studies through November 2012 and highlights recent developments. Conclusions: A review of the literature identifies significant morbidities associated with CS of pediatric onset, which must not be treated in isolation. CS affects children and adolescents in many ways that are different than adults. Post-treatment challenges for the child or adolescent treated for CS include: optimize growth and pubertal development, normalize body composition, and promote psychological health and cognitive maturation. All these factors impact health-related quality of life, which is an important outcome measure to assess the burden of disease as well as the effect of treatment. Future research efforts are needed to improve management of the physical, psychological, and emotional aspects of this disease in order to diminish the residual impairments experienced by the pediatric CS patient population. C1 [Keil, Margaret F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol Genet, Program Dev Endocrinol Genet, NIH, Bethesda, MD 20892 USA. RP Keil, MF (reprint author), NICHHD, Program Dev Endocrinol Genet, NIH, East Labs,CRC, Bldg 10,Room I-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM keilm@mail.nih.gov FU Intramural Programs of the Eunice Kennedy Shriver Intramural Project, National Institute of Child Health and Human Development, National Institutes of Health [Z01-HD-000642-04] FX This work was supported by the Intramural Programs of the Eunice Kennedy Shriver Intramural Project Z01-HD-000642-04 (to C.A.S.), National Institute of Child Health and Human Development, National Institutes of Health. NR 120 TC 10 Z9 10 U1 1 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2013 VL 98 IS 7 BP 2667 EP 2678 DI 10.1210/jc.2013-1123 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 196MV UT WOS:000322780600026 PM 23640970 ER PT J AU Mannisto, T Mendola, P Grewal, J Xie, YL Chen, Z Laughon, SK AF Maennistoe, Tuija Mendola, Pauline Grewal, Jagteshwar Xie, Yunlong Chen, Zhen Laughon, S. Katherine TI Thyroid Diseases and Adverse Pregnancy Outcomes in a Contemporary US Cohort SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HYPOTHYROIDISM COMPLICATING PREGNANCY; BREECH PRESENTATION; LEVOTHYROXINE REQUIREMENTS; SUBCLINICAL HYPOTHYROIDISM; WOMEN; DYSFUNCTION; GESTATION; RISK; ASSOCIATION; POPULATION AB Context: Thyroid diseases are inconsistently reported to increase risk for pregnancy complications. Objective: The objective of this study was to study pregnancy complications associated with common and uncommon thyroid diseases. Design, Setting, and Participants: We analyzed singleton pregnancies (N = 223 512) from a retrospective US cohort, the Consortium on Safe Labor (2002-2008). Thyroid diseases and outcomes were derived from electronic medical records. Multivariable logistic regression with generalized estimating equations estimated adjusted odds ratios (ORs) with 99% confidence intervals (99% CI). Main Outcome Measures: Hypertensive diseases, diabetes, preterm birth, cesarean sections, inductions, and intensive care unit (ICU) admissions were analyzed. Results: Primary hypothyroidism was associated with increased odds of preeclampsia (OR = 1.47, 99% CI = 1.20-1.81), superimposed preeclampsia (OR = 2.25, 99% CI = 1.53-3.29), gestational diabetes (OR = 1.57, 99% CI = 1.33-1.86), preterm birth (OR = 1.34, 99% CI = 1.17-1.53), induction (OR = 1.15, 99% CI = 1.04-1.28), cesarean section (prelabor, OR = 1.31, 99% CI = 1.11-1.54; after spontaneous labor OR = 1.38, 99% CI = 1.14-1.66), and ICU admission (OR = 2.08, 99% CI = 1.04-4.15). Iatrogenic hypothyroidism was associated with increased odds of placental abruption (OR = 2.89, 99% CI = 1.14-7.36), breech presentation (OR = 2.09, 99% CI = 1.07-4.07), and cesarean section after spontaneous labor (OR = 2.05, 99% CI = 1.01-4.16). Hyperthyroidism was associated with increased odds of preeclampsia (OR = 1.78, 99% CI = 1.08-2.94), superimposed preeclampsia (OR = 3.64, 99% CI = 1.82-7.29), preterm birth (OR = 1.81, 99% CI = 1.32-2.49), induction (OR = 1.40, 99% CI = 1.06-1.86), and ICU admission (OR = 3.70, 99% CI = 1.16-11.80). Conclusions: Thyroid diseases were associated with obstetrical, labor, and delivery complications. Although we lacked information on treatment during pregnancy, these nationwide data suggest either that there is a need for better thyroid disease management during pregnancy or that there may be an intrinsic aspect of thyroid disease that causes poor pregnancy outcomes. C1 [Maennistoe, Tuija; Mendola, Pauline; Grewal, Jagteshwar; Laughon, S. Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Xie, Yunlong; Chen, Zhen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,7B05, Rockville, MD 20852 USA. EM pauline.mendola@nih.gov OI Mannisto, Tuija/0000-0002-6382-9153; Grewal, Jagteshwar/0000-0002-0141-4876; Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200603425C] FX This work was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The data included in this article were obtained from the Consortium on Safe Labor, which was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, through Contract HHSN267200603425C. The named authors alone are responsible for the views expressed in this article, which do not necessarily represent the decisions or the stated policy of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 38 TC 40 Z9 46 U1 1 U2 22 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2013 VL 98 IS 7 BP 2725 EP 2733 DI 10.1210/jc.2012-4233 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 196MV UT WOS:000322780600035 PM 23744409 ER PT J AU Thearle, MS Pannacciulli, N Bonfiglio, S Pacak, K Krakoff, J AF Thearle, Marie S. Pannacciulli, Nicola Bonfiglio, Susan Pacak, Karel Krakoff, Jonathan TI Extent and Determinants of Thermogenic Responses to 24 Hours of Fasting, Energy Balance, and Five Different Overfeeding Diets in Humans SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RESPIRATORY CHAMBER; OBESE WOMEN; WEIGHT-GAIN; METABOLIC-RESPONSE; PEPTIDE YY; EXPENDITURE; FOOD; CARBOHYDRATE; FAT; PROTEIN AB Context: Individual variation in the ability to convert excess calories to heat and the effects of dietary macronutrient composition are unclear. Objective: Stability and determinants of the energy expenditure (EE) response to overconsumption were assessed. Design, Setting, and Participants: Twenty subjects (75% male) with normal glucose regulation were evaluated during 24 hours each of energy balance, fasting, and 5 different diets with 200% energy requirements in a clinical research unit. Interventions: Five 1-day overfeeding diets were given in random order: high carbohydrate (75%) and low protein (3%); high carbohydrate and normal protein (20%); high fat (46%) and low protein; high fat (60%) and normal protein; and balanced (50% carbohydrates, 20% protein). Main Outcome Measures: The 24-hour EE, sleeping EE, and thermic effect of food (TEF) during each diet were measured with a metabolic chamber. Appetitive hormones were measured before and after the diets. Results: The EE response to overfeeding exhibited good intraindividual reproducibility. Similar increases above eucaloric feeding in 24-hour EE (mean 10.7 +/- 5.7%, P < .001; range 2.9-18.8%) and sleeping EE (14.4 +/- 11.3%, P < .001; range 1.0-45.1%) occurred when overfeeding diets containing 20% protein, despite differences in fat and carbohydrate content, but the EE response during overfeeding diets containing 3% protein was attenuated. The percent body fat negatively correlated with TEF during normal protein overfeeding (r = -0.53, P < .01). Fasting peptide YY negatively correlated with TEF (r = -0.56, P < .01) and the increase in sleeping EE (r = -0.54, P < .01) during overfeeding. Conclusions: There is an intrinsic EE response to overfeeding that negatively associates with adiposity, although it represents a small percentage of consumed calories. C1 [Thearle, Marie S.; Pannacciulli, Nicola; Bonfiglio, Susan; Krakoff, Jonathan] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. [Pacak, Karel] NICHHD, Med Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Thearle, MS (reprint author), NIDDK, Obes & Diabet Clin Res Sect, NIH, 4212 North 16th St,5th Floor, Phoenix, AZ 85016 USA. EM thearlem@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 40 TC 11 Z9 11 U1 1 U2 14 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2013 VL 98 IS 7 BP 2791 EP 2799 DI 10.1210/jc.2013-1289 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 196MV UT WOS:000322780600043 PM 23666976 ER PT J AU Kim, SH Schneider, SM Bevans, M Kravitz, L Mermier, C Qualls, C Burge, MR AF Kim, Sang Hwan Schneider, Suzanne M. Bevans, Margaret Kravitz, Len Mermier, Christine Qualls, Clifford Burge, Mark R. TI PTSD Symptom Reduction With Mindfulness-Based Stretching and Deep Breathing Exercise: Randomized Controlled Clinical Trial of Efficacy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; HEART-RATE-VARIABILITY; CORTISOL-LEVELS; URINARY CORTISOL; PLASMA-CORTISOL; WOMEN; SURVIVORS; PREVALENCE; EXPOSURE; NURSES AB Context: Abnormal cortisol levels are a key pathophysiological indicator of post-traumatic stress disorder (PTSD). Endogenous normalization of cortisol concentration through exercise may be associated with PTSD symptom reduction. Objective: The aim of the study was to determine whether mindfulness-based stretching and deep breathing exercise (MBX) normalizes cortisol levels and reduces PTSD symptom severity among individuals with subclinical features of PTSD. Design and Setting: A randomized controlled trial was conducted at the University of New Mexico Health Sciences Center. Participants: Twenty-nine nurses (28 female) aged 45-66 years participated in the study. Intervention: Sixty-minute MBX sessions were conducted semiweekly for 8 weeks. Main Outcome Measures: Serum cortisol was measured, and the PTSD Checklist-Civilian version (PCL-C) was performed at baseline and weeks 4, 8, and 16. Results: Twenty-nine participants completed the study procedures, 22 (79%) with PTSD symptoms (MBX, n = 11; control, n = 11), and 7 (21%) without PTSD (BASE group). Eight-week outcomes for the MBX group were superior to those for the control group (mean difference for PCL-C scores, -13.6; 95% confidence interval [CI], -25.6, -1.6; P = .01; mean difference for serum cortisol, 5.8; 95% CI, 0.83, 10.8; P = .01). No significant differences were identified between groups in any other items. The changes in the MBX group were maintained at the 16-week follow-up (P = .85 for PCL-C; P = .21 for cortisol). Our data show that improved PTSD scores were associated with normalization of cortisol levels (P < .05). Conclusions: The results suggest that MBX appears to reduce the prevalence of PTSD-like symptoms in individuals exhibiting subclinical features of PTSD. C1 [Kim, Sang Hwan; Bevans, Margaret] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Schneider, Suzanne M.; Kravitz, Len; Mermier, Christine] Univ New Mexico, Dept Hlth Exercise & Sports Sci, Albuquerque, NM 87131 USA. [Qualls, Clifford; Burge, Mark R.] Univ New Mexico, Clin & Translat Sci Ctr, Albuquerque, NM 87131 USA. [Burge, Mark R.] Univ New Mexico, Dept Internal Med Endocrinol & Metab, Albuquerque, NM 87131 USA. RP Kim, SH (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Room 2B10A,MSC 1151, Bethesda, MD 20892 USA. EM sanghk@gmail.com FU DHHS/NIH/NCATS [UL1RR031977-01]; UNM Clinical and Translational Science Center [5KL2RR031976-02] FX This work was supported by DHHS/NIH/NCATS UL1RR031977-01 and 5KL2RR031976-02, UNM Clinical and Translational Science Center. NR 40 TC 13 Z9 13 U1 3 U2 40 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2013 VL 98 IS 7 BP 2984 EP 2992 DI 10.1210/jc.2012-3742 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 196MV UT WOS:000322780600065 PM 23720785 ER PT J AU Sempos, CT Durazo-Arvizu, RA Dawson-Hughes, B Yetley, EA Looker, AC Schleicher, RL Cao, GC Burt, V Kramer, H Bailey, RL Dwyer, JT Zhang, XL Gahche, J Coates, PM Picciano, MF AF Sempos, Christopher T. Durazo-Arvizu, Ramon A. Dawson-Hughes, Bess Yetley, Elizabeth A. Looker, Anne C. Schleicher, Rosemary L. Cao, Guichan Burt, Vicki Kramer, Holly Bailey, Regan L. Dwyer, Johanna T. Zhang, Xinli Gahche, Jaime Coates, Paul M. Picciano, Mary Frances TI Is There a Reverse J-Shaped Association Between 25-Hydroxyvitamin D and All-Cause Mortality? Results from the U.S. Nationally Representative NHANES SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CARDIOVASCULAR-DISEASE MORTALITY; VITAMIN-D; GENERAL-POPULATION; SERUM CREATININE; OLDER MEN; RISK; ADULTS; COMMUNITY; HEALTH; CANCER AB Context: A reverse J-shaped association between serum 25-hydroxyvitamin D (25[OH]D) concentration and all-cause mortality was suggested in a 9-year follow-up (1991-2000) analysis of the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). Objective: Our objective was to repeat the analyses with 6 years additional follow-up to evaluate whether the association persists through 15 years of follow-up. Participants: The study included 15 099 participants aged >= 20 years with 3784 deaths. Main Outcome Measure: Relative risk (RR) of death from all causes was adjusted for age, sex, race/ethnicity, and season using 2 Poisson regression approaches: traditional categorical and cubic splines. Results were given for 9 25(OH) D levels: <20, 20 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 74, 75 to 99 (reference), 100 to 119, and >= 120 nmol/L. Results: The reverse J-shaped association became stronger with longer follow-up and was not affected by excluding deaths within the first 3 years of follow-up. Similar results were found from both statistical approaches for levels <20 through 119 nmol/L. Adjusted RR (95% confidence interval [CI]) estimates for all levels <60 nmol/L were significantly >1 compared with the reference group. The nadir of risk was 81 nmol/L (95% CI, 73-90 nmol/L). For 25(OH)D >= 120 nmol/L, results (RR, 95% CI) were slightly different using traditional categorical (1.5, 1.02-2.3) and cubic splines approaches (1.2, 0.9-1.4). The association appeared in men, women, adults ages 20 to 64 years, and non-Hispanic whites but was weaker in older adults. The study was too small to evaluate the association in non-Hispanic black and Mexican-American adults. Conclusions: A reverse J-shaped association between serum 25(OH)D and all-cause mortality appears to be real. It is uncertain whether the association is causal. C1 [Sempos, Christopher T.; Yetley, Elizabeth A.; Schleicher, Rosemary L.; Dwyer, Johanna T.; Coates, Paul M.; Picciano, Mary Frances] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Durazo-Arvizu, Ramon A.; Cao, Guichan; Kramer, Holly] Loyola Univ Chicago Stritch, Sch Med, Dept Prevent Med & Epidemiol, Maywood, IL 60153 USA. [Dawson-Hughes, Bess] Tufts Univ, Bone Metab Lab, Jean Mayer S Dept Agr Human Nutr, Boston, MA 02111 USA. [Looker, Anne C.; Burt, Vicki; Zhang, Xinli; Gahche, Jaime] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Schleicher, Rosemary L.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. RP Sempos, CT (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01, Bethesda, MD 20892 USA. EM semposch@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769; Kramer, Holly/0000-0002-6374-837X FU National Institute on Aging, National Institutes of Health (NIH) [AG10353]; Office of Dietary Supplements administrative supplement to NIH [5R37 HL045508-17] FX This work was supported by the National Institute on Aging, National Institutes of Health (NIH) (Grant AG10353) and by an Office of Dietary Supplements administrative supplement to NIH Grant 5R37 HL045508-17. NR 44 TC 45 Z9 45 U1 1 U2 13 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2013 VL 98 IS 7 BP 3001 EP 3009 DI 10.1210/jc.2013-1333 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 196MV UT WOS:000322780600067 PM 23666975 ER PT J AU Chen, KY Brychta, RJ Linderman, JD Smith, S Courville, A Dieckmann, W Herscovitch, P Millo, CM Remaley, A Lee, P Celi, FS AF Chen, Kong Y. Brychta, Robert J. Linderman, Joyce D. Smith, Sheila Courville, Amber Dieckmann, William Herscovitch, Peter Millo, Corina M. Remaley, Alan Lee, Paul Celi, Francesco S. TI Brown Fat Activation Mediates Cold-Induced Thermogenesis in Adult Humans in Response to a Mild Decrease in Ambient Temperature SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ADIPOSE-TISSUE; ENERGY-EXPENDITURE; METABOLISM; PREVALENCE; EXPOSURE; MEN; AGE AB Context: The contribution of brown adipose tissue (BAT) to the energy balance in humans exposed to sustainable cold has not been completely established, partially because of measurement limitations of both BAT activity and energy expenditure (EE). Objective: The objective of the study was to characterize the role of BAT activation in cold-induced thermogenesis (CIT). Design: This study was a single-blind, randomized crossover intervention. Setting: The study was conducted at the National Institutes of Health Clinical Center. Study Participants: Thirty-one healthy volunteers participated in the study. Interventions: The intervention included mild cold exposure. Main Outcomes: CIT and BAT activation were the main outcomes in this study. Methods: Overnight EE measurement by whole-room indirect calorimeter at 24 degrees C or 19 degrees C was followed by 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (PET) scan. After 36 hours, volunteers crossed over to the alternate study temperature under identical conditions. BAT activity was measured in a 3-dimensional region of interest in the upper torso by comparing the uptake at the two temperatures. Results: Twenty-four volunteers (14 males, 10 females) had a complete data set. When compared with 24 degrees C, exposure at 19 degrees C resulted in increased EE (5.3 +/- 5.9%, P < .001), indicating CIT response and mean BAT activity (10.5 +/- 11.1%, P < .001). Multiple regression analysis indicated that a difference in BAT activity (P < .001), age (P = .01), and gender (P = .037) were independent contributors to individual variability of CIT. Conclusions: A small reduction in ambient temperature, within the range of climate-controlled buildings, is sufficient to increase human BAT activity, which correlates with individual CIT response. This study uncovers for the first time a spectrum of BAT activation among healthy adults during mild cold exposure not previously recognized by conventional PET and PET-computed tomography methods. The enhancement of cold-induced BAT stimulation may represent a novel environmental strategy in obesity treatment. C1 [Chen, Kong Y.; Brychta, Robert J.; Linderman, Joyce D.; Smith, Sheila; Lee, Paul; Celi, Francesco S.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Courville, Amber] NIH, Dept Nutr, Ctr Clin, Bethesda, MD 20892 USA. [Dieckmann, William; Herscovitch, Peter; Millo, Corina M.] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. [Remaley, Alan] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Celi, FS (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, CRC, Bldg 10,Room 6-3940,10 Ctr Dr,MSC 1613, Bethesda, MD 20892 USA. EM fc93a@nih.gov OI Chen, Kong/0000-0002-0306-1904 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases [Z01-DK047057-06, Z01-DK075001-09, Z01 DK071014] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, Programs Z01-DK047057-06 and Z01-DK075001-09 (to F.S.C.), and Program Z01 DK071014 (to K.Y.C.). NR 20 TC 42 Z9 42 U1 1 U2 14 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2013 VL 98 IS 7 BP E1218 EP E1223 DI 10.1210/jc.2012-4213 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 196MV UT WOS:000322780600010 PM 23780370 ER PT J AU Lee, CJ Brown, T Magnuson, TH Egan, JM Carlson, O Elahi, D AF Lee, Clare J. Brown, Todd Magnuson, Thomas H. Egan, Josephine M. Carlson, Olga Elahi, Dariush TI Hormonal Response to a Mixed-Meal Challenge After Reversal of Gastric Bypass for Hypoglycemia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GLUCAGON-LIKE PEPTIDE-1; NONINSULINOMA PANCREATOGENOUS HYPOGLYCEMIA; DEPENDENT INSULINOTROPIC POLYPEPTIDE; HYPERINSULINEMIC HYPOGLYCEMIA; ISLET HYPERPLASIA; SURGERY; GLUCOSE; SECRETION; NESIDIOBLASTOSIS; PANCREATECTOMY AB Context: Severe hypoglycemia is a rare and challenging complication of Roux-en-Y gastric bypass (RYGB), which is characterized by hypersecretion of insulin and incretin hormones in the postprandial state. Objective: The objective of the study was to determine the clinical and hormonal responses to a mixed-meal challenge after the reversal of RYGB in 2 patients with post-RYGB hypoglycemia. We hypothesized that the reversal of RYGB would lead to clinical improvement in hypoglycemia through the attenuation of incretin hormone secretion. Design/Setting/Subjects/Outcome Measures: Two patients with post-RYGB hypoglycemia underwent a standardized meal tolerance test prior to and 8 and 18 months after RYGB reversal, respectively, with the measurement of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, and glucose levels. Gastric bypass was reversed by reattaching the small gastric pouch to the bypassed distal stomach and resecting the Roux limb to restore the normal flow of food bolus. Results: Both subjects showed persistent evidence of hypoglycemia with marked hyperinsulinemia after the RYGB reversal. GLP-1 levels after the RYGB reversal decreased by 76% and 70%, respectively, from their prereversal levels and to the level of nonhypoglycemic post-RYGB controls. In contrast, GIP levels after theRYGBreversal increased by 3-10 times the level before the reversal and 8-26 times that of the nonhypoglycemic post-RYGB controls. Conclusions: Reversal of RYGB did not alleviate hyperinsulinemic hypoglycemia upon a mixed-meal challenge in our patients, thus suggesting its limited clinical benefit as treatment of post-RYGB hypoglycemia. The marked increase in GIP levels and concurrent decrease in GLP-1 levels in our patients suggest a possible role of GIP in persistent hyperinsulinemic hypoglycemia after the reversal of RYGB. C1 [Lee, Clare J.; Brown, Todd] Johns Hopkins Univ, Div Endocrinol & Metab, Baltimore, MD 21287 USA. [Magnuson, Thomas H.] Johns Hopkins Univ, Dept Surg, Baltimore, MD 21287 USA. NIH, Clin Physiol Branch, Baltimore, MD 21224 USA. [Elahi, Dariush] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. RP Brown, T (reprint author), Johns Hopkins Univ, Div Endocrinol & Metab, 1830 East Monument St,Suite 333, Baltimore, MD 21287 USA. EM tbrown27@jhmi.edu FU Johns Hopkins Institute of Clinical and Translational Research (National Center for Advancing Translational Sciences) [UL1 TR000424] FX This study was partially supported by the Johns Hopkins Institute of Clinical and Translational Research UL1 TR000424 (National Center for Advancing Translational Sciences). NR 19 TC 21 Z9 21 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2013 VL 98 IS 7 BP E1208 EP E1212 DI 10.1210/jc.2013-1151 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 196MV UT WOS:000322780600008 PM 23666968 ER PT J AU Jiang, P Chen, C Wang, RM Chechneva, OV Chung, SH Rao, MS Pleasure, DE Liu, Y Zhang, QG Deng, WB AF Jiang, Peng Chen, Chen Wang, Ruimin Chechneva, Olga V. Chung, Seung-Hyuk Rao, Mahendra S. Pleasure, David E. Liu, Ying Zhang, Quanguang Deng, Wenbin TI hESC-derived Olig2(+) progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury SO NATURE COMMUNICATIONS LA English DT Article ID PLURIPOTENT STEM-CELLS; CNS SYNAPTOGENESIS; OXIDATIVE STRESS; MOTOR-NEURON; ASTROCYTES; EXPRESSION; DISEASE; GLIA; DIFFERENTIATION; RAT AB Human pluripotent stem cells (hPSCs) have been differentiated to astroglia, but the utilization of hPSC-derived astroglia as cell therapy for neurological diseases has not been well studied. Astroglia are heterogeneous, and not all astroglia are equivalent in promoting neural repair. A prerequisite for cell therapy is to derive defined cell populations with superior therapeutic effects. Here we use an Olig2-GFP human embryonic stem cell (hESC) reporter to demonstrate that hESC-derived Olig2(+) progenitors generate a subtype of previously uncharacterized astroglia (Olig2PC-Astros). These Olig2PC-Astros differ substantially from astroglia differentiated from Olig2-negative hESC-derived neural progenitor cells (NPC-Astros), particularly in their neuroprotective properties. When grafted into brains subjected to global ischaemia, Olig2PC-Astros exhibit superior neuroprotective effects and improved behavioural outcome compared to NPC-Astros. Thus, this new paradigm of human astroglial differentiation is useful for studying the heterogeneity of human astroglia, and the unique Olig2PC-Astros may constitute a new cell therapy for treating cerebral ischaemia and other neurological diseases. C1 [Jiang, Peng; Chen, Chen; Chechneva, Olga V.; Chung, Seung-Hyuk; Deng, Wenbin] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA 95817 USA. [Jiang, Peng; Chen, Chen; Chechneva, Olga V.; Chung, Seung-Hyuk; Pleasure, David E.; Deng, Wenbin] Shriners Hosp Children Northern Calif, Inst Pediat Regenerat Med, Sacramento, CA 95817 USA. [Wang, Ruimin; Zhang, Quanguang] Med Coll Georgia, Dept Neurol, Inst Mol Med & Genet, Augusta, GA 30912 USA. [Rao, Mahendra S.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Pleasure, David E.] Univ Calif Davis, Sch Med, Dept Neurol, Davis, CA 95817 USA. [Pleasure, David E.] Univ Calif Davis, Sch Med, Dept Pediat, Davis, CA 95817 USA. [Liu, Ying] Univ Texas Hlth Sci Ctr Houston, Dept Neurosurg, Houston, TX 77030 USA. [Liu, Ying] Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med Prevent Human Dis, Ctr Stem Cell & Regenerat Med, Houston, TX 77030 USA. RP Deng, WB (reprint author), Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA 95817 USA. EM wbdeng@ucdavis.edu FU National Institutes of Health [R01NS061983, R01ES015988, R01NS025044]; National Multiple Sclerosis Society; Shriners Hospitals for Children; California Institute for Regenerative Medicine; Memorial Hermann Foundation (Staman Ogilvie Fund); Bentsen Stroke Center FX We thank Dr. Haitao Shen for his help with FACS experiments. This work was in part supported by grants from National Institutes of Health (R01NS061983 and R01ES015988 to W.D., and R01NS025044 to D.P.), the National Multiple Sclerosis Society (to W.D.), and Shriners Hospitals for Children (to W.D.). P.J. is a recipient of a postdoctoral fellowship from Shriners Hospitals for Children. C.C. is supported by a postdoctoral fellowship from California Institute for Regenerative Medicine. Y.L. is supported by the Memorial Hermann Foundation (Staman Ogilvie Fund) and the Bentsen Stroke Center. NR 54 TC 18 Z9 18 U1 2 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2013 VL 4 AR 2196 DI 10.1038/ncomms3196 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 208XW UT WOS:000323716900003 PM 23880652 ER PT J AU Chang, Q Bournazou, E Sansone, P Berishaj, M Gao, SP Daly, L Wels, J Theilen, T Granitto, S Zhang, XM Cotari, J Alpaugh, ML de Stanchina, E Manova, K Li, M Bonafe, M Ceccarelli, C Taffurelli, M Santini, D Altan-Bonnet, G Kaplan, R Norton, L Nishimoto, N Huszar, D Lyden, D Bromberg, J AF Chang, Qing Bournazou, Eirini Sansone, Pasquale Berishaj, Marjan Gao, Sizhi Paul Daly, Laura Wels, Jared Theilen, Till Granitto, Selena Zhang, Xinmin Cotari, Jesse Alpaugh, Mary L. de Stanchina, Elisa Manova, Katia Li, Ming Bonafe, Massimiliano Ceccarelli, Claudio Taffurelli, Mario Santini, Donatella Altan-Bonnet, Gregoire Kaplan, Rosandra Norton, Larry Nishimoto, Norihiro Huszar, Dennis Lyden, David Bromberg, Jacqueline TI The IL-6/JAK/Stat3 Feed-Forward Loop Drives Tumorigenesis and Metastasis SO NEOPLASIA LA English DT Article ID BREAST-CANCER MODEL; SUPPRESSOR-CELLS; INHIBITOR AZD1480; STAT3 ACTIVATION; IL-6 PRODUCTION; MAMMARY-TUMOR; MYELOID CELLS; IMMUNE CELLS; LUNG; DIFFERENTIATION AB We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis. C1 [Chang, Qing; Bournazou, Eirini; Sansone, Pasquale; Berishaj, Marjan; Gao, Sizhi Paul; Daly, Laura; Norton, Larry; Bromberg, Jacqueline] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Wels, Jared; Theilen, Till; Granitto, Selena; Lyden, David] Weill Cornell Med Coll, Dept Pediat, Childrens Canc & Blood Fdn Labs, New York, NY 10021 USA. [Wels, Jared; Theilen, Till; Granitto, Selena; Lyden, David] Weill Cornell Med Coll, Dept Cell, New York, NY USA. [Wels, Jared; Theilen, Till; Granitto, Selena; Lyden, David] Weill Cornell Med Coll, Dept Dev Biol, New York, NY USA. [Zhang, Xinmin] Hofstra North Shore LIJ Sch Med, Manhasset, NY USA. [Cotari, Jesse; Altan-Bonnet, Gregoire] MSKCC, Computat Biol Program, New York, NY USA. [Alpaugh, Mary L.] MSKCC, Dept Mol Pharmacol, New York, NY USA. [de Stanchina, Elisa; Manova, Katia] MSKCC, New York, NY USA. [Li, Ming] MSKCC, Sloan Kettering Inst, Program Immunol, New York, NY USA. [Bonafe, Massimiliano; Ceccarelli, Claudio] Policlin Univ S Orsola Malpighi, Dept Expt Diagnost & Specialty Med, Bologna, Italy. [Taffurelli, Mario] Policlin Univ S Orsola Malpighi, Dept Med & Surg Sci, Bologna, Italy. [Santini, Donatella] Policlin Univ S Orsola Malpighi, Dept Anat & Histol Pathol, Bologna, Italy. [Kaplan, Rosandra] NCI, Tumor Microenvironm Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Norton, Larry; Lyden, David] Champalimaud Metastasis Programme, Lisbon, Portugal. [Nishimoto, Norihiro] Tokyo Med Univ, Tokyo 1608402, Japan. [Huszar, Dennis] AstraZeneca, Oncol iMED, Waltham, MA USA. [Lyden, David] MSKCC, Dept Pediat, New York, NY USA. [Bromberg, Jacqueline] WCMC, New York, NY USA. RP Bromberg, J (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave,Box 397, New York, NY 10021 USA. EM dcl2001@med.cornell.edu; bromberj@mskcc.org OI Norton, Larry/0000-0003-3701-9250; Ceccarelli, Claudio/0000-0003-0743-2087 FU National Institutes of Health [U54: CA148967, R01: CA87637]; Charles and Marjorie Holloway Foundation; Sussman Family Fund; Lerner Foundation; AstraZeneca; Breast Cancer Alliance; Manhasset Women's Coalition Against Breast Cancer; NYS Women's Bowling Association; American Hellenic Educational Progressive Association 5th District; Department of Defense [W81XWH-10-1-1013]; Fondazione Carisbo di Bologna; Children's Cancer and Blood Foundation; Manning Foundation; Hartwell Foundation; Pediatric Oncology Experimental Therapeutics Investigators Consortium; Stavros S. Niarchos Foundation; Champalimaud Foundation; Nancy C. and Daniel P. Paduano Foundation; Mary Kay Foundation; Malcolm Hewitt Wiener Foundation; George Best Costacos Foundation; National Cancer Institute [R01CA 098234-01, U54-CA143836]; Susan G. Komen; Beth C. Tortolani Foundation FX Our work was supported by grants from the National Institutes of Health [U54: CA148967 (J.B. and G.A.-B.) and R01: CA87637 (J.B.)], Charles and Marjorie Holloway Foundation (J.B.), Sussman Family Fund (J.B.), Lerner Foundation (J.B.), AstraZeneca (J.B.), Breast Cancer Alliance (J.B.), Manhasset Women's Coalition Against Breast Cancer (J.B.), NYS Women's Bowling Association (J.B.), American Hellenic Educational Progressive Association 5th District (E. B. and D. L.), Department of Defense (Postdoctoral Award W81XWH-10-1-1013) and Fondazione Carisbo di Bologna (P. S.), Children's Cancer and Blood Foundation (D. L.), The Manning Foundation (D. L.), The Hartwell Foundation (D. L.), Pediatric Oncology Experimental Therapeutics Investigators Consortium (D. L.), Stavros S. Niarchos Foundation (D. L.), Champalimaud Foundation (D. L.), The Nancy C. and Daniel P. Paduano Foundation (D. L.), The Mary Kay Foundation (D. L.), The Malcolm Hewitt Wiener Foundation (D. L.), The George Best Costacos Foundation (D. L.), National Cancer Institute [R01CA 098234-01 and U54-CA143836 PSOC training grant (D. L.)], Susan G. Komen for the Cure (D. L.), and The Beth C. Tortolani Foundation (J.B. and D. L.). J.B. has consulted for Roche, Medimmune, and Bristol-Myers Squibb and has received research support from AstraZeneca. No potential conflicts of interest were disclosed by the other authors. NR 50 TC 83 Z9 86 U1 3 U2 16 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD JUL PY 2013 VL 15 IS 7 BP 848 EP + DI 10.1593/neo.13706 PG 21 WC Oncology SC Oncology GA 219DY UT WOS:000324487100016 PM 23814496 ER PT J AU Strupinska, M Rostafinska-Suchar, G Pirianowicz-Chaber, E Stables, JP Jiang, J Paruszewski, R AF Strupinska, Marzanna Rostafinska-Suchar, Grazyna Pirianowicz-Chaber, Elzbieta Stables, James P. Jiang, Jeff Paruszewski, Ryszard TI SYNTHESIS AND RESEARCH OF BENZYLAMIDES OF SOME ISOCYCLIC AND HETEROCYCLIC ACIDS AS POTENTIAL ANTICONVULSANTS SO ACTA POLONIAE PHARMACEUTICA LA English DT Article DE Anticonvulsant; isocyclic; heterocyclic benzylamides; hydrophobicity ID DERIVATIVES; SEIZURE AB A series of benzylamides of isocyclic and heterocyclic acids was synthesized and tested in Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Near all synthesized derivatives of heterocyclic acids showed activity. All obtained derivatives of mono- and bicyclic isocyclic acids were inactive. The power of action of heterocyclic acids derivatives seems does not depend upon kind of heteroatom (N, O or S). One of the compounds (2-furoic acid benzylamide (4)) appeared most promising. It showed in minimal clonic seizure (6Hz) test (ASP) in rats after i. p. administration: MES ED50 = 36.5 mg/kg, TOX TD50 = 269.75 mg/kg, and PI = 7.39. C1 [Strupinska, Marzanna; Rostafinska-Suchar, Grazyna; Pirianowicz-Chaber, Elzbieta; Paruszewski, Ryszard] Med Univ Warsaw, Dept Drug Chem, PL-02097 Warsaw, Poland. [Stables, James P.; Jiang, Jeff] NINDS, Epilepsy Branch, Rockville, MD 20852 USA. RP Paruszewski, R (reprint author), Med Univ Warsaw, Dept Drug Chem, PL-02097 Warsaw, Poland. EM ryszard.paruszewski@neostrada.pl FU Warsaw Medical University; National Science Centre [2011/01/B/NZ4/01065]; National Institute of Neurological Disorders and Stroke (NINDS) FX This investigation was supported in part by Warsaw Medical University, National Science Centre (Grant 2011/01/B/NZ4/01065) and National Institute of Neurological Disorders and Stroke (NINDS). NR 14 TC 2 Z9 2 U1 0 U2 2 PU POLSKIE TOWARZYSTWO FARMACEUTYCZNE PI WARSAW PA DLUGA 16, 00-238 WARSAW, POLAND SN 0001-6837 J9 ACTA POL PHARM JI ACTA POL. PHARM. PD JUL-AUG PY 2013 VL 70 IS 4 BP 681 EP 686 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 210TU UT WOS:000323858400011 PM 23923392 ER PT J AU Tice, RR Austin, CP Kavlock, RJ Bucher, JR AF Tice, Raymond R. Austin, Christopher P. Kavlock, Robert J. Bucher, John R. TI Improving the Human Hazard Characterization of Chemicals: A Tox21 Update SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE chemical hazard characterization; computational biology; high throughput testing; in vitro models; systems biology; Tox21 ID THROUGHPUT SCREENING DATA; IN-VITRO MODEL; ENVIRONMENTAL CHEMICALS; DEVELOPMENTAL TOXICITY; REPRODUCTIVE TOXICITY; TOXCAST CHEMICALS; PROTECTION; TOXICOLOGY; PATHWAYS; PROGRAM AB BACKGROUND: In 2008, the National Institute of Environmental Health Sciences/National Toxicology Program, the U.S. Environmental Protection Agency's National Center for Computational Toxicology, and the National Human Genome Research Institute/National Institutes of Health Chemical Genomics Center entered into an agreement on "high throughput screening, toxicity pathway profiling, and biological interpretation of findings." In 2010, the U.S. Food and Drug Administration (FDA) joined the collaboration, known informally as Tox21. OBJECTIVES: The Tox21 partners agreed to develop a vision and devise an implementation strategy to shift the assessment of chemical hazards away from traditional experimental animal toxicology studies to one based on target-specific, mechanism-based, biological observations largely obtained using in vitro assays. DISCUSSION: Here we outline the efforts of the Tox21 partners up to the time the FDA joined the collaboration, describe the approaches taken to develop the science and technologies that are currently being used, assess the current status, and identify problems that could impede further progress as well as suggest approaches to address those problems. CONCLUSION: Tox21 faces some very difficult issues. However, we are making progress in integrating data from diverse technologies and end points into what is effectively a systems-biology approach to toxicology. This can be accomplished only when comprehensive knowledge is obtained with broad coverage of chemical and biological/toxicological space. The efforts thus far reflect the initial stage of an exceedingly complicated program, one that will likely take decades to fully achieve its goals. However, even at this stage, the information obtained has attracted the attention of the international scientific community, and we believe these efforts foretell the future of toxicology. C1 [Tice, Raymond R.; Bucher, John R.] NIEHS, Div Natl Toxicol Program, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Austin, Christopher P.] NIH, Natl Ctr Adv Translat Sci, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kavlock, Robert J.] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. RP Tice, RR (reprint author), NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, Mail Code K2-17,POB 12233, Res Triangle Pk, NC 27709 USA. EM tice@niehs.nih.gov NR 65 TC 112 Z9 118 U1 12 U2 78 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 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2013 VL 121 IS 7 BP 756 EP 765 DI 10.1289/ehp.1205784 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208VY UT WOS:000323711000013 PM 23603828 ER PT J AU Taylor, KW Novak, RF Anderson, HA Birnbaum, LS Blystone, C DeVito, M Jacobs, D Kohrle, J Lee, DH Rylander, L Rignell-Hydbom, A Tornero-Velez, R Turyk, ME Boyles, AL Thayer, KA Lind, L AF Taylor, Kyla W. Novak, Raymond F. Anderson, Henry A. Birnbaum, Linda S. Blystone, Chad DeVito, Michael Jacobs, David Koehrle, Josef Lee, Duk-Hee Rylander, Lars Rignell-Hydbom, Anna Tornero-Velez, Rogelio Turyk, Mary E. Boyles, Abee L. Thayer, Kristina A. Lind, Lars TI Evaluation of the Association between Persistent Organic Pollutants (POPs) and Diabetes in Epidemiological Studies: A National Toxicology Program Workshop Review SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE chemically induced; diabetes; environment; epidemiology; glucose; hormone; insulin; metabolic syndrome; obesity; persistent organic pollutants; pollution; toxicology ID OPERATION RANCH HAND; 2,3,7,8-TETRACHLORODIBENZO-PARA-DIOXIN (TCDD)-TREATED RATS; POLYCHLORINATED-BIPHENYLS PCBS; STIMULATED INSULIN-SECRETION; NUTRITION EXAMINATION SURVEY; BROWN ADIPOSE-TISSUE; AIR-POLLUTION; SERUM CONCENTRATIONS; GLUCOSE-HOMEOSTASIS; ORGANOCHLORINE PESTICIDES AB BACKGROUND: Diabetes is a major threat to public health in the United States and worldwide. Understanding the role of environmental chemicals in the development or progression of diabetes is an emerging issue in environmental health. OBJECTIVE: We assessed the epidemiologic literature for evidence of associations between persistent organic pollutants (POPs) and type 2 diabetes. METHODS: Using a PubMed search and reference lists from relevant studies or review articles, we identified 72 epidemiological studies that investigated associations of persistent organic pollutants (POPs) with diabetes. We evaluated these studies for consistency, strengths and weaknesses of study design (including power and statistical methods), clinical diagnosis, exposure assessment, study population characteristics, and identification of data gaps and areas for future research. CONCLUSIONS: Heterogeneity of the studies precluded conducting a meta-analysis, but the overall evidence is sufficient for a positive association of some organochlorine POPs with type 2 diabetes. Collectively, these data are not sufficient to establish causality. Initial data mining revealed that the strongest positive correlation of diabetes with POPs occurred with organochlorine compounds, such as trans-nonachlor, dichlorodiphenyldichloroethylene (DDE), polychlorinated biphenyls (PCBs), and dioxins and dioxin-like chemicals. There is less indication of an association between other nonorganochlorine POPs, such as perfluoroalkyl acids and brominated compounds, and type 2 diabetes. Experimental data are needed to confirm the causality of these POPs, which will shed new light on the pathogenesis of diabetes. This new information should be considered by governmental bodies involved in the regulation of environmental contaminants. C1 [Taylor, Kyla W.; Boyles, Abee L.; Thayer, Kristina A.] NIEHS, Off Hlth Assessment & Translat, Div Natl Toxicol Program, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Novak, Raymond F.] Shriners Hosp Children Int, Tampa, FL USA. [Anderson, Henry A.] Bur Environm Hlth, Wisconsin Div Publ Hlth, Madison, WI USA. [Birnbaum, Linda S.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Blystone, Chad; DeVito, Michael] NIEHS, Toxicol Branch, Div Natl Toxicol Program, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Jacobs, David] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Koehrle, Josef] Humboldt Univ, Charite Univ Med, Inst Expt Endocrinol, D-10099 Berlin, Germany. [Lee, Duk-Hee] Kyungpook Natl Univ, Sch Med, Dept Preventat Med, Taegu, South Korea. [Rylander, Lars; Rignell-Hydbom, Anna] Lund Univ, Div Occupat & Environm Med, Lund, Sweden. [Tornero-Velez, Rogelio] US EPA, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA. [Turyk, Mary E.] Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL USA. [Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. RP Taylor, KW (reprint author), NIEHS, Natl Toxicol Program, POB 12233,MD K2-04, Res Triangle Pk, NC 27709 USA. EM taylorkw@niehs.nih.gov RI Tuomisto, Jouko/J-7450-2012; OI Boyles, Abee/0000-0002-8711-2077; Kohrle, Josef/0000-0002-9187-9078 FU National Institute of Environmental Health Sciences (NIEHS)/National Toxicology Program (NTP); U.S. Environmental Protection Agency (EPA); Food and Drug Administration National Center for Toxicological Research FX This review is based on deliberations that occurred at an 11-13 January 2011 workshop sponsored by the National Institute of Environmental Health Sciences (NIEHS)/National Toxicology Program (NTP), U.S. Environmental Protection Agency (EPA), and the Food and Drug Administration National Center for Toxicological Research (http://ntp.niehs.nih.gov/go/36433). NR 102 TC 81 Z9 84 U1 9 U2 148 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 2013 VL 121 IS 7 BP 774 EP 783 DI 10.1289/ehp.1205502 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208VY UT WOS:000323711000015 PM 23651634 ER PT J AU Ostroumova, E Rozhko, A Hatch, M Furukawa, K Polyanskaya, O McConnell, RJ Nadyrov, E Petrenko, S Romanov, G Yauseyenka, V Drozdovitch, V Minenko, V Prokopovich, A Savasteeva, I Zablotska, LB Mabuchi, K Brenner, AV AF Ostroumova, Evgenia Rozhko, Alexander Hatch, Maureen Furukawa, Kyoji Polyanskaya, Olga McConnell, Robert J. Nadyrov, Eldar Petrenko, Sergey Romanov, George Yauseyenka, Vasilina Drozdovitch, Vladimir Minenko, Viktor Prokopovich, Alexander Savasteeva, Irina Zablotska, Lydia B. Mabuchi, Kiyohiko Brenner, Alina V. TI Measures of Thyroid Function among Belarusian Children and Adolescents Exposed to Iodine-131 from the Accident at the Chernobyl Nuclear Plant SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE antithyroid antibodies; autoimmune thyroiditis; Chernobyl; Chornobyl; dose response; hyperthyroidism; hypothyroidism; radioiodine; thyroid gland ID ATOMIC-BOMB SURVIVORS; NEVADA TEST-SITE; FOLLOW-UP; AUTOIMMUNE-THYROIDITIS; IODINE DEFICIENCY; RADIATION; DISEASE; CANCER; CHILDHOOD; FALLOUT AB BACKGROUND: Thyroid dysfunction after exposure to low or moderate doses of radioactive iodine-131 (I-131) at a young age is a public health concern. However, quantitative data are sparse concerning I-131-related risk of these common diseases. OBJECTIVE: Our goal was to assess the prevalence of thyroid dysfunction in association with I-131 exposure during childhood (<= 18 years) due to fallout from the Chernobyl accident. METHODS: We conducted a cross-sectional analysis of hypothyroidism, hyperthyroidism, autoimmune thyroiditis (AIT), serum concentrations of thyroid-stimulating hormone (TSH), and autoantibodies to thyroperoxidase (ATPO) in relation to measurement-based I-131 dose estimates in a Belarusian cohort of 10,827 individuals screened for various thyroid diseases. RESULTS: Mean age at exposure (+/- SD) was 8.2 +/- 5.0 years. Mean (median) estimated I-131 thyroid dose was 0.54 (0.23) Gy (range, 0.001-26.6 Gy). We found significant positive associations of I-131 dose with hypothyroidism (mainly subclinical and antibody-negative) and serum TSH concentration. The excess odds ratio per 1 Gy for hypothyroidism was 0.34 (95% CI: 0.15, 0.62) and varied significantly by age at exposure and at examination, presence of goiter, and urban/rural residency. We found no evidence of positive associations with antibody-positive hypothyroidism, hyperthyroidism, AIT, or elevated ATPO. CONCLUSIONS: The association between I-131 dose and hypothyroidism in the Belarusian cohort is consistent with that previously reported for a Ukrainian cohort and strengthens evidence of the effect of environmental I-131 exposure during childhood on hypothyroidism, but not other thyroid outcomes. C1 [Ostroumova, Evgenia; Hatch, Maureen; Drozdovitch, Vladimir; Mabuchi, Kiyohiko; Brenner, Alina V.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rozhko, Alexander; Polyanskaya, Olga; Nadyrov, Eldar; Romanov, George; Yauseyenka, Vasilina; Prokopovich, Alexander; Savasteeva, Irina] Republican Res Ctr Radiat Med & Human Ecol, Gomel, Byelarus. [Furukawa, Kyoji] Radiat Effects Res Fdn, Dept Stat, Hiroshima, Japan. [McConnell, Robert J.] Columbia Univ, Thyroid Ctr, New York, NY USA. [Petrenko, Sergey] Int Sakharov Environm Univ, Dept Anthropoecol & Epidemiol, Minsk, Byelarus. [Minenko, Viktor] Belarusian Med Acad Postgrad Educ, Minsk, Byelarus. [Zablotska, Lydia B.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Ostroumova, E (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 9609 Med Ctr Dr,Room 7E560 MSC 9778, Bethesda, MD 20892 USA. EM ostroume@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; Department of Energy; U.S. Nuclear Regulatory Commission FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the Department of Energy. The U.S. Nuclear Regulatory Commission provided the initial funds for equipment purchase. The funding agencies had no influence on study design, conduct, or reporting. NR 44 TC 13 Z9 13 U1 2 U2 15 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 2013 VL 121 IS 7 BP 865 EP 871 DI 10.1289/ehp.1205783 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208VY UT WOS:000323711000028 PM 23651658 ER PT J AU Birnbaum, LS Aungst, J Schug, TT Goodman, JL AF Birnbaum, Linda S. Aungst, Jason Schug, Thaddeus T. Goodman, Jesse L. TI Working Together: Research- and Science-Based Regulation of BPA SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material ID BISPHENOL-A; MONKEYS C1 [Birnbaum, Linda S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIH, NTP, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Aungst, Jason] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Schug, Thaddeus T.] NIEHS, Cellular Organ & Syst Pathobiol Branch, Div Extramural Res & Training, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Goodman, Jesse L.] US FDA, Off Chief Scientist, Silver Spring, MD USA. RP Birnbaum, LS (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov NR 8 TC 1 Z9 1 U1 0 U2 4 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 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2013 VL 121 IS 7 BP A206 EP A207 DI 10.1289/ehp.1306963 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 208VY UT WOS:000323711000001 PM 23817036 ER PT J AU Little, MP Goodhead, DT Bridges, BA Bouffler, SD AF Little, Mark P. Goodhead, Dudley T. Bridges, Bryn A. Bouffler, Simon D. TI Evidence relevant to untargeted and transgenerational effects in the offspring of irradiated parents SO MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH LA English DT Review DE Transgenerational effects; Radiation; Genetic effects; Minisatellites; Radiotherapy; Chemotherapy ID ATOMIC-BOMB SURVIVORS; CHILDHOOD-CANCER SURVIVORS; MINISATELLITE MUTATION-RATE; G(2) CHROMOSOMAL RADIOSENSITIVITY; LOW-PENETRANCE PREDISPOSITION; NUCLEAR INDUSTRY EMPLOYEES; CHERNOBYL CLEANUP WORKERS; POPULATION-BASED COHORT; PATERNAL X-IRRADIATION; F-0 RADIATION HISTORY AB In this article we review health effects in offspring of human populations exposed as a result of radiotherapy and some groups exposed to chemotherapy. We also assess risks in offspring of other radiation-exposed groups, in particular those of the Japanese atomic bomb survivors and occupationally and environmentally exposed groups. Experimental findings are also briefly surveyed. Animal and cellular studies tend to suggest that the irradiation of males, at least at high doses (mostly 1 Gy and above), can lead to observable effects (including both genetic and epigenetic) in the somatic cells of their offspring over several generations that are not attributable to the inheritance of a simple mutation through the parental germline. However, studies of disease in the offspring of irradiated humans have not identified any effects on health. The available evidence therefore suggests that human health has not been significantly affected by transgenerational effects of radiation. It is possible that transgenerational effects are restricted to relatively short times post-exposure and in humans conception at short times after exposure is likely to be rare. Further research that may help resolve the apparent discrepancies between cellular/animal studies and studies of human health are outlined. Published by Elsevier B.V. C1 [Little, Mark P.] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [Goodhead, Dudley T.] MRC, Harwell, Oxon, England. [Bridges, Bryn A.] Univ Sussex, Genome Damage & Stabil Ctr, Brighton, E Sussex, England. [Bouffler, Simon D.] Publ Hlth England, Ctr Radiat Chem & Environm Hazards, Didcot OX11 0RQ, Oxon, England. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, 9609 Med Ctr Dr,MSC 9778, Bethesda, MD 20892 USA. EM mark.little@nih.gov; d.goodhead@har.mrc.ac.uk; bryn.bridges@virgin.net; Simon.Bouffler@phe.gov.uk OI Little, Mark/0000-0003-0980-7567 FU UK Health Protection Agency (HPA); National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics; HPA FX This work was initiated and supported by the UK Health Protection Agency (HPA). The work of MPL was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. The work of SDB was supported by the HPA. However, these bodies had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. BAB and DTG received no financial support apart from meeting expenses. NR 135 TC 13 Z9 18 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5742 J9 MUTAT RES-REV MUTAT JI Mutat. Res.-Rev. Mutat. Res. PD JUL-SEP PY 2013 VL 753 IS 1 BP 50 EP 67 DI 10.1016/j.mrrev.2013.04.001 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 212PG UT WOS:000323994700005 PM 23648355 ER PT J AU Chae, YC Angelin, A Lisanti, S Kossenkov, AV Speicher, KD Wang, H Powers, JF Tischler, AS Pacak, K Fliedner, S Michalek, RD Karoly, ED Wallace, DC Languino, LR Speicher, DW Altieri, DC AF Chae, Young Chan Angelin, Alessia Lisanti, Sofia Kossenkov, Andrew V. Speicher, Kaye D. Wang, Huan Powers, James F. Tischler, Arthur S. Pacak, Karel Fliedner, Stephanie Michalek, Ryan D. Karoly, Edward D. Wallace, Douglas C. Languino, Lucia R. Speicher, David W. Altieri, Dario C. TI Landscape of the mitochondrial Hsp90 metabolome in tumours SO NATURE COMMUNICATIONS LA English DT Article ID SUCCINATE-DEHYDROGENASE; PROTEIN HOMEOSTASIS; CELL METABOLISM; CANCER; DYSFUNCTION; PHEOCHROMOCYTOMA; STRESS; CYCLE; PARAGANGLIOMA; PGC1-ALPHA AB Reprogramming of tumour cell metabolism contributes to disease progression and resistance to therapy, but how this process is regulated on the molecular level is unclear. Here we report that heat shock protein 90-directed protein folding in mitochondria controls central metabolic networks in tumour cells, including the electron transport chain, citric acid cycle, fatty acid oxidation, amino acid synthesis and cellular redox status. Specifically, mitochondrial heat shock protein 90, but not cytosolic heat shock protein 90, binds and stabilizes the electron transport chain Complex II subunit succinate dehydrogenase-B, maintaining cellular respiration under low-nutrient conditions, and contributing to hypoxia-inducible factor-1 alpha-mediated tumorigenesis in patients carrying succinate dehydrogenase-B mutations. Thus, heat shock protein 90-directed proteostasis in mitochondria regulates tumour cell metabolism, and may provide a tractable target for cancer therapy. C1 [Chae, Young Chan; Lisanti, Sofia; Languino, Lucia R.; Altieri, Dario C.] Wistar Inst Anat & Biol, Prostate Canc Discovery & Dev Program, Philadelphia, PA 19104 USA. [Angelin, Alessia; Wallace, Douglas C.] Childrens Hosp Philadelphia, Ctr Mitochondrial & Epigen Med, Philadelphia, PA 19104 USA. [Kossenkov, Andrew V.; Speicher, Kaye D.; Wang, Huan; Speicher, David W.; Altieri, Dario C.] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, Philadelphia, PA 19104 USA. [Kossenkov, Andrew V.; Speicher, Kaye D.; Wang, Huan; Speicher, David W.; Altieri, Dario C.] Wistar Inst Anat & Biol, Ctr Syst & Computat Biol, Philadelphia, PA 19104 USA. [Powers, James F.; Tischler, Arthur S.] Tufts Med Ctr, Dept Pathol, Boston, MA 02111 USA. [Pacak, Karel; Fliedner, Stephanie] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Michalek, Ryan D.; Karoly, Edward D.] Metabolon Inc, Durham, NC 27713 USA. [Languino, Lucia R.] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA. RP Altieri, DC (reprint author), Wistar Inst Anat & Biol, Prostate Canc Discovery & Dev Program, Philadelphia, PA 19104 USA. EM daltieri@wistar.org OI Languino, Lucia/0000-0001-9011-7031 FU PheoPara Alliance; National Institutes of Health (NIH) [CA140043, CA78810, HL54131, CA118005, NS021328]; Department of Defense [PR100171]; Cancer Center Support Grant (CCSG) [CA010815] FX We gratefully acknowledge the assistance of The Wistar Institute Proteomics Core for performing LC-MS/MS analyses, Tony Chang-Wong for assistance in computational processing of proteomics data, and Sira Sriswasdi for preparing heat maps. This work was supported by the PheoPara Alliance, National Institutes of Health (NIH) Grants CA140043, CA78810, HL54131 and CA118005 to DCA, NS021328 to DCW and Department of Defense grant PR100171 to AST. Support for Core Facilities utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute. NR 44 TC 37 Z9 38 U1 2 U2 20 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 2013 VL 4 AR 2139 DI 10.1038/ncomms3139 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 208XR UT WOS:000323716300009 PM 23842546 ER PT J AU Townsley, DM AF Townsley, Danielle M. TI Hematologic Complications of Pregnancy SO SEMINARS IN HEMATOLOGY LA English DT Article ID SICKLE-CELL-DISEASE; NEONATAL ALLOIMMUNE THROMBOCYTOPENIA; ACQUIRED HEMOPHILIA-A; VENOUS THROMBOEMBOLISM; HELLP-SYNDROME; BLEEDING DISORDERS; CONTROLLED-TRIAL; PLASMA-EXCHANGE; WOMEN; RISK AB Pregnancy induces a number of physiologic changes that affect the hematologic indices, either directly or indirectly. Recognizing and treating hematologic disorders that occur during pregnancy is difficult owing to the paucity of evidence available to guide consultants. This review discusses specifically the diagnosis and management of benign hematologic disorders occurring during pregnancy. Anemia secondary to iron deficiency is the most frequent hematologic complication and is easily treated with oral iron formulations; however, care must be taken not to miss other causes of anemia, such as sickle cell disease. Thrombocytopenia is also a common reason for consulting the hematologist, and distinguishing gestational thrombocytopenia from immune thrombocytopenia (ITP), preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), or thrombotic thrombocytopenic purpura (TTP) is essential since the treatment differs widely. Occasionally the management of mother and infant involves the expeditious recognition of neonatal alloimmune thrombocytopenia (NAM, a condition that is responsible for severe life-threatening bleeding of the newborn. Additionally, inherited and acquired bleeding disorders affect pregnant women disproportionately and often require careful monitoring of coagulation parameters to prevent bleeding in the puerperium. Finally, venous thromboembolism (VTE) during pregnancy is still largely responsible for mortality during pregnancy, and the diagnosis, treatment options and guidelines for prevention of VTE during pregnancy are explored. Semin Hematol 50:222-231. Published by Elsevier Inc. C1 [Townsley, Danielle M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Townsley, DM (reprint author), NIH, 10 Ctr Dr,CRC 3-5216, Bethesda, MD 20892 USA. EM Danielle.townsley@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 74 TC 10 Z9 14 U1 1 U2 14 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 2013 VL 50 IS 3 BP 222 EP 231 DI 10.1053/j.seminhematol.2013.06.004 PG 10 WC Hematology SC Hematology GA 212TO UT WOS:000324005900006 PM 23953339 ER PT J AU Xu, D Young, JH Krahn, JM Song, D Corbett, KD Chazin, WJ Pedersen, LC Esko, JD AF Xu, Ding Young, Jeffrey H. Krahn, Juno M. Song, Danyin Corbett, Kevin D. Chazin, Walter J. Pedersen, Lars C. Esko, Jeffrey D. TI Stable RAGE-Heparan Sulfate Complexes Are Essential for Signal Transduction SO ACS CHEMICAL BIOLOGY LA English DT Article ID GLYCATION END-PRODUCTS; STRUCTURAL BASIS; CRYSTAL-STRUCTURE; SOLUBLE RECEPTOR; ACTIVATION; DIMERIZATION; RECOGNITION; ENDPRODUCTS; BINDING; HMGB1 AB RAGE (Receptor for Advanced Glycation End-Products) has emerged as a major receptor that mediates vascular inflammation. Signaling through RAGE by damage-associated molecular pattern molecules often leads to uncontrolled inflammation that exacerbates the impact of the underlying disease. Oligomertzation of RAGE is believed to play an essential role in signal transduction, but the molecular mechanism of oligomerization remains elusive. Here we report that RAGE activation of Erki(1/2) phosphorylation on endothelial cells in response to a number of ligands depends on a mechanism that involves heparan sulfate-induced hexamerization of the RAGE extracellular domain. Structural studies of the extracellular V-C1 domain-dodecasaccharide complex by X-ray diffraction and small-angle X-ray scattering revealed that the hexamer consists of a trimer of dimers, with a stoichiometry of 2:1 RAGE:dodecasaccharide. Mutagenesis studies mapped the heparan sulfate binding site and the interfacial surface between the monomers and demonstrated that electrostatic interactions with heparan sulfate and intermonomer hydrophobic interactions work in concert to stabilize the dimer. The importance of oligomerization was demonstrated by inhibition of signaling with a new epitope-defined monoclonal antibody that specifically targets oligomerization. These findings indicate that RAGE-heparan sulfate oligomeric complexes are essential for signaling and that interfering with RAGE oligomerization might be of therapeutic value. C1 [Xu, Ding; Young, Jeffrey H.; Song, Danyin; Esko, Jeffrey D.] Univ Calif San Diego, Glycobiol Res & Training Ctr, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Krahn, Juno M.; Pedersen, Lars C.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Corbett, Kevin D.] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Corbett, Kevin D.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Chazin, Walter J.] Vanderbilt Univ, Dept Biochem, Struct Biol Ctr, Nashville, TN 37232 USA. [Chazin, Walter J.] Vanderbilt Univ, Dept Biochem, Struct Biol Ctr, Nashville, TN 37232 USA. [Chazin, Walter J.] Vanderbilt Univ, Dept Chem, Struct Biol Ctr, Nashville, TN 37232 USA. RP Xu, D (reprint author), Univ Calif San Diego, Glycobiol Res & Training Ctr, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. EM dxu@ucsd.edu RI Xu, Ding/B-2493-2009 OI Xu, Ding/0000-0001-9380-2712 FU American Heart Association [13BGIA14150008]; National Institutes of Health [P01 HL57345, P01 HL107150, R56 AI091771]; Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health [1 ZIA ES102645-03]; Ludwig Institute for Cancer Research; DOE program Integrated Diffraction Analysis Technologies (IDAT) [DE-AC02-05CH11231]; U.S. Department of Energy FX This work was supported by grants 13BGIA14150008 from the American Heart Association (to D.X.), P01 HL57345 and P01 HL107150 (to J.D.E.), R56 AI091771 (to WJ.C.) from the National Institutes of Health, the Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health (1 ZIA ES102645-03, to L.C.P.), and by the Ludwig Institute for Cancer Research (to K.D.C.). We would like to thank G. Srikrishna and H. Freeze for providing S100A8/A9 and S100A12 proteins and SIBYLS beamline scientists M. Hammel and G. Hura for helpful discussions. SAXS data collection at the SIBYLS beamline of Advanced Light Source, Lawrence Berkeley National Laboratory, is supported in part by the DOE program Integrated Diffraction Analysis Technologies (IDAT) under Contract Number DE-AC02-05CH11231 with the U.S. Department of Energy. NR 37 TC 21 Z9 21 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JUL PY 2013 VL 8 IS 7 BP 1611 EP 1620 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 188RA UT WOS:000322210100030 PM 23679870 ER PT J AU Whitaker, D Milam, AJ Graham, CM Cooley-Strickland, M Belcher, HM Furr-Holden, CD AF Whitaker, Damiya Milam, Adam J. Graham, Camelia M. Cooley-Strickland, Michele Belcher, Harolyn M. Furr-Holden, C. Debra TI Neighborhood Environment and Urban Schoolchildren's Risk for Being Overweight SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Article DE Youth; Overweight; Gender; Environmental Exposure; Prevention Research ID BODY-MASS INDEX; PHYSICAL-ACTIVITY; BUILT ENVIRONMENT; CHILDHOOD OBESITY; VIOLENT CRIME; FOOD OUTLETS; CHILDREN; WALKING; ADOLESCENTS; PREVENTION AB Purpose. Child and adolescent obesity is increasingly prevalent and predisposes risk for poor physical and psychosocial health. Physical and social factors in the environment, such as neighborhood disorder, may be associated with childhood obesity. This study examines the association between living in a disordered neighborhood and being overweight among a sample of urban schoolchildren. Design. Baseline interview data, including height, weight, and hip circumference, were obtained from 313 elementary school-aged participants in a community-based epidemiologic study. Setting. The setting was Baltimore, Maryland, a large metropolitan city. Subjects. Subjects were elementary school students ages 8 to 12 years. Measures. To assess neighborhood characteristics, independent evaluators conducted objective environmental assessments using the Neighborhood Inventory for Environmental Typology instrument on the block faces (defined as one side of a city block between two intersections) where the children resided. Analysis. Logistic regression models with generalized estimating equations were used to examine the association between neighborhood disorder and children being overweight. Results. Neighborhood disorder showed a trend toward a statistically significant association with being overweight during childhood (odds ratio [OR], 1.03; confidence interval [CI], .99-1.07; p = .07) in the unadjusted model. Gender was significantly associated with being overweight, with female gender increasing the odds of being overweight by 50% in the sample (OR, 1.50; CI, 1.18-1.92; p < .01). After controlling for race, age, and comparative time spent on a sport, multivariable analyses revealed that gender (adjusted odds ratio [AOR], 2.42; CI, 1.63-3.59; p < .01) and neighborhood disorder (AOR, 1.09; CI, 1.03-1.15; p < .01) were associated with being overweight. Further, an examination of interactions revealed girls (AOR, 2.40; CI, 1.65-3.49; p < .01) were more likely to be overweight compared with boys (AOR, 2.20; CI, 1.57-3.11; p < .01) living in neighborhoods with the same level of neighborhood disorder. Conclusion. Results suggest neighborhood hazards warrant additional consideration for their potential as obesogenic elements affecting gender-based disparities in weight among urban schoolchildren. Future studies in this area should include longitudinal examinations. C1 [Whitaker, Damiya; Milam, Adam J.; Graham, Camelia M.; Cooley-Strickland, Michele; Belcher, Harolyn M.; Furr-Holden, C. Debra] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21202 USA. [Whitaker, Damiya] NIDA, Intramural Res Program, Clin Pharmacol & Therapeut Res Branch, NIH,Biomed Res Ctr, Baltimore, MD USA. [Cooley-Strickland, Michele] Univ Calif Los Angeles, Semel Inst NPI, Ctr Culture & Hlth, Los Angeles, CA USA. [Cooley-Strickland, Michele; Furr-Holden, C. Debra] Johns Hopkins Univ, Ctr Hlth Dispar Solut, Baltimore, MD 21202 USA. [Belcher, Harolyn M.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21202 USA. [Belcher, Harolyn M.] Kennedy Krieger Inst, Family Ctr, Baltimore, MD USA. RP Whitaker, D (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Div Studies Lab, 111 Market Pl,Suite 850, Baltimore, MD 21202 USA. EM dwhitake@jhsph.edu FU NCIPC CDC HHS [1U49CE000728]; NIAAA NIH HHS [R01AA015196]; NIDA NIH HHS [R01DA018318, T32 DA007292] NR 71 TC 3 Z9 3 U1 0 U2 15 PU AMER JOURNAL HEALTH PROMOTION INC PI TROY PA PO BOX 1254, TROY, MI 48099-1254 USA SN 0890-1171 J9 AM J HEALTH PROMOT JI Am. J. Health Promot. PD JUL-AUG PY 2013 VL 27 IS 6 BP 410 EP 416 DI 10.4278/ajhp.100827-QUAN-285 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 205YT UT WOS:000323481600017 PM 23458376 ER PT J AU Rowe, J Grim, SA Peace, D Lai, C Sweiss, K Layden, JE Clark, NM AF Rowe, Julie Grim, Shellee A. Peace, David Lai, Catherine Sweiss, Karen Layden, Jennifer E. Clark, Nina M. TI The significance of cytomegalovirus viremia at day 100 or more following allogeneic hematopoietic stem cell transplantation SO CLINICAL TRANSPLANTATION LA English DT Article DE cytomegalovirus; hematopoietic stem cell transplantation; infection ID BONE-MARROW-TRANSPLANTATION; RISK-FACTORS; REDUCED-INTENSITY; CMV INFECTION; RECIPIENTS; DISEASE; BLOOD; COMPLICATIONS; THERAPY; ANTIGEN AB We conducted a single-center retrospective review of patients who had received allogeneic hematopoietic stem cell transplantation (HSCT) between January 2003 and December 2007, to assess the incidence and risk factors for late CMV infection and evaluate its effects on outcomes. Twenty of 49 HSCT recipients (41%) developed CMV infection at day 100 after transplant. Univariable analysis showed that having a matched unrelated donor, having early CMV infection, having a diagnosis of lymphoma, and receipt of antithymocyte globulin were risks for developing late CMV. On multivariable analysis, the occurrence of CMV prior to day 100 and lymphoma conferred a significant risk for late CMV infection. Of the 20 patients with late CMV infection, two patients manifested CMV disease (10%). Despite the relatively low incidence of CMV disease, patients with late CMV infection had a 4.8-fold increased risk of death compared to patients without late CMV. Identifying patients at increased risk for developing late CMV infection may be important for prompting more intensive monitoring of infection late after HSCT, particularly because this manifestation of CMV is associated with poorer outcomes. C1 [Rowe, Julie] Univ Texas Hlth Sci Ctr San Antonio, Dept Internal Med, Hematol Oncol Sect, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Grim, Shellee A.] Univ Illinois Hosp & Hlth Sci Syst, Dept Med, Infect Dis Sect, Chicago, IL USA. [Grim, Shellee A.; Sweiss, Karen] Univ Illinois Hosp & Hlth Sci Syst, Dept Pharm Practice, Chicago, IL USA. [Peace, David; Sweiss, Karen] Univ Illinois Hosp & Hlth Sci Syst, Dept Med, Sect Hematol Oncol, Chicago, IL USA. [Lai, Catherine] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Layden, Jennifer E.; Clark, Nina M.] Loyola Univ, Med Ctr, Dept Med, Div Infect Dis, Maywood, IL 60153 USA. RP Clark, NM (reprint author), Loyola Univ, Med Ctr, 2160 S 1st Ave,Fahey Bldg 54,Room 112, Maywood, IL 60153 USA. EM nmclark@lumc.edu OI Clark, Nina/0000-0001-5670-4443 NR 26 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0902-0063 J9 CLIN TRANSPLANT JI Clin. Transplant. PD JUL PY 2013 VL 27 IS 4 BP 510 EP 516 DI 10.1111/ctr.12128 PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA 197AM UT WOS:000322819400029 PM 23621704 ER PT J AU Dossey, L AF Dossey, Larry TI The Shannon Error: Trying to Catch Up When You Are Already Ahead SO EXPLORE-THE JOURNAL OF SCIENCE AND HEALING LA English DT Article C1 [Dossey, Larry] Med City Dallas Hosp, Dallas, TX USA. [Dossey, Larry] Natl Inst Hlth, Natl Ctr Complementary & Alternat Med, Panel Mind Body Intervent, Bethesda, MD 20892 USA. NR 26 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1550-8307 J9 EXPLORE-NY JI Explore-J Sci. Heal. PD JUL-AUG PY 2013 VL 9 IS 4 BP 197 EP 202 PG 6 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 205PS UT WOS:000323457400001 PM 23906096 ER PT J AU Chew, EY SanGiovanni, JP Ferris, FL Wong, WT Agron, E Clemons, TE Sperduto, R Danis, R Chandra, SR Blodi, BA Domalpally, A Elman, MJ Antoszyk, AN Ruby, AJ Orth, D Bressler, SB Fish, GE Hubbard, GB Klein, ML Friberg, TR Rosenfeld, PJ Toth, CA Bernstein, P AF Chew, Emily Y. SanGiovanni, John Paul Ferris, Frederick L. Wong, Wai T. Agron, Elvira Clemons, Traci E. Sperduto, Robert Danis, Ronald Chandra, Suresh R. Blodi, Barbara A. Domalpally, Amitha Elman, Michael J. Antoszyk, Andrew N. Ruby, Alan J. Orth, David Bressler, Susan B. Fish, Gary E. Hubbard, George B. Klein, Michael L. Friberg, Thomas R. Rosenfeld, Philip J. Toth, Cynthia A. Bernstein, Paul TI Lutein/Zeaxanthin for the Treatment of Age-Related Cataract AREDS2 Randomized Trial Report No. 4 SO JAMA OPHTHALMOLOGY LA English DT Article ID BETA-CAROTENE; VISUAL IMPAIRMENT; LENS OPACITIES; EYE DISEASE; VITAMIN-E; CLINICAL-TRIAL; UNITED-STATES; RISK-FACTORS; ZEAXANTHIN; LUTEIN AB IMPORTANCE Age-related cataract is a leading cause of visual impairment in the United States. The prevalence of age-related cataract is increasing, with an estimated 30.1 million Americans likely to be affected by 2020. OBJECTIVE To determine whether daily oral supplementation with lutein/zeaxanthin affects the risk for cataract surgery. DESIGN, SETTING, AND PATIENTS The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, double-masked clinical trial, enrolled 4203 participants, aged 50 to 85 years, at risk for progression to advanced age-related macular degeneration. INTERVENTIONS Participants were randomly assigned to daily placebo; lutein/zeaxanthin, 10mg/2mg; omega-3 long-chain polyunsaturated fatty acids, 1 g; or a combination to evaluate the effects on the primary outcome of progression to advanced age-related macular degeneration. MAIN OUTCOMES AND MEASURES Cataract surgery was documented at annual study examination with the presence of pseudophakia or aphakia, or reported during telephone calls at 6-month intervals between study visits. Annual best-corrected visual acuity testing was performed. A secondary outcome of AREDS2 was to evaluate the effects of lutein/zeaxanthin on the subsequent need for cataract surgery. RESULTS A total of 3159 AREDS2 participants were phakic in at least 1 eye and 1389 of 6027 study eyes underwent cataract surgery during the study, with median follow-up of 4.7 years. The 5-year probability of progression to cataract surgery in the no lutein/zeaxanthin group was 24%. For lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratios for progression to cataract surgery was 0.96 (95% CI, 0.84-1.10; P = .54). For participants in the lowest quintile of dietary intake of lutein/zeaxanthin, the hazard ratio comparing lutein/zeaxanthin vs no lutein/zeaxanthin for progression to cataract surgery was 0.68 (95% CI, 0.48-0.96; P = .03). The hazard ratio for 3 or more lines of vision loss was 1.03 (95% CI, 0.93-1.13; P = .61 for lutein/zeaxanthin vs no lutein/zeaxanthin). CONCLUSIONS AND RELEVANCE Daily supplementation with lutein/zeaxanthin had no statistically significant overall effect on rates of cataract surgery or vision loss. C1 [SanGiovanni, John Paul; Ferris, Frederick L.; Wong, Wai T.; Agron, Elvira] NIH, NEI, Bethesda, MD 20892 USA. [Clemons, Traci E.; Sperduto, Robert] EMMES Corp, Rockville, MD USA. [Danis, Ronald; Chandra, Suresh R.; Blodi, Barbara A.; Domalpally, Amitha] Univ Wisconsin, Madison, WI USA. [Elman, Michael J.] Elman Retina Grp PA, Baltimore, MD USA. [Antoszyk, Andrew N.] Charlotte Eye Ear Nose & Throat Assoc, Charlotte, NC USA. [Ruby, Alan J.] Vision Res Fdn, Royal Oak, MI USA. [Orth, David] Ingalls Mem Hosp, Harvey, IL USA. [Bressler, Susan B.] Wilmer Eye Inst, Retina Div, Baltimore, MD 21287 USA. [Fish, Gary E.] Texas Retina Assoc, Dallas, TX USA. [Hubbard, George B.] Emory Univ, Ctr Eye, Atlanta, GA 30322 USA. [Klein, Michael L.] Devers Eye Inst, Portland, OR USA. [Friberg, Thomas R.] Univ Pittsburgh, Med Ctr Eye Ctr, Pittsburgh, PA USA. [Rosenfeld, Philip J.] Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Toth, Cynthia A.] Duke Univ, Durham, NC USA. [Bernstein, Paul] Univ Utah, Moran Eye Ctr, Salt Lake City, UT USA. RP Chew, EY (reprint author), NIH, NEI, Bldg 10,CRC Rm 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov RI Domalpally, Amitha/B-2367-2015; Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute/National Institutes of Health; Department of Health and Human Services, Bethesda, MD [HHS-N-260-2005-00007-C, N01-EY-5-0007]; National Institutes of Health institute: Office of Dietary Supplements; National Institutes of Health institute: National Center for Complementary and Alternative Medicine; National Institutes of Health institute: National Institute on Aging; National Institutes of Health institute: National Heart, Lung and Blood Institute; National Institutes of Health institute: National Institute of Neurological Disorders and Stroke FX This study was supported by the intramural program funds and contracts from the National Eye Institute/National Institutes of Health, the Department of Health and Human Services, Bethesda, MD (contract No. HHS-N-260-2005-00007-C and ADB contract No. N01-EY-5-0007). Funds were contributed to these contracts by the following National Institutes of Health institutes: Office of Dietary Supplements; National Center for Complementary and Alternative Medicine; National Institute on Aging; National Heart, Lung and Blood Institute; and National Institute of Neurological Disorders and Stroke. The study medications and raw materials were provided by Alcon, Bausch and Lomb, DSM, and Pfizer. NR 36 TC 39 Z9 39 U1 0 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6165 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD JUL PY 2013 VL 131 IS 7 BP 843 EP 850 DI 10.1001/jamaophthalmol.2013.4412 PG 8 WC Ophthalmology SC Ophthalmology GA 206VW UT WOS:000323553600004 ER PT J AU Horowitz, LM Bridge, JA Pao, M AF Horowitz, Lisa M. Bridge, Jeffrey A. Pao, Maryland TI What Is Meant by "Increased Risk for Suicide"? Reply SO JAMA PEDIATRICS LA English DT Letter ID PREVALENCE C1 [Horowitz, Lisa M.; Pao, Maryland] NIMH, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Bridge, Jeffrey A.] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. [Bridge, Jeffrey A.] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. RP Horowitz, LM (reprint author), NIMH, Off Clin Director, NIH, Clin Res Ctr, Ctr Dr,Bldg 10,Room 6-5362, Bethesda, MD 20892 USA. EM horowitzl@mail.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6203 J9 JAMA PEDIATR JI JAMA Pediatr. PD JUL PY 2013 VL 167 IS 7 BP 676 EP 676 DI 10.1001/jamapediatrics.2013.149 PG 1 WC Pediatrics SC Pediatrics GA 206UV UT WOS:000323550200023 PM 23817854 ER PT J AU Gimbel, RW Fontelo, P Stephens, MB Olsen, CH Bunt, C Ledford, CJW Cook, CAL Liu, F Burke, HB AF Gimbel, Ronald W. Fontelo, Paul Stephens, Mark B. Olsen, Cara H. Bunt, Christopher Ledford, Christy J. W. Cook, Cynthia A. Loveland Liu, Fang Burke, Harry B. TI Radiation Exposure and Cost Influence Physician Medical Image Decision Making A Randomized Controlled Trial SO MEDICAL CARE LA English DT Article DE patient safety; medical imaging; cost; radiation exposure; physicians; clinical decision support; decision making ID ORDER ENTRY SYSTEMS; EMERGENCY-DEPARTMENT; COMPUTED-TOMOGRAPHY; IONIZING-RADIATION; CANCER-RISKS; CT SCANS; SUPPORT; APPROPRIATENESS; CHARGES; PATIENT AB Background: It is estimated that 20%-40% of advanced medical imaging in the United States is unnecessary, resulting in patient overexposure to radiation and increasing the cost of care. Previous imaging utilization studies have focused on clinical appropriateness. An important contributor to excessive use of advanced imaging may be a physician "knowledge gap" regarding the safety and cost of the tests. Objectives: To determine whether safety and cost information will change physician medical image decision making. Research Design: Double-blinded, randomized controlled trial. Following standardized case presentation, physicians made an initial imaging choice. This was followed by the presentation of guidelines, radiation exposure and health risk, and cost information. Results: Approximately half (57 of 112, 50.9%) of participants initially selected computed tomography (CT). When presented with guideline recommendations, participants did not modify their initial imaging choice (P=0.197). A significant reduction (56.3%, P<0.001) in CT ordering occurred after presentation of radiation exposure/health risk information; ordering changed to magnetic resonance imaging or ultrasound (US). A significant reduction (48.3%, P<0.001) in CT and magnetic resonance imaging ordering occurred after presentation of Medicare reimbursement information; ordering changed to US. The majority of physicians (31 of 40, 77.5%) selecting US never modified their ordering. No significant relationship between physician demographics and decision making was observed. Conclusions: This study suggests that physician decision making can be influenced by safety and cost information and the order in which information is provided to physicians can affect their decisions. C1 [Gimbel, Ronald W.; Ledford, Christy J. W.; Burke, Harry B.] Uniformed Serv Univ Hlth Sci, Dept Biomed Informat, Bethesda, MD 20814 USA. [Fontelo, Paul; Liu, Fang] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. [Stephens, Mark B.; Bunt, Christopher] Uniformed Serv Univ Hlth Sci, Dept Family Med, Bethesda, MD 20814 USA. [Olsen, Cara H.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Cook, Cynthia A. Loveland] St Louis Univ, Dept Family & Community Med, St Louis, MO 63103 USA. RP Gimbel, RW (reprint author), Uniformed Serv Univ Hlth Sci, Dept Biomed Informat, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM ronald.gimbel@usuhs.edu RI Stephens, Mark/A-2679-2015; OI Bunt, Christopher/0000-0002-5130-6902 FU Uniformed Services University [R02930.3]; US Department of Defense Patient Safety Program FX Intramural funding was provided by the Uniformed Services University, Grant #R02930.3 and the US Department of Defense Patient Safety Program. NR 43 TC 10 Z9 11 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2013 VL 51 IS 7 BP 628 EP 632 DI 10.1097/MLR.0b013e3182928fd5 PG 5 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 202ML UT WOS:000323221000011 PM 23604013 ER PT J AU Martin-Montalvo, A Mercken, EM Mitchell, SJ Palacios, HH Mote, PL Scheibye-Knudsen, M Gomes, AP Ward, TM Minor, RK Blouin, MJ Schwab, M Pollak, M Zhang, YQ Yu, YB Becker, KG Bohr, VA Ingram, DK Sinclair, DA Wolf, NS Spindler, SR Bernier, M de Cabo, R AF Martin-Montalvo, Alejandro Mercken, Evi M. Mitchell, Sarah J. Palacios, Hector H. Mote, Patricia L. Scheibye-Knudsen, Morten Gomes, Ana P. Ward, Theresa M. Minor, Robin K. Blouin, Marie-Jose Schwab, Matthias Pollak, Michael Zhang, Yongqing Yu, Yinbing Becker, Kevin G. Bohr, Vilhelm A. Ingram, Donald K. Sinclair, David A. Wolf, Norman S. Spindler, Stephen R. Bernier, Michel de Cabo, Rafael TI Metformin improves healthspan and lifespan in mice SO NATURE COMMUNICATIONS LA English DT Article ID ANTIDIABETIC DRUG METFORMIN; ACTIVATED PROTEIN-KINASE; OXIDATIVE STRESS; HEPATIC GLUCONEOGENESIS; DIETARY RESTRICTION; DNA-DAMAGE; COMPLEX I; RESPIRATION; AMPK; CANCER AB Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging. C1 [Martin-Montalvo, Alejandro; Mercken, Evi M.; Mitchell, Sarah J.; Palacios, Hector H.; Ward, Theresa M.; Minor, Robin K.; Bernier, Michel; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Mitchell, Sarah J.] Royal N Shore Hosp, Kolling Inst Med Res, St Leonards, NSW 2065, Australia. [Mitchell, Sarah J.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Mote, Patricia L.; Spindler, Stephen R.] Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA. [Scheibye-Knudsen, Morten; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Gomes, Ana P.; Sinclair, David A.] Harvard Univ, Sch Med, Dept Genet, Paul F Glenn Labs Biol Mech Aging, Boston, MA 02115 USA. [Blouin, Marie-Jose; Pollak, Michael] McGill Univ, Dept Med & Oncol, Montreal, PQ H3A 2B3, Canada. [Schwab, Matthias] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany. [Schwab, Matthias] Univ Tubingen, D-70376 Stuttgart, Germany. [Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. [Yu, Yinbing] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ingram, Donald K.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA 70808 USA. [Wolf, Norman S.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP de Cabo, R (reprint author), NIA, Translat Gerontol Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov RI de Cabo, Rafael/J-5230-2016; Martin-Montalvo, Alejandro/C-2031-2017; OI de Cabo, Rafael/0000-0002-3354-2442; Martin-Montalvo, Alejandro/0000-0002-3886-5355; Sinclair, David/0000-0002-9936-436X; Bernier, Michel/0000-0002-5948-368X; Scheibye-Knudsen, Morten/0000-0002-6637-1280; Becker, Kevin/0000-0002-6794-6656; , rafael/0000-0003-2830-5693 FU Intramural Research Program of the NIA, NIH; Portuguese Foundation for Science and Technology [SFRH/BD//44674/ 2008]; National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (RIMS) [2010-01671] FX We thank Federico Butelman from Farmhispania S. A., a FDA-approved cGMP company, for providing us with the metformin used in C57BL/6 mouse study; W. Wood and E. Lehrmann for microarray assistance; D. Phillips-Boyer, D. Nines and J. Lucas for animal care; and O. Carlson for insulin measurements. This research was supported, in part, by the Intramural Research Program of the NIA, NIH, and parts of this work was done under a CRADA with SIRTRIS, a GlaxoSmithKline (GSK) company. A. P. G. is the recipient of an individual fellowship from the Portuguese Foundation for Science and Technology (SFRH/BD//44674/ 2008). S.J.M. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (RIMS Project ID 2010-01671). NR 51 TC 199 Z9 206 U1 14 U2 79 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 2013 VL 4 AR 2192 DI 10.1038/ncomms3192 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 208XU UT WOS:000323716700001 PM 23900241 ER PT J AU Boratyn, GM Camacho, C Cooper, PS Coulouris, G Fong, A Ma, N Madden, TL Matten, WT McGinnis, SD Merezhuk, Y Raytselis, Y Sayers, EW Tao, T Ye, J Zaretskaya, I AF Boratyn, Grzegorz M. Camacho, Christiam Cooper, Peter S. Coulouris, George Fong, Amelia Ma, Ning Madden, Thomas L. Matten, Wayne T. McGinnis, Scott D. Merezhuk, Yuri Raytselis, Yan Sayers, Eric W. Tao, Tao Ye, Jian Zaretskaya, Irena TI BLAST: a more efficient report with usability improvements SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SEQUENCE-ANALYSIS; PSI-BLAST; SEARCHES AB The Basic Local Alignment Search Tool (BLAST) website at the National Center for Biotechnology (NCBI) is an important resource for searching and aligning sequences. A new BLAST report allows faster loading of alignments, adds navigation aids, allows easy downloading of subject sequences and reports and has improved usability. Here, we describe these improvements to the BLAST report, discuss design decisions, describe other improvements to the search page and database documentation and outline plans for future development. The NCBI BLAST URL is http://blast.ncbi.nlm.nih.gov. C1 [Boratyn, Grzegorz M.; Camacho, Christiam; Cooper, Peter S.; Coulouris, George; Fong, Amelia; Ma, Ning; Madden, Thomas L.; Matten, Wayne T.; McGinnis, Scott D.; Merezhuk, Yuri; Raytselis, Yan; Sayers, Eric W.; Tao, Tao; Ye, Jian; Zaretskaya, Irena] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Madden, TL (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 45,8600 Rockville Pike, Bethesda, MD 20894 USA. EM madden@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health; National Library of Medicine; National Institutes of Health FX Intramural Research Program of the National Institutes of Health; National Library of Medicine. Funding for open access charge: National Institutes of Health. NR 9 TC 94 Z9 97 U1 0 U2 21 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2013 VL 41 IS W1 BP W29 EP W33 DI 10.1093/nar/gkt282 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 207MC UT WOS:000323603200006 PM 23609542 ER PT J AU Wei, CH Kao, HY Lu, ZY AF Wei, Chih-Hsuan Kao, Hung-Yu Lu, Zhiyong TI PubTator: a web-based text mining tool for assisting biocuration SO NUCLEIC ACIDS RESEARCH LA English DT Article AB Manually curating knowledge from biomedical literature into structured databases is highly expensive and time-consuming, making it difficult to keep pace with the rapid growth of the literature. There is therefore a pressing need to assist biocuration with automated text mining tools. Here, we describe PubTator, a web-based system for assisting biocuration. PubTator is different from the few existing tools by featuring a PubMed-like interface, which many biocurators find familiar, and being equipped with multiple challenge-winning text mining algorithms to ensure the quality of its automatic results. Through a formal evaluation with two external user groups, PubTator was shown to be capable of improving both the efficiency and accuracy of manual curation. PubTator is publicly available at http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/PubTator/. C1 [Wei, Chih-Hsuan; Lu, Zhiyong] US Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Wei, Chih-Hsuan; Kao, Hung-Yu] Natl Cheng Kung Univ, Dept Comp Sci & Informat Engn, Tainan 701, Taiwan. RP Lu, ZY (reprint author), US Natl Lib Med, Natl Ctr Biotechnol Informat, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM zhiyong.lu@nih.gov FU NIH, National Library of Medicine; U.S. National Library of Medicine FX Intramural Research Program of the NIH, National Library of Medicine. Funding for open access charge: U.S. National Library of Medicine. NR 24 TC 59 Z9 59 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2013 VL 41 IS W1 BP W518 EP W522 DI 10.1093/nar/gkt441 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 207MC UT WOS:000323603200083 PM 23703206 ER PT J AU Ye, J Ma, N Madden, TL Ostell, JM AF Ye, Jian Ma, Ning Madden, Thomas L. Ostell, James M. TI IgBLAST: an immunoglobulin variable domain sequence analysis tool SO NUCLEIC ACIDS RESEARCH LA English DT Article ID B-CELLS; V-J; GENE; GENERATION; DATABASE; IG AB The variable domain of an immunoglobulin (IG) sequence is encoded by multiple genes, including the variable (V) gene, the diversity (D) gene and the joining (J) gene. Analysis of IG sequences typically requires identification of each gene, as well as a comparison of sequence variations in the context of defined regions. General purpose tools, such as the BLAST program, have only limited use for such tasks, as the rearranged nature of an IG sequence and the variable length of each gene requires multiple rounds of BLAST searches for a single IG sequence. Additionally, manual assembly of different genes is difficult and error-prone. To address these issues and to facilitate other common tasks in analysing IG sequences, we have developed the sequence analysis tool IgBLAST (http://www.ncbi.nlm.nih.gov/igblast/). With this tool, users can view the matches to the germline V, D and J genes, details at rearrangement junctions, the delineation of IG V domain framework regions and complementarity determining regions. IgBLAST has the capability to analyse nucleotide and protein sequences and can process sequences in batches. Furthermore, IgBLAST allows searches against the germline gene databases and other sequence databases simultaneously to minimize the chance of missing possibly the best matching germline V gene. C1 [Ye, Jian; Ma, Ning; Madden, Thomas L.; Ostell, James M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Ye, J (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM jianye@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine; NIH FX Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine. Funding for open access charge: NIH. NR 15 TC 115 Z9 118 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2013 VL 41 IS W1 BP W34 EP W40 DI 10.1093/nar/gkt382 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 207MC UT WOS:000323603200007 PM 23671333 ER PT J AU Rickels, MR Bellin, M Toledo, FGS Robertson, RP Andersen, DK Chari, ST Brand, R Frulloni, L Anderson, MA Whitcomb, DC AF Rickels, Michael R. Bellin, Melena Toledo, Frederico G. S. Robertson, R. Paul Andersen, Dana K. Chari, Suresh T. Brand, Randall Frulloni, Luca Anderson, Michelle A. Whitcomb, David C. CA PancreasFest Recommendation Confer TI Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis:. Recommendations from PancreasFest 2012 SO PANCREATOLOGY LA English DT Article DE Diabetes mellitus; Chronic pancreatitis; Incretin; Pancreatogenic diabetes; Insulin; Glucose tolerance test; Pancreatic polypeptide; GLP-1 ID DISEASES TYPE 3C; ENZYME SUBSTITUTION; HEREDITARY PANCREATITIS; POLYPEPTIDE RESPONSE; FECAL ELASTASE-1; CYSTIC-FIBROSIS; CELL FUNCTION; RISK-FACTORS; PREVALENCE; MANAGEMENT AB Description: Diabetes and glucose intolerance are common complications of chronic pancreatitis, yet clinical guidance on their detection, classification, and management is lacking. Methods: A working group reviewed the medical problems, diagnostic methods, and treatment options for chronic pancreatitis-associated diabetes for a consensus meeting at PancreasFest 2012. Results: Guidance Statement 1.1: Diabetes mellitus is common in chronic pancreatitis. While any patient with chronic pancreatitis should be monitored for development of diabetes, those with long-standing duration of disease, prior partial pancreatectomy, and early onset of calcific disease may be at higher risk. Those patients developing diabetes mellitus are likely to have co-existing pancreatic exocrine insufficiency. Guidance Statement 1.2: Diabetes occurring secondary to chronic pancreatitis should be recognized as pancreatogenic diabetes (type 3c diabetes). Guidance Statement 2.1: The initial evaluation should include fasting glucose and HbA1c. These tests should be repeated annually. Impairment in either fasting glucose or HbA1c requires further evaluation. Guidance Statement 2.2: Impairment in either fasting glucose or HbA1c should be further evaluated by a standard 75 g oral glucose tolerance test. Guidance Statement 2.3: An absent pancreatic polypeptide response to mixed-nutrient ingestion is a specific indicator of type 3c diabetes. Guidance Statement 2.4: Assessment of pancreatic endocrine reserve, and importantly that of functional beta-cell mass, should be performed as part of the evaluation and follow-up for total pancreatectomy with islet autotransplantation (TPIAT). Guidance Statement 3: Patients with pancreatic diabetes shall be treated with specifically tailored medical nutrition and pharmacologic therapies. Conclusions: Physicians should evaluate and treat glucose intolerance in patients with pancreatitis. Copyright (c) 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved. C1 [Rickels, Michael R.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Bellin, Melena] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Toledo, Frederico G. S.; Brand, Randall; Whitcomb, David C.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. [Robertson, R. Paul] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Andersen, Dana K.] Natl Inst Diabet & Digest & Kidney Dis, Div Digest Dis & Nutr, NIH, Bethesda, MD USA. [Chari, Suresh T.] Mayo Clin, Dept Med, Rochester, MN USA. [Frulloni, Luca] Univ Verona, Dept Med, I-37100 Verona, Italy. [Anderson, Michelle A.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Whitcomb, David C.] Univ Pittsburgh, Dept Cell Biol & Mol Physiol, Pittsburgh, PA 15213 USA. [Whitcomb, David C.] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15213 USA. RP Whitcomb, DC (reprint author), Univ Pittsburgh, Div Gastroenterol Hepatol & Nutr, 3708 5th Ave,Room 401-4, Pittsburgh, PA 15213 USA. EM whitcomb@pitt.edu RI Lerch, Markus M./E-2206-2016; OI Lerch, Markus M./0000-0002-9643-8263; Frulloni, Luca/0000-0001-7417-2655; Kim, Kyung Mo/0000-0001-7896-6751 FU National Institute of Diabetes and Digestive and Kidney Diseases [R13DK083216, R13DK088452, R13DK09604]; Abbott Laboratories; Aptalis Pharma; Boston Scientific; Cook Medical; Lilly; Olympus through the University of Pittsburgh office of Continuing Medical Education FX This work was supported in part by conference grants from the National Institute of Diabetes and Digestive and Kidney Diseases [R13DK083216 (2009), R13DK088452 (2010), and R13DK09604 (2012)] and accredited physician education supported by Abbott Laboratories, Aptalis Pharma, Boston Scientific, Cook Medical, Lilly, and Olympus through the University of Pittsburgh office of Continuing Medical Education. The authors thank Ms. Michelle Kienholz, Ms. Joy Jenko Merusi, and Ms. Marianne Davis for their expert assistance with the editing of this manuscript. NR 40 TC 39 Z9 39 U1 2 U2 18 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1424-3903 J9 PANCREATOLOGY JI Pancreatology PD JUL-AUG PY 2013 VL 13 IS 4 BP 336 EP 342 DI 10.1016/j.pan.2013.05.002 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 205SH UT WOS:000323464600003 PM 23890130 ER PT J AU Alegria, AA Blanco, C Petry, NM Skodol, AE Liu, SM Grant, B Hasin, D AF Alegria, Analucia A. Blanco, Carlos Petry, Nancy M. Skodol, Andrew E. Liu, Shang-Min Grant, Bridget Hasin, Deborah TI Sex Differences in Antisocial Personality Disorder: Results From the National Epidemiological Survey on Alcohol and Related Conditions SO PERSONALITY DISORDERS-THEORY RESEARCH AND TREATMENT LA English DT Article DE antisocial personality disorder; sex; gender; epidemiology ID PSYCHIATRIC DIAGNOSTIC MODULES; IMPULSIVE AGGRESSIVE-BEHAVIOR; GENERAL-POPULATION SAMPLE; SUBSTANCE USE DISORDERS; DRUG-USE DISORDERS; IV AUDADIS-IV; GENDER-DIFFERENCES; UNITED-STATES; DIVALPROEX SODIUM; CONTROLLED-TRIAL AB Despite the 3:1 prevalence ratio of men versus women with Antisocial Personality Disorder (ASPD), research on sex differences on correlates of ASPD in the general population is scarce. The purpose of this study was to examine sex differences in childhood and adult adverse events, lifetime psychiatric comorbidity, and clinical correlates of DSM-IV ASPD. The sample included 819 men and 407 women with DSM-IV ASPD diagnosis. Data were derived from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (N = 43,093). Compared to men, women with ASPD reported more frequent childhood emotional neglect (AOR = 2.25; 95% CI:.1.52-3.34) and sexual abuse (AOR = 4.20; 95% CI: 2.78-6.35), any parent-related adverse event during childhood (e.g., parental substance use disorder) (AOR = 2.47; 95% CI: 1.60-3.82), and adverse events during adulthood (AOR = 4.20; 95% CI: 2.78-6.35). Although women with ASPD present less violent antisocial behaviors and higher rates of aggressiveness and irritability (OR = 0.46; 95% CI: 0.31-0.67), they have higher rates of victimization, greater impairment, and lower social support. Our findings suggest increased mental health needs in women with ASPD, meriting development of different treatment programs for women and men. C1 [Alegria, Analucia A.; Blanco, Carlos; Liu, Shang-Min; Hasin, Deborah] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Alegria, Analucia A.] Kings Coll London, Inst Psychiat, London, England. [Blanco, Carlos; Skodol, Andrew E.; Hasin, Deborah] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Petry, Nancy M.] Univ Connecticut, Sch Med, Calhoun Cardiol Ctr, Storrs, CT 06260 USA. [Skodol, Andrew E.] Univ Arizona, Coll Med, Dept Psychiat, Tucson, AZ 85721 USA. [Grant, Bridget] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD USA. [Hasin, Deborah] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. RP Blanco, C (reprint author), Columbia Univ Coll Phys & Surg, Dept Psychiat, 1051 Riverside Dr Unit 69, New York, NY 10032 USA. EM cb255@columbia.edu RI Blanco, Carlos/I-4906-2013; OI Blanco, Carlos/0000-0001-6187-3057; Alegria, Analucia /0000-0001-6044-3311 FU Intramural NIH HHS; NIAAA NIH HHS [K05AA00161, U01 AA018111, U01AA018111, K02 AA000161, P60 AA003510]; NIDA NIH HHS [P30 DA023918, DA019606, DA020783, DA023973, K02 DA023200, DA023200, R01 DA019606, R01 DA020783, R01 DA023973]; NIMH NIH HHS [R01 MH076051, R01 MH082773, MH082773, MH076051] NR 52 TC 8 Z9 8 U1 3 U2 21 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1949-2715 J9 PERSONAL DISORD JI Personal. Disord. PD JUL PY 2013 VL 4 IS 3 BP 214 EP 222 DI 10.1037/a0031681 PG 9 WC Psychology, Clinical SC Psychology GA 203MI UT WOS:000323296900003 PM 23544428 ER PT J AU Wu, HK Li, J Fronczek, FR Ferreira, D Burandt, CL Setola, V Roth, BL Zjawiony, JK AF Wu, Hankui Li, Jun Fronczek, Frank R. Ferreira, Daneel Burandt, Charles L., Jr. Setola, Vincent Roth, Bryan L. Zjawiony, Jordan K. TI Labdane Diterpenoids from Leonotis leonurus SO PHYTOCHEMISTRY LA English DT Article DE Leonotis leonurus; Lamiaceae; Psychoactive plant; Labdane diterpenoids; Leoleorins A-J; X-ray diffraction; G-protein-coupled receptors ID AQUEOUS EXTRACT; PLANTS; R.BR.; RATS AB Three known (leoleorins A-C) and eight hitherto unknown (leoleorins D-J and 16-epi-leoleorin F) labdane diterpenoids, were isolated from leaves of Leonotis leonurus. The absolute configurations of leoleorins A and D were established by X-ray crystallographic analyses. In a competitive binding assay, all isolated compounds showed inhibition in excess of 50% at various CNS receptors. Leoleorin C showed moderate binding affinity (K-i = 2.9 mu M) for the Sigma 1 receptor. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Wu, Hankui; Li, Jun; Ferreira, Daneel; Zjawiony, Jordan K.] Univ Mississippi, Sch Pharm, Dept Pharmacognosy, University, MS 38677 USA. [Ferreira, Daneel; Zjawiony, Jordan K.] Univ Mississippi, Sch Pharm, Pharmaceut Sci Res Inst, University, MS 38677 USA. [Burandt, Charles L., Jr.] Univ Mississippi, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Wu, Hankui] Anyang Normal Univ, Coll Chem & Chem Engn, Anyang 455002, Peoples R China. [Fronczek, Frank R.] Louisiana State Univ, Dept Chem, Baton Rouge, LA 70803 USA. [Setola, Vincent; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Setola, Vincent; Roth, Bryan L.] Univ N Carolina, NIMH Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. RP Zjawiony, JK (reprint author), Univ Mississippi, Sch Pharm, Dept Pharmacognosy, University, MS 38677 USA. EM jordan@olemiss.edu RI Roth, Bryan/F-3928-2010; Li, Jun /M-9884-2016 OI Li, Jun /0000-0001-8243-5267 FU National Institutes of Health [R03DA023491] FX The project was supported by a Grant from the National Institutes of Health (R03DA023491). We are grateful to Ms. Bin Wang at the Department of Pharmacognosy for assistance with the HR-ESIMS data acquisition. NR 25 TC 13 Z9 13 U1 4 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9422 J9 PHYTOCHEMISTRY JI Phytochemistry PD JUL PY 2013 VL 91 BP 229 EP 235 DI 10.1016/j.phytochem.2012.02.021 PG 7 WC Biochemistry & Molecular Biology; Plant Sciences SC Biochemistry & Molecular Biology; Plant Sciences GA 182FM UT WOS:000321727100024 PM 22445074 ER PT J AU Sundaram, S Kertbundit, S Shakirov, EV Iyer, LM Juricek, M Hall, TC AF Sundaram, Sabarinath Kertbundit, Sunee Shakirov, Eugene V. Iyer, Lakshminarayan M. Juricek, Miloslav Hall, Timothy C. TI Gene Networks and Chromatin and Transcriptional Regulation of the Phaseolin Promoter in Arabidopsis SO PLANT CELL LA English DT Article ID SEED MATURATION GENES; ABSCISIC-ACID; RNA-SEQ; ARTIFICIAL MICRORNAS; SYSTEMS BIOLOGY; IN-VIVO; EXPRESSION; ABI3; ACTIVATION; PROTEINS AB The complete lack of seed storage protein expression in vegetative tissues and robust expression during embryogenesis makes seed development an ideal system to study tissue-specific expression of genes. The promoter for the Phaseolin (phas) gene, which encodes the major seed storage protein in bean (Phaseolus vulgaris), is activated in two sequential steps: Phaseolus vulgaris ABI3-like factor (Pv-ALF)-dependent potentiation and abscisic acid-mediated activation. In this study, a heterologous in vivo Pv-ALF/phas-GUS (for beta-glucuronidase) expression system in transgenic Arabidopsis thaliana leaves was used in conjunction with the powerful RNA-Seq approach to capture transcriptional landscapes of phas promoter expression. Remarkably, expression of over 1300 genes from 11 functional categories coincided with changes in the transcriptional status of the phas promoter. Gene network analysis of induced genes and artificial microRNA-mediated loss-of-function genetic assays identified transcriptional regulators RINGLET 2 (RLT2) and AINTEGUMENTA-LIKE 5 (AIL5) as being essential for phas transcription. Pv-ALF binding to the RLT2 and AIL5 promoter regions was confirmed by electrophoretic mobility shift assay. RLT2 and AIL5 knockdown lines displayed reduced expression of several endogenous seed genes, suggesting that these factors are involved in activation of endogenous Arabidopsis seed storage gene expression. Overall, the identification of these key factors involved in phas activation provides important insight into the two-step transcriptional regulation of seed-specific gene expression. C1 [Sundaram, Sabarinath; Kertbundit, Sunee; Shakirov, Eugene V.; Hall, Timothy C.] Texas A&M Univ, Inst Dev & Mol Biol, College Stn, TX 77843 USA. [Sundaram, Sabarinath; Kertbundit, Sunee; Shakirov, Eugene V.; Hall, Timothy C.] Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA. [Kertbundit, Sunee; Juricek, Miloslav] Acad Sci Czech Republic, Inst Expt Bot, CR-16502 Prague 6, Czech Republic. [Iyer, Lakshminarayan M.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Hall, TC (reprint author), Texas A&M Univ, Inst Dev & Mol Biol, College Stn, TX 77843 USA. EM tim@idmb.tamu.edu RI Juricek, Miloslav/H-2203-2014; Shakirov, Eugene/A-1363-2012 OI Shakirov, Eugene/0000-0003-2689-7410 FU National Science Foundation [MCB 0843692, MCB 1260947]; MEYS-Czech [ME10038]; National Institutes of Health-National Library of Medicine FX This work was supported by National Science Foundation Grants MCB 0843692 and MCB 1260947 to T. C. H., by MEYS-Czech Grant ME10038 to M. J., and by intramural funds of the National Institutes of Health-National Library of Medicine to L. M. I. We thank Charles Johnson and Eun-Gyu No (TX AgriLife Bioinformatics Service) for their help with Illumina GAII; Patricia Klien, Rodolfo Aramayo, and Phil Beremand for help with data analysis; Ginger Stuessy for plant culture; James Hardin and David Reed for computational services; and Gene Technologies Laboratory staff for sequencing. NR 74 TC 5 Z9 6 U1 1 U2 20 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 1040-4651 J9 PLANT CELL JI Plant Cell PD JUL PY 2013 VL 25 IS 7 BP 2601 EP 2617 DI 10.1105/tpc.113.112714 PG 17 WC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology SC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology GA 208BO UT WOS:000323650900019 PM 23872538 ER PT J AU Jenson, A Dize, L Mkocha, H Munoz, B Lee, J Gaydos, C Quinn, T West, SK AF Jenson, Alexander Dize, Laura Mkocha, Harran Munoz, Beatriz Lee, Jennifer Gaydos, Charlotte Quinn, Thomas West, Sheila K. TI Field Evaluation of the Cepheid GeneXpert Chlamydia trachomatis Assay for Detection of Infection in a Trachoma Endemic Community in Tanzania SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID POLYMERASE CHAIN-REACTION; NEISSERIA-GONORRHOEAE; ANTIBIOTIC-TREATMENT; DIAGNOSTIC-ACCURACY; CT/NG ASSAY; TUBERCULOSIS; PERFORMANCE; SAMPLES; GAMBIA AB Purpose: To determine the sensitivity, specificity, and field utility of the Cepheid GeneXpert Chlamydia trachomatis (CT) Assay (GeneXpert) for ocular chlamydia infection compared to Roche Amplicor CT assay (Amplicor). Methods: In a trachoma-endemic community in Kongwa Tanzania, 144 children ages 0 to 9 were surveyed to assess clinical trachoma and had two ocular swabs taken. One swab was processed at Johns Hopkins University, Baltimore MD, using Amplicor, (Roche Molecular Diagnostics) and the other swab was processed at a field station in Kongwa using the GeneXpert Chlamydia trachomatis/Neisseria gonorrhoeae assay (Cepheid). The sensitivity and specificity of GeneXpert was compared to the Amplicor assay. Results: Of the 144 swabs taken the prevalence of follicular trachoma by clinical exam was 43.7%, and by evidence of infection according to Amplicor was 28.5%. A total of 17 specimens (11.8%) could not be processed by GeneXpert in the field due to lack of sample volume, other specimen issues or electricity failure. The sensitivity of GeneXpert when compared to Amplicor was 100% and the specificity was 95%. The GeneXpert test identified more positives in individuals with clinical trachoma than Amplicor, 55% versus 52%. Conclusion: The GeneXpert test for C. trachomatis performed with high sensitivity and specificity and demonstrated excellent promise as a field test for trachoma control. C1 [Jenson, Alexander; Munoz, Beatriz; Lee, Jennifer; West, Sheila K.] Johns Hopkins Univ, Wilmer Eye Inst, Dana Ctr Prevent Ophthalmol, Baltimore, MD 21218 USA. [Dize, Laura; Mkocha, Harran; Gaydos, Charlotte] Johns Hopkins Univ, Int Sexually Transmitted Dis Res Lab, Div Infect Dis, Baltimore, MD USA. [Mkocha, Harran] Kongwa Trachoma Project, Kongwa, Tanzania. [Quinn, Thomas] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Jenson, A (reprint author), Johns Hopkins Univ, Wilmer Eye Inst, Dana Ctr Prevent Ophthalmol, Baltimore, MD 21218 USA. EM shwest@jhmi.edu FU Bill and Melinda Gates Foundation; Division of Intramural Research, NIAID, NIH FX This work was supported by the Bill and Melinda Gates Foundation and in part by the Division of Intramural Research, NIAID, NIH, and equipment and test kits donated by Cephied. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 11 Z9 11 U1 0 U2 2 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 2013 VL 7 IS 7 AR e2265 DI 10.1371/journal.pntd.0002265 PG 6 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 190EJ UT WOS:000322321500005 PM 23861986 ER PT J AU Zhou, Y Baidoo, KE Brechbiel, MW AF Zhou, Yang Baidoo, Kwamena E. Brechbiel, Martin W. TI Mapping biological behaviors by application of longer-lived positron emitting radionuclides SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Immuno-PET; Radioimmunoimaging; Monoclonal antibodies; Oncology; Y-86; Zr-89; I-124; Cu-64 ID RECEPTOR-POSITIVE TUMORS; ED-B DOMAIN; EMISSION-TOMOGRAPHY; MONOCLONAL-ANTIBODY; COLORECTAL-CANCER; BISPECIFIC ANTIBODY; MEMBRANE ANTIGEN; PET RADIOPHARMACEUTICALS; INTERNALIZING ANTIBODY; SE-72/AS-72 GENERATOR AB With the technological development of positron emission tomography (PET) and the advent of novel antibody-directed drug delivery systems, longer-lived positron-emitting radionuclides are moving to the forefront to take important roles in tracking the distribution of biotherapeutics such as antibodies, and for monitoring biological processes and responses. Longer half-life radionuclides possess advantages of convenient on-site preparation procedures for both clinical and non-clinical applications. The suitability of the long half-life radionuclides for imaging intact monoclonal antibodies (mAbs) and their respective fragments, which have inherently long biological half-lives, has attracted increased interest in recent years. In this review, we provide a survey of the recent literature as it applies to the development of nine-selected longer-lived positron emitters with half-lives of 9-140 h (e.g., I-124, Cu-64, Y-86 and Zr-89), and describe the biological behaviors of radionuclide-labeled mAbs with respect to distribution and targeting characteristics, potential toxicities, biological applications, and clinical translation potentials. Published by Elsevier B.V. C1 [Zhou, Yang; Baidoo, Kwamena E.; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, ROB, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,Rm B3B69, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI); Center for Cancer Research (CCR) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), and Center for Cancer Research (CCR). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NCI or CCR. NR 119 TC 11 Z9 11 U1 2 U2 33 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X EI 1872-8294 J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD JUL PY 2013 VL 65 IS 8 BP 1098 EP 1111 DI 10.1016/j.addr.2012.10.012 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 204VG UT WOS:000323398800011 PM 23123291 ER PT J AU Kobayashi, H Longmire, MR Choyke, PL AF Kobayashi, Hisataka Longmire, Michelle R. Choyke, Peter L. TI Polychromatic in vivo imaging of multiple targets using visible and near infrared light SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Molecular imaging; Fluorescence; Multi-color; Cancer; Surgery; Endoscope; Fluorescence-guidance ID QUANTUM DOTS; OVARIAN-CANCER; MONOCLONAL-ANTIBODIES; FLUORESCENCE; NANOCRYSTALS; PROTEINS; AGENTS; CELLS; CHEMISTRY; COLORS AB Conventional diagnostic imaging methods such as X-ray CT, MRI, and nuclear medicine are inherently monochromatic meaning that they can depict only one molecular target at a time. Optical imaging has the unique ability to be polychromatic and therefore multi-color imaging employing targeted agents conjugated to fluorophores of varying wavelength enables multiple simultaneous readouts thus providing greater multiplexed information. Numerous successful multicolor imaging techniques have recently been reported using optical imaging in in vivo animal disease models, thus adding to a growing body of research supporting the clinical viability and applicability of these technologies. Herein, we review multicolor optical imaging from the basic chemistry and physics perspective and then extend this to biological and medical applications. Published by Elsevier B.V. C1 [Kobayashi, Hisataka; Longmire, Michelle R.; Choyke, Peter L.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, NIH, Bldg 10,Room B3B69,MSC1088, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 46 TC 5 Z9 5 U1 3 U2 41 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD JUL PY 2013 VL 65 IS 8 BP 1112 EP 1119 DI 10.1016/j.addr.2012.10.015 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 204VG UT WOS:000323398800012 PM 23220327 ER PT J AU Hofer, CB Harris, DR Saavedra, MC Haberer, JE Romeiro, J Mussi-Pinhata, MM Stankievich, E Gomes, IM Kreitchmann, R Read, JS AF Hofer, Cristina B. Harris, D. Robert Saavedra, Mariza C. Haberer, Jessica E. Romeiro, Juliana Mussi-Pinhata, Marisa M. Stankievich, Erica Gomes, Ivete M. Kreitchmann, Regis Read, Jennifer S. CA NISDI LILAC Study Team TI Adherence to antiretroviral prophylaxis during early infancy in Latin America SO BRAZILIAN JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID SINGLE-DOSE NEVIRAPINE; TO-CHILD TRANSMISSION; HIV; PREVENTION; REGIMEN C1 [Hofer, Cristina B.] Univ Fed Rio de Janeiro, Inst Puericultura & Pediat Martagao Gesteira, Rio De Janeiro, RJ, Brazil. [Hofer, Cristina B.] Univ Fed Rio de Janeiro, Dept Prevent Med, Rio De Janeiro, RJ, Brazil. [Harris, D. Robert] Westat Corp, Rockville, MD USA. [Saavedra, Mariza C.] Hosp Fed Servidores Estado, Rio De Janeiro, RJ, Brazil. [Haberer, Jessica E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Romeiro, Juliana] Univ Fed Minas Gerais, Sch Med, Grp Estudos HIV AIDS, Belo Horizonte, MG, Brazil. [Mussi-Pinhata, Marisa M.] Univ Sao Paulo, Dept Pediat, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil. [Stankievich, Erica] Hosp Gen Agudos JM Ramos Mejia, Serv Inmunocomprometidos, Buenos Aires, DF, Argentina. [Gomes, Ivete M.] Hosp Geral Nova Iguacu, Rio De Janeiro, RJ, Brazil. [Kreitchmann, Regis] Irmandade de Santa Casa Misercordia Porto Alegre, Porto Alegre, RS, Brazil. [Read, Jennifer S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. RP Hofer, CB (reprint author), Rua Bruno Lobo 50, Rio De Janeiro, RJ, Brazil. EM cbhofer@hucff.ufrj.br RI Melo, Anderson/L-6758-2014; OI Mofenson, Lynne/0000-0002-2818-9808; Melo, Anderson/0000-0002-4606-7791; Harris, Donald/0000-0002-8262-3716; Alarcon, Jorge/0000-0002-0800-2380 FU NICHD NIH HHS [HHSN267200800001C, HHSN275201300003C, N01-HD-3-3345, N01-HD-8-0001]; NIDDK NIH HHS [HHSN267200800001G]; PHS HHS [HHSN267200800001C] NR 5 TC 0 Z9 0 U1 0 U2 1 PU CONTEXTO PI SALVADOR PA RUA ALFREDO MAGALHAES, 04-BARRA, SALVADOR, BAHIA 40140-140, BRAZIL SN 1413-8670 J9 BRAZ J INFECT DIS JI Braz. J. Infect. Dis. PD JUL-AUG PY 2013 VL 17 IS 4 BP 495 EP 496 DI 10.1016/j.bjid.2012.11.006 PG 2 WC Infectious Diseases SC Infectious Diseases GA 204AN UT WOS:000323336800019 PM 23680065 ER PT J AU de Mendonca, VRR Alcantara, T Andrade, N Andrade, BB Barral-Netto, M Boaventura, V AF Ramos de Mendonca, Vitor Rosa Alcantara, Thiago Andrade, Nilvano Andrade, Bruno Bezerril Barral-Netto, Manoel Boaventura, Viviane TI Analysis of theoretical knowledge and the practice of science among brazilian otorhinolaryngologists SO BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY LA English DT Article DE education, medical; knowledge; otolaryngology ID RESEARCH CURRICULA; RESIDENT RESEARCH; CAREER CHOICE; IMPACT; EDUCATION; STUDENTS AB Physicians from all medical specialties are required to understand the principles of science and to interpret medical literature. Yet, the levels of theoretical and practical knowledge held by Brazilian otorhinolaryngologists has not been evaluated to date. Objective: To assess the background and level of scientific knowledge of Brazilian otorhinolaryngologists. Method: Participants of two national ENT meetings were invited to answer a questionnaire to assess scientific practice and knowledge. Results and Conclusion: This study included 73 medical doctors (52% otorhinolaryngologists and 38% residents) aged between 18 and 65 years. About two-thirds have been involved in some form of scientific activity during undergraduate education and/or reported to have written at least one scientific paper. Physicians who took part in research projects felt better prepared to interpret scientific papers and carry out research projects (p = 0.0103 and p = 0.0240, respectively). Respondents who claimed to have participated in research or to have written papers had higher scores on theoretical scientific concepts (p = 0.0101 and p = 0.0103, respectively). However, the overall rate of right answers on questions regarding scientific knowledge was 46.1%. Therefore, a deficiency was observed in the scientific education of Brazilian otorhinolaryngologists. Such deficiency may be mitigated through participation in research. C1 [Alcantara, Thiago] Santa Casa Misericordia Bahia Santa Izabel Hosp, Salvador, BA, Brazil. [Andrade, Nilvano] Santa Casa Misericordia Bahia Santa Izabel Hosp, Med Residency Program, Salvador, BA, Brazil. [Andrade, Bruno Bezerril] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [Barral-Netto, Manoel; Boaventura, Viviane] FIOCRUZ BA, Goncalo Moniz Res Ctr, Salvador, BA, Brazil. [Barral-Netto, Manoel; Boaventura, Viviane] Univ Fed Bahia, Dept Pathol, Sch Med, BR-41170290 Salvador, BA, Brazil. [Boaventura, Viviane] Santa Izabel Hosp, Salvador, BA, Brazil. [Boaventura, Viviane] Univ Fed Bahia, BR-41170290 Salvador, BA, Brazil. RP Boaventura, V (reprint author), Rua Waldemar Falcao,121 Candeal, BR-40296710 Salvador, BA, Brazil. EM vsboaventura@gmail.com RI Andrade, Bruno/J-9111-2012; Boaventura, Viviane /H-9165-2015; OI Andrade, Bruno/0000-0001-6833-3811; Barral Netto, Manoel/0000-0002-5823-7903 NR 16 TC 0 Z9 0 U1 1 U2 3 PU ASSOC BRASILEIRA OTORRINOLARINGOLOGIA & CIRURGIA CERVICOFACIAL PI SAO PAULO PA AV INDIANOPOLOS 740, MOEMA, SAO PAULO, SP 04062-001, BRAZIL SN 1808-8694 J9 BRAZ J OTORHINOLAR JI Braz. J. Otorhinolaryngol. PD JUL-AUG PY 2013 VL 79 IS 4 BP 487 EP 493 DI 10.5935/1808-8694.20130087 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA 203MP UT WOS:000323297600016 ER PT J AU Andersen, SW Trentham-Dietz, A Gangnon, RE Hampton, JM Figueroa, JD Skinner, HG Engelman, CD Klein, BE Titus, LJ Newcomb, PA AF Andersen, Shaneda Warren Trentham-Dietz, Amy Gangnon, Ronald E. Hampton, John M. Figueroa, Jonine D. Skinner, Halcyon G. Engelman, Corinne D. Klein, Barbara E. Titus, Linda J. Newcomb, Polly A. TI The associations between a polygenic score, reproductive and menstrual risk factors and breast cancer risk SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Epidemiology; Reproductive and menstrual factors; Breast cancer; Breast cancer susceptibility loci ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; 14Q24.1 RAD51L1; CONSORTIUM; VARIANTS; SUBTYPES; 1P11.2; WOMEN AB We evaluated whether 13 single nucleotide polymorphisms (SNPs) identified in genome-wide association studies interact with one another and with reproductive and menstrual risk factors in association with breast cancer risk. DNA samples and information on parity, breastfeeding, age at menarche, age at first birth, and age at menopause were collected through structured interviews from 1,484 breast cancer cases and 1,307 controls who participated in a population-based case-control study conducted in three US states. A polygenic score was created as the sum of risk allele copies multiplied by the corresponding log odds estimate. Logistic regression was used to test the associations between SNPs, the score, reproductive and menstrual factors, and breast cancer risk. Nonlinearity of the score was assessed by the inclusion of a quadratic term for polygenic score. Interactions between the aforementioned variables were tested by including a cross-product term in models. We confirmed associations between rs13387042 (2q35), rs4973768 (SLC4A7), rs10941679 (5p12), rs2981582 (FGFR2), rs3817198 (LSP1), rs3803662 (TOX3), and rs6504950 (STXBP4) with breast cancer. Women in the score's highest quintile had 2.2-fold increased risk when compared to women in the lowest quintile (95 % confidence interval: 1.67-2.88). The quadratic polygenic score term was not significant in the model (p = 0.85), suggesting that the established breast cancer loci are not associated with increased risk more than the sum of risk alleles. Modifications of menstrual and reproductive risk factors associations with breast cancer risk by polygenic score were not observed. Our results suggest that the interactions between breast cancer susceptibility loci and reproductive factors are not strong contributors to breast cancer risk. C1 [Andersen, Shaneda Warren; Trentham-Dietz, Amy; Hampton, John M.; Newcomb, Polly A.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53726 USA. [Andersen, Shaneda Warren; Trentham-Dietz, Amy; Gangnon, Ronald E.; Skinner, Halcyon G.; Engelman, Corinne D.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI 53726 USA. [Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Klein, Barbara E.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI 53726 USA. [Titus, Linda J.] Dartmouth Med Sch, Norris Cotton Canc Ctr, Lebanon, NH 03756 USA. [Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. RP Andersen, SW (reprint author), Univ Wisconsin, Carbone Canc Ctr, 610 Walnut St,WARF Room 307, Madison, WI 53726 USA. EM snandersen@uwalumni.com FU National Institutes of Health [R01CA47147, R01CA47305, R01CA69664, U10EY006594]; Department of Defense Breast Cancer Research Program [W81XWH-11-1-0047] FX The authors are grateful to Dr. Kathleen M Egan for her input and advice over the course of the study. The authors have no conflicts of interest to disclose. This work was supported by the National Institutes of Health Intramural Research funds and grants (R01CA47147, R01CA47305, R01CA69664, U10EY006594), and by the Department of Defense Breast Cancer Research Program (W81XWH-11-1-0047). NR 20 TC 6 Z9 6 U1 0 U2 4 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 2013 VL 140 IS 2 BP 427 EP 434 DI 10.1007/s10549-013-2646-3 PG 8 WC Oncology SC Oncology GA 202UN UT WOS:000323245200022 ER PT J AU Hapilina, O Raiser, O Tagimanova, D Kakimzhanova, A AF Hapilina, Oxana Raiser, Olesya Tagimanova, Damelya Kakimzhanova, Almagul TI Certification of wheat varieties using retrotransposons SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Meeting Abstract CT European Biotechnology Congress CY MAY 16-18, 2013 CL Comenius Univ, Bratislava, SLOVAKIA SP European Biotechnol Themat Network Assoc (EBTNA), Comenius Univ, Fac Nat Sci HO Comenius Univ C1 [Hapilina, Oxana; Raiser, Olesya; Tagimanova, Damelya; Kakimzhanova, Almagul] Natl Biotechnol Ctr, Astana, Kazakhstan. EM oksfur@mail.ru NR 0 TC 0 Z9 0 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0958-1669 J9 CURR OPIN BIOTECH JI Curr. Opin. Biotechnol. PD JUL PY 2013 VL 24 SU 1 BP S131 EP S131 DI 10.1016/j.copbio.2013.05.419 PG 1 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 203MU UT WOS:000323298100388 ER PT J AU Kakimzhanova, AA Karimova, V Magzumova, G Esimseitova, A Tokbergenova, Z AF Kakimzhanova, Almagul Apsalamovna Karimova, Venera Magzumova, Gulmira Esimseitova, Asel Tokbergenova, Zhursinkul TI Creating valuable forms and varieties of potatoes that are resistant to fungal diseases SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Meeting Abstract CT European Biotechnology Congress CY MAY 16-18, 2013 CL Comenius Univ, Bratislava, SLOVAKIA SP European Biotechnol Themat Network Assoc (EBTNA), Comenius Univ, Fac Nat Sci HO Comenius Univ C1 [Kakimzhanova, Almagul Apsalamovna; Karimova, Venera; Magzumova, Gulmira; Esimseitova, Asel] Natl Biotechnol Ctr, Astana, Kazakhstan. EM kakimzhanova@mail.ru NR 0 TC 0 Z9 0 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0958-1669 J9 CURR OPIN BIOTECH JI Curr. Opin. Biotechnol. PD JUL PY 2013 VL 24 SU 1 BP S125 EP S125 DI 10.1016/j.copbio.2013.05.396 PG 1 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 203MU UT WOS:000323298100366 ER PT J AU Manabayeva, SA Scholthof, HB AF Manabayeva, Shuga A. Scholthof, Herman B. TI Heterologous expression of a viral coat protein facilitates long-distance movement of a recombinant protein expressing virus vector SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Meeting Abstract CT European Biotechnology Congress CY MAY 16-18, 2013 CL Comenius Univ, Bratislava, SLOVAKIA SP European Biotechnol Themat Network Assoc (EBTNA), Comenius Univ, Fac Nat Sci HO Comenius Univ C1 [Manabayeva, Shuga A.] Natl Ctr Biotechnol Republ Kazakhstan, Astana 010000, Kazakhstan. [Scholthof, Herman B.] Texas A&M Univ, Dept Plant Pathol & Microbiol, College Stn, TX 77843 USA. EM manabayeva@biocenter.kz NR 0 TC 0 Z9 0 U1 1 U2 5 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0958-1669 J9 CURR OPIN BIOTECH JI Curr. Opin. Biotechnol. PD JUL PY 2013 VL 24 SU 1 BP S35 EP S36 DI 10.1016/j.copbio.2013.05.067 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 203MU UT WOS:000323298100054 ER PT J AU Turganbayeva, A Hapilina, O Shek, G Kakimzhanova, A AF Turganbayeva, Assiya Hapilina, Oksana Shek, Galina Kakimzhanova, Almagul TI Development important forms of soft spring wheat in North Kazakhstan SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Meeting Abstract CT European Biotechnology Congress CY MAY 16-18, 2013 CL Comenius Univ, Bratislava, SLOVAKIA SP European Biotechnol Themat Network Assoc (EBTNA), Comenius Univ, Fac Nat Sci HO Comenius Univ C1 [Turganbayeva, Assiya; Hapilina, Oksana; Shek, Galina; Kakimzhanova, Almagul] Natl Biotechnol Ctr, Astana, Kazakhstan. EM ass.turg@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0958-1669 J9 CURR OPIN BIOTECH JI Curr. Opin. Biotechnol. PD JUL PY 2013 VL 24 SU 1 BP S127 EP S127 DI 10.1016/j.copbio.2013.05.404 PG 1 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 203MU UT WOS:000323298100374 ER PT J AU Freeman, AF Renner, ED Henderson, C Langenbeck, A Olivier, KN Hsu, AP Hagl, B Boos, A Davis, J Marciano, BE Boris, L Welch, P Sawalle-Belohradsky, J Belohradsky, BH Kwong, KF Holland, SM AF Freeman, Alexandra F. Renner, Ellen D. Henderson, Carolyn Langenbeck, Anne Olivier, Kenneth N. Hsu, Amy P. Hagl, Beate Boos, Annette Davis, Joie Marciano, Beatriz E. Boris, Lisa Welch, Pamela Sawalle-Belohradsky, Julie Belohradsky, Bernd H. Kwong, King F. Holland, Steven M. TI Lung Parenchyma Surgery in Autosomal Dominant Hyper-IgE Syndrome SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Hyper-IgE syndrome; STAT3; Job's syndrome; lung surgery; pulmonary complications; IgE; bronchopleural fistula ID PULMONARY ASPERGILLOMA; MUTATIONS; REPAIR AB Purpose Autosomal dominant hyper-IgE syndrome (ADHIES) due to heterozygous STAT3 mutation is a primary immunodeficiency characterized by eczema, elevated serum IgE, recurrent infections, and connective tissue and skeletal findings. Healing of pneumonias is often abnormal with formation of pneumatoceles and bronchiectasis. We aimed to explore whether healing after lung surgery is also aberrant. Methods We retrospectively analyzed the medical records of 32 patients with AD-HIES who received lung surgery for the management of pulmonary infections from 1960 to 2011. We collected information including patient demographics, STAT3 mutation status, clinical history, surgical and medical procedures performed, complications, related medical treatments, and outcomes. Results More than 50 % of lung surgeries had associated complications, with the majority being prolonged bronchopleural fistulae. These fistulae often led to empyemas that necessitated additional interventions including prolonged antibiotics, prolonged thoracostomy tube drainage and re-operations. Conclusion Lung surgery in AD-HIES patients is associated with high complication rates. STAT3 mutations likely lead to abnormalities in tissue remodelling that are further exacerbated by infection. C1 [Freeman, Alexandra F.; Henderson, Carolyn; Olivier, Kenneth N.; Hsu, Amy P.; Davis, Joie; Marciano, Beatriz E.; Boris, Lisa; Welch, Pamela; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Renner, Ellen D.; Langenbeck, Anne; Hagl, Beate; Boos, Annette; Sawalle-Belohradsky, Julie; Belohradsky, Bernd H.] Univ Munich, Univ Childrens Hosp, Dr von Haunersches Kinderspital, Munich, Germany. [Kwong, King F.] NCI, Sect Thorac Oncol, Surg Branch, CCR,NIH, Bethesda, MD 20892 USA. RP Freeman, AF (reprint author), NIAID, Lab Clin Infect Dis, NIH, NIH Bldg 10 Room 11 N234,9000 Rockville Pike, Bethesda, MD 20892 USA. EM freemaal@mail.nih.gov RI Hagl, Beate/R-9266-2016 FU Division of Intramural Research of the NIAID; Center for Cancer Research of the National Cancer Institute, NIH, Bethesda, MD; German Research Foundation [DFG RE2799/3-1]; Fritz-Thyssen research foundation [Az. 10.07.1.159]; Kindness for Kids FX We thank all of the participants in this study, their families, and referring physicians who make our research possible. This research was supported by the Division of Intramural Research of the NIAID and the Center for Cancer Research of the National Cancer Institute, NIH, Bethesda, MD 20892. The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. Government. This work was supported by the German Research Foundation (DFG RE2799/3-1), the Fritz-Thyssen research foundation grant (Az. 10.07.1.159) (to EDR), and Kindness for Kids (to J.S-B.). NR 17 TC 5 Z9 5 U1 1 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JUL PY 2013 VL 33 IS 5 BP 896 EP 902 DI 10.1007/s10875-013-9890-5 PG 7 WC Immunology SC Immunology GA 201FR UT WOS:000323126600003 PM 23584561 ER PT J AU Wang, YJ Marciano, BE Shen, DF Bishop, RJ Park, S Holland, SM Chan, CC AF Wang, Yujuan Marciano, Beatriz E. Shen, Defen Bishop, Rachel J. Park, Stanley Holland, Steven M. Chan, Chi-Chao TI Molecular Identification of Bacterial DNA in the Chorioretinal Scars of Chronic Granulomatous Disease SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Chronic granulomatous disease; chorioretinitis; bacterial infection; polymerase chain reaction ID CHILDHOOD; LESIONS; MICRODISSECTION; FEATURES; UVEITIS AB Purpose Chronic granulomatous disease (CGD) is an inherited disorder characterized by defects in phagocyte-derived nicotinamide adenine dinucleotide phosphate oxidase. It is typically diagnosed in childhood and leads to severe, recurrent bacterial or fungal infections. Chorioretinal lesions are the most common ocular manifestation. We sought to determine whether there are infectious agents in CGD-associated chorioretinopathy. Methods Medical records and ocular histopathology from CGD cases from January 1983 to January 2012 at the National Institutes of Health were retrospectively reviewed. Chorioretinal cells from normal and lesional tissues of the same eye were microdissected. Primers for Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia sp., and a panbacterial 16S ribosomal DNA were used for polymerase chain reaction. Results Seventeen CGD patients had ocular tissues (16 autopsied cases and 1 chorioretinal biopsy) examined. Of these 17, 8 demonstrated CGD-associated chorioretinal lesions in at least one eye on histopathology. Of these 8, 7 showed amplification of 16S ribosomal DNA within the lesion; of these 7, two also amplified S. epidermidis and one P. aeruginosa. One had no bacterial DNA amplified. Importantly, no microbial DNA was amplified from the normal, non-lesional ocular tissues of these 8 cases. Furthermore, only 1 of the 9 eyes without chorioretinopathy had amplified Burkholderia DNA, that patient had a history of Burkholderia infection. Conclusions We detected bacterial DNA in 7 of 8 (88 %) cases with CGD-associated chorioretinopathy and only in 1 normal ocular tissue of 17 CGD cases. Bacterial infection may play a role in the pathogenesis of CGD-associated chorioretinal lesions. C1 [Wang, Yujuan; Shen, Defen; Park, Stanley; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Marciano, Beatriz E.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Bishop, Rachel J.] NEI, Clin Branch, NIH, Bethesda, MD 20892 USA. [Wang, Yujuan] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510275, Guangdong, Peoples R China. [Park, Stanley] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, 10 Ctr Dr,10-10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov RI wang, yujuan/C-8428-2016 FU Intramural Research Programs of the National Eye Institute; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The study was funded by the Intramural Research Programs of the National Eye Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 34 TC 5 Z9 5 U1 0 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JUL PY 2013 VL 33 IS 5 BP 917 EP 924 DI 10.1007/s10875-013-9899-9 PG 8 WC Immunology SC Immunology GA 201FR UT WOS:000323126600006 PM 23636897 ER PT J AU Bax, HI Freeman, AF Ding, L Hsu, AP Marciano, B Kristosturyan, E Jancel, T Spalding, C Pechacek, J Olivier, KN Barnhart, LA Boris, L Frein, C Claypool, RJ Anderson, V Zerbe, CS Holland, SM Sampaio, EP AF Bax, H. I. Freeman, A. F. Ding, L. Hsu, A. P. Marciano, B. Kristosturyan, E. Jancel, T. Spalding, C. Pechacek, J. Olivier, K. N. Barnhart, L. A. Boris, L. Frein, C. Claypool, R. J. Anderson, V. Zerbe, C. S. Holland, S. M. Sampaio, E. P. TI Interferon Alpha Treatment of Patients with Impaired Interferon Gamma Signaling SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE IFN-gamma receptor deficiency; mycobacterial disease; IFN-alpha; STAT1; IFN-gamma; nontuberculous mycobacteria ID AVIUM COMPLEX INFECTION; NECROSIS-FACTOR-ALPHA; IL-1-BETA PRODUCTION; CLINICAL-FEATURES; HUMAN MACROPHAGES; INBORN-ERRORS; I INTERFERON; HEPATITIS-C; TUBERCULOSIS; DEFICIENCY AB Patients with deficiency in the interferon gamma receptor (IFN-gamma R) are unable to respond properly to IFN-gamma and develop severe infections with nontuberculous mycobacteria (NTM). IFN-gamma and IFN-alpha are known to signal through STAT1 and activate many downstream effector genes in common. Therefore, we added IFN-alpha for treatment of patients with disseminated mycobacterial disease in an effort to complement their IFN-gamma signaling defect. We treated four patients with IFN-gamma R deficiency with adjunctive IFN-alpha therapy in addition to best available antimicrobial therapy, with or without IFN-gamma, depending on the defect. During IFN-alpha treatment, ex vivo induction of IFN target genes was detected. In addition, IFN-alpha driven gene expression in patients' cells and mycobacteria induced cytokine response were observed in vitro. Clinical responses varied in these patients. IFN-alpha therapy was associated with either improvement or stabilization of disease. In no case was disease exacerbated. In patients with profoundly impaired IFN-gamma signaling who have refractory infections, IFN-alpha may have adjunctive anti-mycobacterial effects. C1 [Bax, H. I.; Freeman, A. F.; Ding, L.; Hsu, A. P.; Marciano, B.; Kristosturyan, E.; Spalding, C.; Pechacek, J.; Olivier, K. N.; Barnhart, L. A.; Boris, L.; Frein, C.; Claypool, R. J.; Anderson, V.; Zerbe, C. S.; Holland, S. M.; Sampaio, E. P.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Bax, H. I.] Erasmus MC, Div Infect Dis, Dept Internal Med, Rotterdam, Netherlands. [Jancel, T.] NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. RP Sampaio, EP (reprint author), NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, CRC B3-4233 MSC 1684, Bethesda, MD 20892 USA. EM sampaioe@niaid.nih.gov FU Division of Intramural Research of National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We are grateful to M.E. Hanks for technical assistance. The research was supported by the Division of Intramural Research of National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 43 TC 9 Z9 9 U1 1 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JUL PY 2013 VL 33 IS 5 BP 991 EP 1001 DI 10.1007/s10875-013-9882-5 PG 11 WC Immunology SC Immunology GA 201FR UT WOS:000323126600014 PM 23512243 ER PT J AU Birdsill, AC Carlsson, CM Willette, AA Okonkwo, OC Johnson, SC Xu, GF Oh, JM Gallagher, CL Koscik, RL Jonaitis, EM Hermann, BP LaRue, A Rowley, HA Asthana, S Sager, MA Bendlin, BB AF Birdsill, Alex C. Carlsson, Cynthia M. Willette, Auriel A. Okonkwo, Ozioma C. Johnson, Sterling C. Xu, Guofan Oh, Jennifer M. Gallagher, Catherine L. Koscik, Rebecca L. Jonaitis, Erin M. Hermann, Bruce P. LaRue, Asenath Rowley, Howard A. Asthana, Sanjay Sager, Mark A. Bendlin, Barbara B. TI Low Cerebral Blood Flow is Associated with Lower Memory Function in Metabolic Syndrome SO OBESITY LA English DT Article ID PRECLINICAL ALZHEIMERS-DISEASE; MILD COGNITIVE IMPAIRMENT; PERFUSION MRI; DEMENTIA; RISK; INVERSION; DECLINE; PET AB Background: Metabolic syndrome (MetS)-a cluster of cardiovascular risk factors-is linked with cognitive decline and dementia. However, the brain changes underlying this link are presently unknown. In this study, we tested the relationship between MetS, cerebral blood flow (CBF), white matter hyperintensity burden, and gray matter (GM) volume in cognitively healthy late middle-aged adults. Additionally, the extent to which MetS was associated with cognitive performance was assessed. Design and Methods: Late middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention (N = 69, mean age = 60.4 years) underwent a fasting blood draw, arterial spin labeling perfusion MRI, T1-weighted MRI, T2FLAIR MRI, and neuropsychological testing. MetS was defined as abnormalities on three or more factors, including abdominal obesity, triglycerides, HDL-cholesterol, blood pressure, and fasting glucose. Results: Mean GM CBF was 15% lower in MetS compared to controls. Voxel-wise image analysis indicated that the MetS group had lower CBF across a large portion of the cortical surface, with the exception of medial and inferior parts of the occipital and temporal lobes. The MetS group also had lower immediate memory function; a mediation analysis indicated this relationship was partially mediated by CBF. Among the MetS factors, abdominal obesity and elevated triglycerides were most strongly associated with lower CBF. Conclusions: The results underscore the importance of reducing the number of cardiovascular risk factors for maintaining CBF and cognition in an aging population. C1 [Birdsill, Alex C.; Carlsson, Cynthia M.; Okonkwo, Ozioma C.; Johnson, Sterling C.; Xu, Guofan; Oh, Jennifer M.; Asthana, Sanjay; Bendlin, Barbara B.] William S Middleton Mem Vet Adm Med Ctr, GRECC, Madison, WI USA. [Birdsill, Alex C.; Carlsson, Cynthia M.; Okonkwo, Ozioma C.; Johnson, Sterling C.; Xu, Guofan; Oh, Jennifer M.; Gallagher, Catherine L.; Rowley, Howard A.; Asthana, Sanjay; Sager, Mark A.; Bendlin, Barbara B.] Univ Wisconsin, Dept Med, Wisconsin Alzheimers Dis Res Ctr, Madison, WI USA. [Willette, Auriel A.] NIA, Baltimore, MD 21224 USA. [Gallagher, Catherine L.] Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Madison, WI 53792 USA. [Gallagher, Catherine L.] Univ Wisconsin, Dept Neurol, Madison, WI 53706 USA. [Koscik, Rebecca L.; Jonaitis, Erin M.; Hermann, Bruce P.; LaRue, Asenath; Sager, Mark A.] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimers Inst, Madison, WI USA. [Rowley, Howard A.] Univ Wisconsin, Dept Radiol, Sch Med & Publ Hlth, Madison, WI 53706 USA. RP Bendlin, BB (reprint author), William S Middleton Mem Vet Adm Med Ctr, GRECC, Madison, WI USA. EM bbb@medicine.wisc.edu OI Bendlin, Barbara/0000-0002-0580-9875 FU Alzheimer's Association [NIRG-09-132626]; National Institute on Aging [R01 AG027161, ADRC P50 AG033514]; National Center for Research Resources/National Institutes of Health Clinical and Translational Science Award [1UL1RR025011]; University of Wisconsin Institute for Clinical and Translational Research FX This project was supported by the Alzheimer's Association, NIRG-09-132626, and in part by the National Institute on Aging (R01 AG027161 [MAS], ADRC P50 AG033514 [SA]), and the University of Wisconsin Institute for Clinical and Translational Research, funded through a National Center for Research Resources/National Institutes of Health Clinical and Translational Science Award, 1UL1RR025011. The project was also facilitated by the facilities and resources at the Geriatric Research, Education, and Clinical Center (GRECC) of the William S. Middleton Memorial Veterans Hospital, Madison, WI. GRECC MS # 2012-10. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 26 Z9 27 U1 2 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 J9 OBESITY JI Obesity PD JUL PY 2013 VL 21 IS 7 BP 1313 EP 1320 DI 10.1002/oby.20170 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 204FV UT WOS:000323351400002 PM 23687103 ER PT J AU Liao, LM Schwartz, K Pollak, M Graubard, BI Li, Z Ruterbusch, J Rothman, N Davis, F Wacholder, S Colt, J Chow, WH Purdue, MP AF Liao, Linda M. Schwartz, Kendra Pollak, Michael Graubard, Barry I. Li, Zhen Ruterbusch, Julie Rothman, Nathaniel Davis, Faith Wacholder, Sholom Colt, Joanne Chow, Wong-Ho Purdue, Mark P. TI Serum Leptin and Adiponectin Levels and Risk of Renal Cell Carcinoma SO OBESITY LA English DT Article ID BODY-MASS INDEX; ENDOMETRIAL CANCER-RISK; ADIPOSE-TISSUE; KIDNEY CANCER; UNITED-STATES; POSTMENOPAUSAL WOMEN; WHITE WOMEN; OBESITY; ASSOCIATION; SIZE AB Objective: The incidence of renal cell carcinoma (RCC) has increased rapidly in the U. S., particularly among African Americans. Despite a well-established link between obesity and RCC, the mechanism through which obesity increases cancer risk has yet to be established. Adipokines, such as leptin and adiponectin, may link obesity and cancer, with different quantitative effects by race. Design and Methods: We evaluated the association between leptin and adiponectin concentrations and RCC risk among Caucasians (581 cases, 558 controls) and African Americans (187 cases, 359 controls) in a case-control study conducted in Detroit and Chicago. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were estimated using unconditional logistic regression. Results: Among controls, Caucasians had higher median adiponectin than African Americans (males: 8.2 vs. 7.0 mu g/ml, P = 0.001; females: 13.4 vs. 8.4 mu g/ml, P < 0.0001), and lower median leptin than African Americans (males: 11.8 vs. 14.1 ng/ml, P = 0.04; females: 28.3 vs. 45.9 ng/ml, P < 0.0001). Among Caucasians, the ORs for RCC comparing the highest (Q4) to the lowest (Q1) sex-specific quartile of leptin were 3.2 (95% CI: 1.9-5.2) for males and 4.7 (95% CI: 2.6-8.6) for females. Serum leptin was not significantly associated with RCC among African American males (OR 1.5, 95% CI: 0.7-3.1) or females (OR 2.1, 95% CI: 0.8-5.5). Higher adiponectin was associated with RCC risk among African American males (Q4 vs. Q1: OR 2.3, 95% CI: 1.1-4.6) and females (OR 2.1, 95% CI: 1.2-6.7), but not significantly among Caucasian males (OR 1.6, 95% CI: 0.99-2.7) and females (OR 1.6, 95% CI: 0.9-3.1). Conclusion: We observed an association between both leptin and adiponectin concentrations and risk of RCC, which may differ by race. Confirmation in further investigations is needed. C1 [Liao, Linda M.; Graubard, Barry I.; Rothman, Nathaniel; Wacholder, Sholom; Colt, Joanne; Chow, Wong-Ho; Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Schwartz, Kendra; Ruterbusch, Julie] Wayne State Univ, Karmanos Canc Inst, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Pollak, Michael; Li, Zhen] McGill Univ, Jewish Gen Hosp, Canc Prevent Program, Montreal, PQ H3T 1E2, Canada. [Pollak, Michael; Li, Zhen] McGill Univ, Montreal, PQ, Canada. [Davis, Faith] Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL USA. RP Liao, LM (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM liaolm@mail.nih.gov RI Purdue, Mark/C-9228-2016; OI Purdue, Mark/0000-0003-1177-3108; Liao, Linda/0000-0002-1923-5294 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of the Cancer Epidemiology and Genetics FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of the Cancer Epidemiology and Genetics. NR 40 TC 17 Z9 22 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 J9 OBESITY JI Obesity PD JUL PY 2013 VL 21 IS 7 BP 1478 EP 1485 DI 10.1002/oby.20138 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 204FV UT WOS:000323351400024 PM 23666639 ER PT J AU Britton, KA Wang, N Palmisano, J Corsini, E Schlett, CL Hoffmann, U Larson, MG Vasan, RS Vita, JA Mitchell, GF Benjamin, EJ Hamburg, NM Fox, CS AF Britton, Kathryn A. Wang, Na Palmisano, Joseph Corsini, Erin Schlett, Christopher L. Hoffmann, Udo Larson, Martin G. Vasan, Ramachandran S. Vita, Joseph A. Mitchell, Gary F. Benjamin, Emelia J. Hamburg, Naomi M. Fox, Caroline S. TI Thoracic Periaortic and Visceral Adipose Tissue and Their Cross-sectional Associations with Measures of Vascular Function SO OBESITY LA English DT Article ID CORONARY-HEART-DISEASE; BODY-FAT DISTRIBUTION; ENDOTHELIAL DYSFUNCTION; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; AORTIC STIFFNESS; PERIVASCULAR FAT; BRACHIAL-ARTERY; RISK-FACTORS; OBESITY AB Objective: Perivascular fat may have a local adverse effect on the vasculature. We evaluated whether thoracic periaortic adipose tissue (TAT), a type of perivascular fat, and visceral adipose tissue (VAT) were associated with vascular function. Design and Methods: TAT and VAT were quantified in Framingham Heart Study participants using multidetector-computed tomography; vascular function was assessed using brachial artery vasodilator function, peripheral arterial tone, and arterial tonometry (n = 2,735; 48% women; mean age, 50 years; mean body mass index [BMI], 27.7 kg/m(2)). Using multiple linear regression, the relationships between TAT, VAT, and vascular measures was examined while adjusting for cardiovascular risk factors. Results: Mean TAT and VAT volumes were 13.2 and 1763 cm(3). TAT and VAT were associated with multiple vascular function measures after multivariable adjustment. After BMI adjustment, TAT and VAT remained negatively associated with peripheral arterial tone and inverse carotid femoral pulse wave velocity (P < 0.02); TAT was negatively associated with hyperemic mean flow velocity (P = 0.03). Associations of TAT with vascular function were attenuated after VAT adjustment (all P > 0.06). Conclusions: Thoracic periaortic and visceral fat are associated with microvascular function and large artery stiffness after BMI adjustment. These findings support the growing recognition of associations between ectopic fat and vascular function. C1 [Britton, Kathryn A.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Britton, Kathryn A.; Hoffmann, Udo; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Britton, Kathryn A.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Fox, Caroline S.] NHLBI, Framingham, MA USA. [Britton, Kathryn A.; Larson, Martin G.; Vasan, Ramachandran S.; Benjamin, Emelia J.; Fox, Caroline S.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Wang, Na; Palmisano, Joseph] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA. [Corsini, Erin; Schlett, Christopher L.; Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Prevent Med Sect, Evans Dept Med, Boston, MA 02118 USA. [Vita, Joseph A.; Benjamin, Emelia J.; Hamburg, Naomi M.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med, Boston, MA 02118 USA. [Vita, Joseph A.; Benjamin, Emelia J.; Hamburg, Naomi M.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Fox, Caroline S.] Cardiovasc Engn Inc, Norwood, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. Brigham & Womens Hosp, Div Endocrinol Metab & Hypertens, Boston, MA 02115 USA. RP Fox, CS (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM foxca@nhlbi.nih.gov OI Hamburg, Naomi/0000-0001-5504-5589; Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; [RO1 HL70100]; [1ROI HL60040]; [HL077447]; [K12 HL083786] FX This study was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195), and by RO1 HL70100; 1ROI HL60040); HL077447; K12 HL083786. NR 36 TC 14 Z9 14 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 J9 OBESITY JI Obesity PD JUL PY 2013 VL 21 IS 7 BP 1496 EP 1503 DI 10.1002/oby.20166 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 204FV UT WOS:000323351400026 PM 23754461 ER PT J AU Huang, XL Zhang, F Zhu, L Choi, KY Guo, N Guo, JX Tackett, K Anilkumar, P Liu, G Quan, QM Choi, HS Niu, G Sun, YP Lee, S Chen, XY AF Huang, Xinglu Zhang, Fan Zhu, Lei Choi, Ki Young Guo, Ning Guo, Jinxia Tackett, Kenneth Anilkumar, Parambath Liu, Gang Quan, Qimeng Choi, Hak Soo Niu, Gang Sun, Ya-Ping Lee, Seulki Chen, Xiaoyuan TI Effect of Injection Routes on the Biodistribution, Clearance, and Tumor Uptake of Carbon Dots SO ACS NANO LA English DT Article DE biodistribution; carbon dots; clearance; injection routes; translation tumor uptake ID QUANTUM DOTS; IN-VIVO; LIVING SUBJECTS; NANOPARTICLES; TISSUE; FLUOROPHORES; TOXICITY; GRAPHENE; BRIGHT; WINDOW AB The emergence of photoluminescent carbon-based nanomaterials has shown exciting potential in the development of benign nanoprobes. However, the in vivo kinetic behaviors of these particles that are necessary for clinical translation are poorly understood to date. In this study, fluorescent carbon dots (C-dots) were synthesized and the effect of three injection routes on their fate in vivo was explored by using both near-infrared fluorescence and positron emission tomography imaging techniques. We found that C-dots are efficiently and rapidly excreted from the body after all three injection routes. The clearance rate of C-dots is ranked as intravenous > intramuscular > subcutaneous. The particles had relatively low retention in the reticuloendothelial system and showed high tumor-to-background contrast. Furthermore, different injection routes also resulted in different blood clearance patterns and tumor uptakes of C-dots. These results satisfy the need for clinical translation and should promote efforts to further investigate the possibility of using carbon-based nanoprobes in a clinical setting. More broadly, we provide a testing blueprint for in vivo behavior of nanoplatforms under various injection routes, an important step forward toward safety and efficacy analysis of nanoparticles. C1 [Huang, Xinglu; Zhang, Fan; Zhu, Lei; Choi, Ki Young; Guo, Ning; Guo, Jinxia; Quan, Qimeng; Niu, Gang; Lee, Seulki; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Zhang, Fan; Zhu, Lei; Guo, Jinxia; Liu, Gang] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. [Tackett, Kenneth; Anilkumar, Parambath; Sun, Ya-Ping] Clemson Univ, Dept Chem, Clemson, SC 29634 USA. [Tackett, Kenneth; Anilkumar, Parambath; Sun, Ya-Ping] Clemson Univ, Lab Emerging Mat & Technol, Clemson, SC 29634 USA. [Choi, Hak Soo] Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA. RP Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM Shawn.Chen@nih.gov RI Choi, Hak Soo/C-9954-2011; Zhu, Lei/P-9786-2016; CHOI, KI YOUNG/Q-7177-2016 OI Zhu, Lei/0000-0002-1820-4795; FU National Basic Research Program of China (973 Program) [2013CB733802]; National Science Foundation of China (NSFC) [81201086, 81201129, 81101101, 51273165]; Intramural Research Program of the NIBIB, NIH; Henry M. Jackson Foundation; NIH [K99/R00] FX This work was supported, in part, by the National Basic Research Program of China (973 Program 2013CB733802), the National Science Foundation of China (NSFC) (81201086, 81201129, 81101101, and 51273165), the Intramural Research Program of the NIBIB, NIH, and the Henry M. Jackson Foundation. S.L. was partially supported by an NIH Pathway to Independence (K99/R00) Award. NR 45 TC 80 Z9 83 U1 9 U2 210 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD JUL PY 2013 VL 7 IS 7 BP 5684 EP 5693 DI 10.1021/nn401911k PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 191MO UT WOS:000322417400006 PM 23731122 ER PT J AU Felizardo, TC Foley, J Steed, K Dropulic, B Amarnath, S Medin, JA Fowler, DH AF Felizardo, Tania C. Foley, Jason Steed, Kevin Dropulic, Boro Amarnath, Shoba Medin, Jeffrey A. Fowler, Daniel H. TI Harnessing autophagy for cell fate control gene therapy SO AUTOPHAGY LA English DT Article DE autophagy; DTYMK/TMPK; rapamycin; cell-fate control; suicide gene ID VERSUS-HOST-DISEASE; DONOR TH2 CELLS; T-CELLS; IN-VIVO; MAMMALIAN TARGET; IMMUNE-RESPONSES; RAT HEPATOCYTES; SUICIDE GENE; TRANSPLANTATION; LYMPHOCYTES AB We hypothesized that rapamycin, through induction of autophagy and promotion of an antiapoptotic phenotype, would permit lentiviral (LV)-based transgene delivery to human T-Rapa cells, which are being tested in phase II clinical trials in the setting of allogeneic hematopoietic cell transplantation. Manufactured T-Rapa cells were exposed to supernatant enriched for a LV vector encoding a fusion protein consisting of truncated CD19 (for cell surface marking) and DTYMK/TMPK, which provides "cell-fate control" due to its ability to phosphorylate (activate) AZT prodrug. LV-transduction in rapamycin-treated T-Rapa cells: (1) resulted in mitochondrial autophagy and a resultant antiapoptotic phenotype, which was reversed by the autophagy inhibitor 3-MA; (2) yielded changes in MAP1LC3B and SQSTM1 expression, which were reversed by 3-MA; and (3) increased T-Rapa cell expression of the CD19-DTYMK fusion protein, despite their reduced proliferative status. Importantly, although the transgene-expressing T-Rapa cells expressed an antiapoptotic phenotype, they were highly susceptible to cell death via AZT exposure both in vitro and in vivo (in a human-into-mouse xenogeneic transplantation model). Therefore, rapamycin induction of T cell autophagy can be used for gene therapy applications, including the CD19-DTYMK cell-fate control axis to improve the safety of T cell immuno-gene therapy. C1 [Felizardo, Tania C.; Foley, Jason; Steed, Kevin; Amarnath, Shoba; Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Dropulic, Boro] Lentigen Corp, Gaithersburg, MD USA. [Medin, Jeffrey A.] Univ Hlth Network, Toronto, ON, Canada. RP Felizardo, TC (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. EM tania.felizardo@nih.gov FU NCI; Lentigen; Center for Cancer Research, National Cancer Institute, Intramural Research Program FX This work was funded in part through a cooperative research agreement between NCI and Lentigen. J.A.M. and D.H.F. are inventors on a patent relating to the TMPK-AZT cell fate system. This work was supported by the Center for Cancer Research, National Cancer Institute, Intramural Research Program and by a cooperative research agreement between the NCI and Lentigen. The authors would like to thank Drs. Bruce Levine and Carl June at the Abramson Family Cancer Research Institute at the University of Pennsylvania Cancer Center for the provision of reagents and for review of the manuscript. NR 41 TC 2 Z9 2 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD JUL 1 PY 2013 VL 9 IS 7 BP 1069 EP 1079 DI 10.4161/auto.24639 PG 11 WC Cell Biology SC Cell Biology GA 201WS UT WOS:000323174300011 PM 23633667 ER PT J AU Jao, CC Ragusa, MJ Stanley, RE Hurley, JH AF Jao, Christine C. Ragusa, Michael J. Stanley, Robin E. Hurley, James H. TI What the N-terminal domain of Atg13 looks like and what it does A HORMA fold required for PtdIns 3-kinase recruitment SO AUTOPHAGY LA English DT Editorial Material DE Atg13; HORMA; Atg14; protein structure; protein crystallography; yeast genetics; protein degradation AB Atg13 is a subunit of the Atg1 complex that is involved in autophagy. The middle and C-terminal regions of Atg13 are intrinsically disordered and rich in regulatory phosphorylation sites. Thus far, there have been no structural data for any part of Atg13, and no function assigned to its N-terminal domain. We crystallized this domain, and found that it has a HORMA (Hop1, Rev7, Mad2) fold. We showed that the Atg13 HORMA domain is required for autophagy and for recruitment of the phosphatidylinositol (PtdIns) 3-kinase subunit Atg14, but is not required for Atg1 interaction or Atg13 recruitment to the PAS. The HORMA domain of Atg13 is similar to the closed conformation of the spindle checkpoint protein Mad2. A pair of conserved arginines was identified in the structure, and tested functionally in yeast. These residues are important for autophagy, as mutations abrogate autophagy and block Atg14 recruitment. The location of these Arg residues in the structure suggests that the Atg13 HORMA domain could act as a phosphorylation-dependent conformational switch. C1 [Jao, Christine C.; Ragusa, Michael J.; Stanley, Robin E.; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM james.hurley@nih.gov FU NIH/NIDDK Intramural Program; NIH/NIGMS; Damon Runyon Cancer Research Fellowship FX This work was supported by the NIH/NIDDK Intramural Program (J.H.H.), fellowships from the NIH/NIGMS (C.C.J., M.J.R.), and a Damon Runyon Cancer Research Fellowship (R.E.S.). NR 0 TC 5 Z9 5 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD JUL 1 PY 2013 VL 9 IS 7 BP 1112 EP 1114 DI 10.4161/auto.24896 PG 3 WC Cell Biology SC Cell Biology GA 201WS UT WOS:000323174300019 PM 23670046 ER PT J AU Feeney, EJ Spampanato, C Puertollano, R Ballabio, A Parenti, G Raben, N AF Feeney, Erin J. Spampanato, Carmine Puertollano, Rosa Ballabio, Andrea Parenti, Giancarlo Raben, Nina TI What else is in store for autophagy? Exocytosis of autolysosomes as a mechanism of TFEB-mediated cellular clearance in Pompe disease SO AUTOPHAGY LA English DT Editorial Material DE lysosomal exocytosis; TFEB; acid alpha-glucosidase; lysosomal storage; Pompe disease AB It is hard to find an area of biology in which autophagy is not involved. In fact, the topic extends beyond scientific research to stimulate intellectual exercise and entertainment-autophagy has found its way into a crossword puzzle (Klionsky, 2013). We have found yet another function of autophagy while searching for a better treatment for Pompe disease, a devastating metabolic myopathy resulting from excessive lysosomal glycogen storage. To relieve this glycogen burden, we stimulated lysosomal exocytosis through upregulation of transcription factor EB (TFEB). Overexpression of TFEB in Pompe muscle clears the cells of enlarged lysosomes, reduces glycogen levels, and alleviates autophagic buildup, the major secondary abnormality in Pompe disease. Unexpectedly, the process of exocytosis does not seem to be a purely lysosomal event; vesicles arranged along the plasma membrane are double-labeled with the lysosomal marker LAMP1 and the autophagosomal marker LC3, indicating that TFEB induces the exocytosis of autolysosomes. Furthermore, the effects of TFEB are almost abrogated in autophagy-deficient Pompe mice, suggesting a previously unrecognized role of autophagy in TFEB-mediated cellular clearance. C1 [Feeney, Erin J.; Raben, Nina] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Spampanato, Carmine; Ballabio, Andrea; Parenti, Giancarlo] Telethon Inst Genet & Med TIGEM, Naples, Italy. [Spampanato, Carmine; Ballabio, Andrea] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Spampanato, Carmine; Ballabio, Andrea] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA. [Puertollano, Rosa] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Ballabio, Andrea; Parenti, Giancarlo] Univ Naples Federico II, Dept Pediat, Naples, Italy. RP Parenti, G (reprint author), Telethon Inst Genet & Med TIGEM, Naples, Italy. EM parenti@tigem.it; rabenn@mail.nih.gov OI BALLABIO, Andrea/0000-0003-1381-4604 FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health; Fondazione Telethon FX This research was supported (in part) by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 0 TC 12 Z9 12 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD JUL 1 PY 2013 VL 9 IS 7 BP 1117 EP 1118 DI 10.4161/auto.24920 PG 2 WC Cell Biology SC Cell Biology GA 201WS UT WOS:000323174300021 PM 23669057 ER PT J AU Belani, CP Nemunaitis, JJ Chachoua, A Eisenberg, PD Raez, LE Cuevas, JD Mather, CB Benner, RJ Meech, SJ AF Belani, Chandra P. Nemunaitis, John J. Chachoua, Abraham Eisenberg, Peter D. Raez, Luiz E. Cuevas, J. Daniel Mather, Cecile B. Benner, Rebecca J. Meech, Sandra J. TI Phase 2 trial of erlotinib with or without PF-3512676 (CPG 7909, a Toll-like receptor 9 agonist) in patients with advanced recurrent EGFR-positive non-small cell lung cancer SO CANCER BIOLOGY & THERAPY LA English DT Article DE carcinoma; EGFR; epidermal growth factor; erlotinib; non-small cell lung cancer; PF-3512676; receptor; Toll-like receptor 9 ID 1ST-LINE TREATMENT; TLR9 AGONISTS; II TRIAL AB This phase 2 study assessed PF-3512676 plus erlotinib in patients with epidermal growth factor receptor-positive advanced non-small cell lung cancer after prior chemotherapy failure. Patients were randomized 1:1 to PF-3512676 (0.20 mg/kg injected subcutaneously once weekly) plus erlotinib (150 mg daily) or erlotinib alone. The primary objective was to estimate progression-free survival (PFS). Patients received PF-3512676 plus erlotinib (n = 18) or erlotinib alone (n = 21). The study was halted because an unplanned interim analysis indicated that large improvement in PFS with addition of PF-3512676 would be unlikely. In the PF-3512676-plus-erlotinib and erlotinib-alone arms, median PFS was 1.6 and 1.7 mo (hazard ratio, 1.00; 95% confidence interval, 0.5-2.0; P = 0.9335), respectively. Salient grade 3 adverse events in PF-3512676-plus-erlotinib and erlotinib-alone arms were diarrhea (5/0), dyspnea (5/6), fatigue (4/1), other flu-like symptoms (2/0), anemia (2/1), and lymphocytopenia (based on laboratory values, 1/4). Adding PF-3512676 to erlotinib did not show potential for increased progression-free survival over erlotinib alone in patients with advanced recurrent epidermal growth factor receptor-positive non-small cell lung cancer. C1 [Belani, Chandra P.] Milton S Hershey Med Ctr, Penn State Hershey Canc Inst, Hershey, PA USA. [Nemunaitis, John J.] Texas Oncol Phys Associates & Med City Dallas Hos, Mary Crowley Canc Res Ctr, Dallas, TX USA. [Chachoua, Abraham] NYU, Sch Med, Dept Med, New York, NY USA. [Chachoua, Abraham] NYU, Inst Canc, Natl Canc Inst, New York, NY USA. [Eisenberg, Peter D.] Marin Canc Care, Clin Res, Greenbrae, CA USA. [Raez, Luiz E.] Florida Int Univ, Mem Canc Inst, Thorac Oncol Program, Pembroke Pines, FL USA. [Raez, Luiz E.] Florida Int Univ, Herbert Wherteim Coll Med, Pembroke Pines, FL USA. [Cuevas, J. Daniel] St Louis Canc Care, Med Oncol & Hemat, Chesterfield, MO USA. [Mather, Cecile B.; Benner, Rebecca J.; Meech, Sandra J.] Pfizer Inc, Pfizer Oncol Global Res & Dev, Groton, CT 06340 USA. RP Belani, CP (reprint author), Milton S Hershey Med Ctr, Penn State Hershey Canc Inst, Hershey, PA USA. EM cbelani@psu.edu OI Belani, Chandra/0000-0001-5049-5329 FU Pfizer Inc. FX This study (NCT00321815) was sponsored by Pfizer Inc. Medical editorial support was provided by Tamara Fink, PhD, of Accuverus Inc., a division of ProEd Communications, Inc. and was funded by Pfizer Inc. NR 14 TC 9 Z9 11 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL 1 PY 2013 VL 14 IS 7 BP 557 EP 563 DI 10.4161/cbt.24598 PG 7 WC Oncology SC Oncology GA 200BT UT WOS:000323042400001 PM 23792641 ER PT J AU Xia, MH Huang, RL Sakamuru, S Alcorta, D Cho, MH Lee, DH Park, DM Kelley, MJ Sommer, J Austin, CP AF Xia, Menghang Huang, Ruili Sakamuru, Srilatha Alcorta, David Cho, Ming-Hsuang Lee, Dae-Hee Park, Deric M. Kelley, Michael J. Sommer, Josh Austin, Christopher P. TI Identification of repurposed small molecule drugs for chordoma therapy SO CANCER BIOLOGY & THERAPY LA English DT Article DE chordoma; NCGC Pharmaceutical Collection; cell viability; caspase 3; 7; U-CH1; U-CH2; qHTS ID BORTEZOMIB; APOPTOSIS; INHIBITORS; COMBINATION; DOXORUBICIN; MECHANISM; TARGET; ASSAYS; CELLS; TRIAL AB Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan, and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potently in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine, and bortezomib showed similar inhibitory effect on cell lines and 3 primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy. C1 [Xia, Menghang; Huang, Ruili; Sakamuru, Srilatha; Cho, Ming-Hsuang; Austin, Christopher P.] NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Alcorta, David; Kelley, Michael J.] Duke Univ, Dept Med, Durham, NC USA. [Lee, Dae-Hee; Park, Deric M.] Univ Virginia, Charlottesville, VA USA. [Sommer, Josh] Chordoma Fdn, Durham, NC USA. RP Xia, MH (reprint author), NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM mxia@mail.nih.gov FU Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health FX We gratefully acknowledge Dr Gurusingham Sittampalam for critical reading of the manuscript. These studies were supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health. NR 31 TC 9 Z9 10 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL 1 PY 2013 VL 14 IS 7 BP 638 EP 647 DI 10.4161/cbt.24596 PG 10 WC Oncology SC Oncology GA 200BT UT WOS:000323042400009 PM 23792643 ER PT J AU Milenic, DE Baidoo, KE Shih, JH Wong, KJ Brechbiel, MW AF Milenic, Diane E. Baidoo, Kwamena E. Shih, Joanna H. Wong, Karen J. Brechbiel, Martin W. TI Evaluation of Platinum Chemotherapy in Combination with HER2-Targeted alpha-Particle Radiation SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE alpha-particle; Bi-213; carboplatin; cisplatin; HER2; Pb-212; radioimmunotherapy; trastuzumab ID DISSEMINATED PERITONEAL DISEASE; HUMANIZED MONOCLONAL-ANTIBODY; CANCER XENOGRAFTS; TARGETING HER2; OVARIAN-CANCER; SPECTROPHOTOMETRIC METHOD; IN-VITRO; RADIOIMMUNOTHERAPY; CISPLATIN; TRASTUZUMAB AB The studies described herein assess the potential of combining platinum-based chemotherapy with high-linear energy transfer (LET) alpha-particle-targeted radiation therapy using trastuzumab as the delivery vehicle. An initial study explored the combination of cisplatin with Bi-213-trastuzumab in the LS-174T i.p. xenograft model. This initial study determined the administration sequence of cisplatin and Bi-213-trastuzumab. Cisplatin coinjected with Bi-213-trastuzumab increased the median survival (MS) to 90 days versus 65 days for Bi-213-trastuzumab alone. Toxicity was observed with a weight loss of 17.6% in some of the combined treatment groups. Carboplatin proved to be better tolerated. Maximal therapeutic benefit, that is, a 5.1-fold increase in MS, was obtained in the group injected with Bi-213-trastuzumab, followed by carboplatin 24 hours later. This was further improved by administration of multiple weekly doses of carboplatin. The MS achieved with administration of 3 doses of carboplatin was 180 days versus 60 days with Bi-213-trastuzumab alone. The combination of carboplatin with Pb-212 radioimmunotherapy was also evaluated. The therapeutic efficacy of Pb-212-trastuzumab (58-day MS) increased when the mice were pretreated with carboplatin 24 hours prior (157-day MS). These results again demonstrate the necessity of empirically determining the administration sequence when combining therapeutic modalities. C1 [Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Shih, Joanna H.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Wong, Karen J.] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Milenic, DE (reprint author), NIH, 10 Ctr Dr,MSC 1002,Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM dm71q@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 7 Z9 7 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD JUL PY 2013 VL 28 IS 6 BP 441 EP 449 DI 10.1089/cbr.2012.1423 PG 9 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 190CO UT WOS:000322315500003 PM 23758610 ER PT J AU O'Rourke, JG Gareau, JR Ochaba, J Song, W Rasko, T Reverter, D Lee, J Monteys, AM Pallos, J Mee, L Vashishtha, M Apostol, BL Nicholson, TP Illes, K Zhu, YZ Dasso, M Bates, GP Difiglia, M Davidson, B Wanker, EE Marsh, JL Lima, CD Steffan, JS Thompson, LM AF O'Rourke, Jacqueline Gire Gareau, Jaclyn R. Ochaba, Joseph Song, Wan Rasko, Tamas Reverter, David Lee, John Monteys, Alex Mas Pallos, Judit Mee, Lisa Vashishtha, Malini Apostol, Barbara L. Nicholson, Thomas Peter Illes, Katalin Zhu, Ya-Zhen Dasso, Mary Bates, Gillian P. Difiglia, Marian Davidson, Beverly Wanker, Erich E. Marsh, J. Lawrence Lima, Christopher D. Steffan, Joan S. Thompson, Leslie M. TI SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation SO CELL REPORTS LA English DT Article ID DISEASE PATHOGENESIS; POSTTRANSLATIONAL MODIFICATIONS; INTERACTION NETWORK; CONJUGATION; AGGREGATION; SUMOYLATION; REPEAT; MICE; GENE; ACTIVATION AB A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression. C1 [O'Rourke, Jacqueline Gire; Thompson, Leslie M.] Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92697 USA. [O'Rourke, Jacqueline Gire; Mee, Lisa; Vashishtha, Malini; Apostol, Barbara L.; Illes, Katalin; Zhu, Ya-Zhen; Steffan, Joan S.; Thompson, Leslie M.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92697 USA. [O'Rourke, Jacqueline Gire; Ochaba, Joseph; Vashishtha, Malini; Steffan, Joan S.; Thompson, Leslie M.] Univ Calif Irvine, Inst Memory Impairments & Neurol Disorders, Irvine, CA 92697 USA. [Gareau, Jaclyn R.; Reverter, David; Lima, Christopher D.] Sloan Kettering Inst, Struct Biol Program, New York, NY 10065 USA. [Ochaba, Joseph; Thompson, Leslie M.] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA. [Song, Wan; Pallos, Judit; Marsh, J. Lawrence] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA. [Rasko, Tamas; Wanker, Erich E.] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. [Lee, John; Monteys, Alex Mas; Davidson, Beverly] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [Lee, John; Monteys, Alex Mas; Davidson, Beverly] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Neurol, Iowa City, IA 52242 USA. [Lee, John; Monteys, Alex Mas; Davidson, Beverly] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA. [Nicholson, Thomas Peter] Enzo Life Sci UK Ltd, Exeter EX2 8NL, Devon, England. [Dasso, Mary] NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Bates, Gillian P.] Kings Coll London, Sch Med, Dept Med & Mol Genet, London WC2R 2LS, England. [Difiglia, Marian] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Difiglia, Marian] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Thompson, LM (reprint author), Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92697 USA. EM lmthomps@uci.edu OI Reverter, David/0000-0002-5347-0992; Bates, Gillian/0000-0002-4041-6305; Dasso, Mary/0000-0002-5410-1371; Wanker, Erich/0000-0001-8072-1630; Lima, Christopher/0000-0002-9163-6092 FU National Institutes of Health [NS-52789, NS-45283, U01-NS063953, NS072453, GM065872]; DFG; EU [SFB740, SFB618]; EU (EuroSpin); EU (SynSys); Janet Westerfield Foundation; Hereditary Disease Foundation; CHDI Foundation; Huntington's Disease Society of America; Optical Biology Shared Resource of the Cancer Center Support Grant at the University of California, Irvine [CA-62203] FX This work was supported by grants from the National Institutes of Health: NS-52789 to L. M. T., NS-45283 to J.L.M., U01-NS063953 subaward to L. M. T. and J.L.M., and NS072453 to J.S.S. C. D. L., D. R., and J.R.G. were supported in part by GM065872, the DFG, and EU (SFB740, SFB618, EuroSpin, and SynSys to E. E. W.), and J.O. received support from the Janet Westerfield Foundation. Support was also provided by the Hereditary Disease Foundation (to L. M. T. and J.S.S.), CHDI Foundation (to J.L.M., L. M. T., and J.S.S.), and Huntington's Disease Society of America (to L. M. T. and J.L.M.). We would like to thank Ron Hay for His-SUMO-1/2/3 plasmids and many helpful discussions, Hongtao Yu for the GFP-SUMO-1/2 plasmids, Solomon H. Snyder for the Rhes plasmid, and T. P. Yao for HDAC4 plasmids. We also thank Emily Mitchell for assistance with filter retardation assays and Jack Reidling for careful reading of the manuscript. We also acknowledge the Massachusetts Alzheimer's Disease Research Center for human autopsy brain tissue. We acknowledge assistance from Hediye Erdjument-Bromage and the Mass Spectrometry facility at Sloan-Kettering Institute for performing and analyzing mass spectra data (Figure S1). This work was made possible in part by the availability of the Optical Biology Shared Resource of the Cancer Center Support Grant (CA-62203) at the University of California, Irvine. NR 66 TC 19 Z9 20 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUL PY 2013 VL 4 IS 2 BP 362 EP 375 DI 10.1016/j.celrep.2013.06.034 PG 14 WC Cell Biology SC Cell Biology GA 195LR UT WOS:000322704400013 PM 23871671 ER PT J AU Hoffman, AF Lupica, CR AF Hoffman, Alexander F. Lupica, Carl R. TI Synaptic Targets of Delta(9)-Tetrahydrocannabinol in the Central Nervous System SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID LONG-TERM POTENTIATION; VENTRAL TEGMENTAL AREA; CB1 CANNABINOID RECEPTOR; MIDBRAIN DOPAMINE NEURONS; NUCLEUS-ACCUMBENS; CHRONIC DELTA-9-TETRAHYDROCANNABINOL; HIPPOCAMPAL-NEURONS; RAT-BRAIN; ENDOCANNABINOID RELEASE; GLUTAMATERGIC SYNAPSES AB The availability of potent synthetic agonists for cannabinoid receptors has facilitated our understanding of cannabinoid actions on synaptic transmission in the central nervous system. Moreover, the ability of these compounds to inhibit neurotransmitter release at many central synapses is thought to underlie most of the behavioral effects of cannabinoid agonists. However, despite the widespread use and misuse of marijuana, and recognition of its potential adverse psychological effects in humans, comparatively few studies have examined the actions of its primary psychoactive constituent, Delta(9)-tetrahydrocannabinol (THC), at well-defined synaptic pathways. Here we examine the recent literature describing the effects of acute and repeated THC exposure on synaptic function in several brain regions and explore the importance of these neurobiological actions of THC in drug addiction. C1 [Hoffman, Alexander F.; Lupica, Carl R.] NIDA, US Dept HHS, NIH, Intramural Res Program,Electrophysiol Res Sect, Baltimore, MD 21224 USA. RP Lupica, CR (reprint author), NIDA, US Dept HHS, NIH, Intramural Res Program,Electrophysiol Res Sect, Baltimore, MD 21224 USA. EM clupica@intra.nida.nih.gov FU U.S. Department of Health and Human Services; National Institutes of Health; National Institute on Drug Abuse Intramural Research Program; National Institute on Drug Abuse [DA14263] FX This work is supported by the U.S. Department of Health and Human Services, The National Institutes of Health, and the National Institute on Drug Abuse Intramural Research Program, and earlier studies were supported by a grant from the National Institute on Drug Abuse (DA14263 to C.R.L.). NR 109 TC 0 Z9 0 U1 0 U2 13 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 2013 VL 5 IS 7 AR a012203 DI 10.1101/cshperspect.a012237 PG 14 WC Cell Biology SC Cell Biology GA 200EW UT WOS:000323051600014 ER PT J AU Miller, JL AF Miller, Jeffery L. TI Iron Deficiency Anemia: A Common and Curable Disease SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID RETICULOCYTE HEMOGLOBIN CONTENT; RED-CELL MASS; SERUM FERRITIN; PLASMODIUM-FALCIPARUM; PLACENTAL TRANSFUSION; MICRONUTRIENT STATUS; NEONATAL PREVENTION; ZINC PROTOPORPHYRIN; CONTROLLED-TRIAL; BLOOD-DONATION AB Iron deficiency anemia arises when the balance of iron intake, iron stores, and the body's loss of iron are insufficient to fully support production of erythrocytes. Iron deficiency anemia rarely causes death, but the impact on human health is significant. In the developed world, this disease is easily identified and treated, but frequently overlooked by physicians. In contrast, it is a health problem that affects major portions of the population in underdeveloped countries. Overall, the prevention and successful treatment for iron deficiency anemia remains woefully insufficient worldwide, especially among underprivileged women and children. Here, clinical and laboratory features of the disease are discussed, and then focus is placed on relevant economic, environmental, infectious, and genetic factors that converge among global populations. C1 Natl Inst Diabet & Digest & Kidney Dis, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Mol Med Branch, NIH, Bethesda, MD 20892 USA. EM jm7f@nih.gov NR 101 TC 20 Z9 20 U1 1 U2 25 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 2013 VL 3 IS 7 AR a011866 DI 10.1101/cshperspect.a011866 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 194OM UT WOS:000322642600001 ER PT J AU Naik, HB Cowen, EW AF Naik, Haley B. Cowen, Edward W. TI Autoinflammatory Pustular Neutrophilic Diseases SO DERMATOLOGIC CLINICS LA English DT Article DE Pustular psoriasis; Palmoplantar pustulosis; Subcorneal pustular dermatosis; Deficiency of IL-1 receptor antagonist (DIRA); PAPA syndrome; SAPHO syndrome ID RECURRENT MULTIFOCAL OSTEOMYELITIS; CONGENITAL DYSERYTHROPOIETIC ANEMIA; PERSISTENT PALMOPLANTAR PUSTULOSIS; RESPIRATORY-DISTRESS-SYNDROME; SNEDDON-WILKINSON-DISEASE; OF-THE-LITERATURE; ACRODERMATITIS CONTINUA SUPPURATIVA; INFLAMMATORY SKIN-DISEASE; HL-A-ANTIGENS; SAPHO-SYNDROME AB This article provides a new categorization of inflammatory pustular dermatoses in the context of recent genetic and biological insights. Monogenic diseases with pustular phenotypes are discussed, including deficiency of interleukin 1 receptor antagonist, deficiency of the interleukin 36 receptor antagonist, CARD14-associated pustular psoriasis, and pyogenic arthritis, pyoderma gangrenosum, and acne. How these new genetic advancements may inform how previously described pustular diseases are viewed, including pustular psoriasis and its clinical variants, with a focus on historical classification by clinical phenotype, is also discussed. C1 [Naik, Haley B.; Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 218 TC 13 Z9 15 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 0733-8635 EI 1558-0520 J9 DERMATOL CLIN JI Dermatol. Clin. PD JUL PY 2013 VL 31 IS 3 BP 405 EP + DI 10.1016/j.det.2013.04.001 PG 22 WC Dermatology SC Dermatology GA 191NZ UT WOS:000322421200004 PM 23827244 ER PT J AU Mishra, A Yao, XL Levine, SJ AF Mishra, Amarjit Yao, Xianglan Levine, Stewart J. TI From bedside to bench to clinic trials: identifying new treatments for severe asthma SO DISEASE MODELS & MECHANISMS LA English DT Article ID INNATE LYMPHOID-CELLS; RESISTANT AIRWAY HYPERRESPONSIVENESS; GLUCOCORTICOID-RECEPTOR BETA; ALLERGIC LUNG INFLAMMATION; HISTONE DEACETYLASE 1; GUINEA-PIG MODEL; ADAPTIVE IMMUNITY; IFN-GAMMA; T-CELLS; NEUTROPHILIC INFLAMMATION AB Asthmatics with a severe form of the disease are frequently refractory to standard medications such as inhaled corticosteroids, underlining the need for new treatments to prevent the occurrence of potentially life-threatening episodes. A major obstacle in the development of new treatments for severe asthma is the heterogeneous pathogenesis of the disease, which involves multiple mechanisms and cell types. Furthermore, new therapies might need to be targeted to subgroups of patients whose disease pathogenesis is mediated by a specific pathway. One approach to solving the challenge of developing new treatments for severe asthma is to use experimental mouse models of asthma to address clinically relevant questions regarding disease pathogenesis. The mechanistic insights gained from mouse studies can be translated back to the clinic as potential treatment approaches that require evaluation in clinical trials to validate their effectiveness and safety in human subjects. Here, we will review how mouse models have advanced our understanding of severe asthma pathogenesis. Mouse studies have helped us to uncover the underlying inflammatory mechanisms (mediated by multiple immune cell types that produce Th1, Th2 or Th17 cytokines) and non-inflammatory pathways, in addition to shedding light on asthma that is associated with obesity or steroid unresponsiveness. We propose that the strategy of using mouse models to address clinically relevant questions remains an attractive and productive research approach for identifying mechanistic pathways that can be developed into novel treatments for severe asthma. C1 [Mishra, Amarjit; Yao, Xianglan; Levine, Stewart J.] Natl Heart Lung & Blood Inst, Natl Inst Hlth, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), Natl Heart Lung & Blood Inst, Natl Inst Hlth, Cardiovasc & Pulm Branch, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov RI MISHRA, AMARJIT/D-7504-2016 OI MISHRA, AMARJIT/0000-0002-3777-0338 FU Division of Intramural Research of the National Heart, Lung and Blood Institute at the National Institutes of Health, Bethesda, MD, USA FX This work was funded by the Division of Intramural Research of the National Heart, Lung and Blood Institute at the National Institutes of Health, Bethesda, MD, USA. NR 89 TC 3 Z9 4 U1 0 U2 14 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 J9 DIS MODEL MECH JI Dis. Model. Mech. PD JUL PY 2013 VL 6 IS 4 BP 877 EP 888 DI 10.1242/dmm.012070 PG 12 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 188QF UT WOS:000322207900004 PM 23828644 ER PT J AU Raffa, D Maggio, B Raimondi, MV Cusimano, MG Amico, G Carollo, A Conaldi, PG Bai, RL Hamel, E Daidone, G AF Raffa, Demetrio Maggio, Benedetta Raimondi, Maria Valeria Cusimano, Maria Grazia Amico, Giandomenico Carollo, Anna Conaldi, Pier Giulio Bai, Ruoli Hamel, Ernest Daidone, Giuseppe TI 2-Cinnamamido, 2-(3-phenylpropiolamido), and 2-(3-phenylpropanamido)benzamides: Synthesis, antiproliferative activity, and mechanism of action SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE 2-Cinnamamidobenzamides; 2-(3-Phenylpropiolamido)benzamides; 2-(3-Phenylpropanamido)benzamides; Antiproliferative activity; Apoptosis ID TUBULIN; CELLS AB Several new benzamides 4a-q were synthesized by stirring in pyridine the acid chlorides 3a-q with the appropriate anthranilamide derivatives 2a-g. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against a panel of 5 human cell lines (K562 human chronic myelogenous leukemia cells, MCF-7 breast cancer cells, HTC-116 and HT26 colon cancer cells and NCI H460 non-small cell lung cancer cells). (C) 2013 Elsevier Masson SAS. All rights reserved. C1 [Raffa, Demetrio; Maggio, Benedetta; Raimondi, Maria Valeria; Cusimano, Maria Grazia; Daidone, Giuseppe] Dipartimento Sci Tecnol Biol Chim & Farmaceut, I-90123 Palermo, Italy. [Amico, Giandomenico; Conaldi, Pier Giulio] ISMETT Mediterranean Inst Transplantat & Adv Spec, Dept Lab Med & Adv Biotechnol, Palermo, Italy. [Amico, Giandomenico; Conaldi, Pier Giulio] Ri MED Fdn, Unit Regenerat Med & Biomed Technol, Palermo, Italy. [Carollo, Anna] ISMETT Mediterranean Inst Transplantat & Adv Spec, Serv Farm Clin, Palermo, Italy. [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. RP Raffa, D (reprint author), Dipartimento Sci Tecnol Biol Chim & Farmaceut, Via Archirafi 32, I-90123 Palermo, Italy. EM demetrio.raffa@unipa.it; benedetta.maggio@unipa.it OI Daidone, Giuseppe/0000-0002-9529-8449; Raffa, Demetrio/0000-0002-1073-7706 FU Fondo di finanziamento della ricerca di ateneo FX Financial support from Fondo di finanziamento della ricerca di ateneo (ex 60%) is gratefully acknowledged. NR 18 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD JUL PY 2013 VL 65 BP 427 EP 435 DI 10.1016/j.ejmech.2013.04.068 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 197KM UT WOS:000322850100041 PM 23747810 ER PT J AU Holczbauer, A Factor, VM Andersen, JB Marquardt, JU Kleiner, DE Raggi, C Kitade, M Seo, D Akita, H Durkin, ME Thorgeirsson, SS AF Holczbauer, Agnes Factor, Valentina M. Andersen, Jesper B. Marquardt, Jens U. Kleiner, David E. Raggi, Chiara Kitade, Mitsuteru Seo, Daekwan Akita, Hirofumi Durkin, Marian E. Thorgeirsson, Snorri S. TI Modeling Pathogenesis of Primary Liver Cancer in Lineage-Specific Mouse Cell Types SO GASTROENTEROLOGY LA English DT Article DE Cell of Origin; Cancer Stem Cell; HCC; c-MYC ID EPITHELIAL-MESENCHYMAL TRANSITION; PLURIPOTENT STEM-CELLS; C-MYC; HUMAN HEPATOCARCINOGENESIS; HEPATOCELLULAR-CARCINOMA; EMBRYONIC STEM; OVAL CELLS; DIFFERENTIATION; EXPRESSION; ORIGIN AB BACKGROUND & AIMS: Human primary liver cancer is classified into biologically distinct subgroups based on cellular origin. Liver cancer stem cells (CSCs) have been recently described. We investigated the ability of distinct lineages of hepatic cells to become liver CSCs and the phenotypic and genetic heterogeneity of primary liver cancer. METHODS: We transduced mouse primary hepatic progenitor cells, lineage-committed hepatoblasts, and differentiated adult hepatocytes with transgenes encoding oncogenic H-Ras and SV40LT. The CSC properties of transduced cells and their ability to form tumors were tested by standard in vitro and in vivo assays and transcriptome profiling. RESULTS: Irrespective of origin, all transduced cells acquired markers of CSC/progenitor cells, side populations, and self-renewal capacity in vitro. They also formed a broad spectrum of liver tumors, ranging from cholangiocarcinoma to hepatocellular carcinoma, which resembled human liver tumors, based on genomic and histologic analyses. The tumor cells coexpressed hepatocyte (hepatocyte nuclear factor 4 alpha), progenitor/biliary (keratin 19, epithelial cell adhesion molecule, A6), and mesenchymal (vimentin) markers and showed dysregulation of genes that control the epithelial-mesenchymal transition. Gene expression analyses could distinguish tumors of different cellular origin, indicating the contribution of lineage stage-dependent genetic changes to malignant transformation. Activation of c-Myc and its target genes was required to reprogram adult hepatocytes into CSCs and for tumors to develop. Stable knockdown of c-Myc in transformed adult hepatocytes reduced their CSC properties in vitro and suppressed growth of tumors in immunodeficient mice. CONCLUSIONS: Any cell type in the mouse hepatic lineage can undergo oncogenic reprogramming into a CSC by activating different cell type-specific pathways. Identification of common and cell of origin-specific phenotypic and genetic changes could provide new therapeutic targets for liver cancer. C1 [Holczbauer, Agnes; Factor, Valentina M.; Andersen, Jesper B.; Marquardt, Jens U.; Raggi, Chiara; Kitade, Mitsuteru; Seo, Daekwan; Akita, Hirofumi; Durkin, Marian E.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Lab Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 4146A, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov OI Kleiner, David/0000-0003-3442-4453; Andersen , Jesper B/0000-0003-1760-5244; RAGGI, Chiara/0000-0003-2473-3535 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 48 TC 52 Z9 53 U1 1 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2013 VL 145 IS 1 BP 221 EP 231 DI 10.1053/j.gastro.2013.03.013 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 172ZR UT WOS:000321047300036 PM 23523670 ER PT J AU Park, S Shcheynikov, N Hong, JH Zheng, CY Suh, SH Kawaai, K Ando, H Mizutani, A Abe, T Kiyonari, H Seki, G Yule, D Mikoshiba, K Muallem, S AF Park, Seonghee Shcheynikov, Nikolay Hong, Jeong Hee Zheng, Changyu Suh, Suk Hyo Kawaai, Katsuhiro Ando, Hideaki Mizutani, Akihiro Abe, Takaya Kiyonari, Hiroshi Seki, George Yule, David Mikoshiba, Katsuhiko Muallem, Shmuel TI Irbit Mediates Synergy Between Ca2+ and cAMP Signaling Pathways During Epithelial Transport in Mice SO GASTROENTEROLOGY LA English DT Article DE Signal Transduction; Ion and Water Secretion; Fluid; Electrolyte ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; RAT SUBMANDIBULAR-GLAND; PROTEIN-KINASES; CYSTIC-FIBROSIS; HCO3-SECRETION; WNK KINASES; CFTR; PHOSPHORYLATION; FLUID; INHIBITION AB BACKGROUND & AIMS: The cyclic adenosine monophosphate (cAMP) and Ca2+ signaling pathways synergize to regulate many physiological functions. However, little is known about the mechanisms by which these pathways interact. We investigated the synergy between these signaling pathways in mouse pancreatic and salivary gland ducts. METHODS: We created mice with disruptions in genes encoding the solute carrier family 26, member 6 (Slc26a6(-/-) mice) and inositol 1,4,5-triphosphate (InsP3) receptor-binding protein released with InsP3 (Irbit(-/-)) mice. We investigated fluid secretion by sealed pancreatic ducts and the function of Slc26a6 and the cystic fibrosis transmembrane conductance regulator (CFTR) in HeLa cells and in ducts isolated from mouse pancreatic and salivary glands. Slc26a6 activity was assayed by measuring intracellular pH, and CFTR activity was assayed by measuring Cl-current. Protein interactions were determined by immunoprecipitation analyses. RESULTS: Irbit mediated the synergistic activation of CFTR and Slc26a6 by Ca2+ and cAMP. In resting cells, Irbit was sequestered by InsP3 receptors (IP3Rs) in the endoplasmic reticulum. Stimulation of Gs-coupled receptors led to phosphorylation of IP(3)Rs, which increased their affinity for InsP3 and reduced their affinity for Irbit. Subsequent weak stimulation of Gq-coupled receptors, which led to production of low levels of IP3, caused dissociation of Irbit from IP(3)Rs and allowed translocation of Irbit to CFTR and Slc26a6 in the plasma membrane. These processes stimulated epithelial secretion of electrolytes and fluid. These pathways were not observed in pancreatic and salivary glands from Irbit(-/-) or Slc26a6(-/-) mice, or in salivary gland ducts expressing mutant forms of IP(3)Rs that could not undergo protein kinase A-mediated phosphorylation. CONCLUSIONS: Irbit promotes synergy between the Ca2+ and cAMP signaling pathways in cultured cells and in pancreatic and salivary ducts from mice. Defects in this pathway could be involved in cystic fibrosis, pancreatitis, or Sjogren syndrome. C1 [Park, Seonghee; Shcheynikov, Nikolay; Hong, Jeong Hee; Zheng, Changyu; Muallem, Shmuel] Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Park, Seonghee; Suh, Suk Hyo] Ewha Womans Univ, Dept Physiol, Seoul, South Korea. [Kawaai, Katsuhiro; Ando, Hideaki; Mikoshiba, Katsuhiko] Inst Phys & Chem Res RIKEN, Brain Sci Inst, Lab Dev Neurobiol, Saitama, Japan. [Mizutani, Akihiro] Showa Pharmaceut Univ, Dept Pharmacotherapeut, Machida, Tokyo, Japan. [Abe, Takaya; Kiyonari, Hiroshi] RIKEN Ctr Dev Biol, Lab Anim Resources & Genet Engn, Kobe, Hyogo, Japan. [Seki, George] Univ Tokyo, Fac Med, Dept Internal Med, Tokyo 113, Japan. [Yule, David] Univ Rochester, Med Ctr, Sch Med & Dent, Dept Pharmacol & Physiol, Rochester, NY 14642 USA. RP Muallem, S (reprint author), Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. EM Shmuel.muallem@nih.gov RI Mikoshiba, Katsuhiko/N-7943-2015; Kiyonari, Hiroshi/N-7936-2015; Kawaai, Katsuhiro/C-9216-2017; Ando, Hideaki/D-3876-2017 OI Kawaai, Katsuhiro/0000-0002-7502-0722; FU NIH [ZIA-DE000735] FX Supported by an NIH Intramural Research grant ZIA-DE000735 to S.M. NR 31 TC 31 Z9 36 U1 1 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2013 VL 145 IS 1 BP 232 EP 241 DI 10.1053/j.gastro.2013.03.047 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 172ZR UT WOS:000321047300037 PM 23542070 ER PT J AU Moroni, M Maeda, D Whitnall, MH Bonner, WM Redon, CE AF Moroni, Maria Maeda, Daisuke Whitnall, Mark H. Bonner, William M. Redon, Christophe E. TI Evaluation of the Gamma-H2AX Assay for Radiation Biodosimetry in a Swine Model SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Article DE Gottingen minipig; immunocytofluorescence-based gamma-H2AX; ionizing radiation; lymphocytes; fibroblasts ID DOUBLE-STRAND BREAKS; PERIPHERAL-BLOOD LYMPHOCYTES; RESIDUAL 53BP1/GAMMA-H2AX FOCI; IN-VIVO; GOTTINGEN MINIPIG; BIOLOGICAL DOSIMETRY; COMPUTED-TOMOGRAPHY; DOSE-DISTRIBUTION; HUMAN-CELLS; REPAIR AB There is a paucity of large animal models to study both the extent and the health risk of ionizing radiation exposure in humans. One promising candidate for such a model is the minipig. Here, we evaluate the minipig for its potential in gamma-H2AX-based biodosimetry after exposure to ionizing radiation using both Cs137 and Co60 sources. gamma-H2AX foci were enumerated in blood lymphocytes and normal fibroblasts of human and porcine origin after ex vivo gamma-ray irradiation. DNA double-strand break repair kinetics in minipig blood lymphocytes and fibroblasts, based on the gamma-H2AX assay, were similar to those observed in their human counterparts. To substantiate the similarity observed between the human and minipig we show that minipig fibroblast radiosensitivity was similar to that observed with human fibroblasts. Finally, a strong gamma-H2AX induction was observed in blood lymphocytes following minipig total body irradiation. Significant responses were detected 3 days after 1.8 Gy and 1 week after 3.8 and 5 Gy with residual gamma-H2AX foci proportional to the initial radiation doses. These findings show that the Gottingen minipig provides a useful in vivo model for validation of gamma-H2AX biodosimetry for dose assessment in humans. C1 [Moroni, Maria; Whitnall, Mark H.] Uniformed Serv Univ Hlth Sci, Armed Forces Radiobiol Res Inst, Bethesda, MD 20889 USA. [Maeda, Daisuke; Bonner, William M.; Redon, Christophe E.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Redon, CE (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM maria.moroni@usuhs.edu; maedad@mail.nih.gov; mark.whitnall@usuhs.edu; bonnerw@mail.nih.gov; redonc@mail.nih.gov FU NIAID Radiation/Nuclear Countermeasures Program; Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH; Armed Forces Radiobiology Research Institute (RBB2DG) FX This research was supported by the NIAID Radiation/Nuclear Countermeasures Program, the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH and by the Armed Forces Radiobiology Research Institute (RBB2DG). NR 58 TC 22 Z9 25 U1 0 U2 13 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 2013 VL 14 IS 7 BP 14119 EP 14135 DI 10.3390/ijms140714119 PG 17 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA 188DH UT WOS:000322171700071 PM 23880859 ER PT J AU Volkow, ND Baler, RD AF Volkow, Nora D. Baler, Ruben D. TI Brain Imaging Biomarkers to Predict Relapse in Alcohol Addiction SO JAMA PSYCHIATRY LA English DT Editorial Material ID MEDIAL PREFRONTAL CORTEX; HEAVY DRINKING; STRIATUM; COCAINE; CHOICE; CONNECTIVITY; INVOLVEMENT; ACTIVATION; STRESS; SYSTEM C1 [Volkow, Nora D.; Baler, Ruben D.] NIH, Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIH, Natl Inst Drug Abuse, Bldg 10,6001 Executive Blvd,Rm 5274, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 34 TC 18 Z9 18 U1 0 U2 15 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-622X J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JUL PY 2013 VL 70 IS 7 BP 661 EP 663 DI 10.1001/jamapsychiatry.2013.1141 PG 3 WC Psychiatry SC Psychiatry GA 197EA UT WOS:000322831100003 PM 23636789 ER PT J AU Emerson, SU Nguyen, HT Torian, U Mather, K Firth, AE AF Emerson, Suzanne U. Nguyen, Hanh T. Torian, Udana Mather, Karly Firth, Andrew E. TI An essential RNA element resides in a central region of hepatitis E virus ORF2 SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID VIRAL-RNA; FAMILY HEPEVIRIDAE; REPLICATION; GENOME; PROTEIN; GENE; TRANSLATION; GENOTYPE; ENCODES; BINDS AB Hepatitis E virus (genus Hepevirus, family Hepeviridae) is one of the most important causes of acute hepatitis in adults, particularly among pregnant women, throughout Asia and Africa where mortality rates can be 20-30%. Hepatitis E virus has a single-stranded positive-sense RNA genome that contains three translated ORFs. The two 3' ORFs are translated from a subgenomic RNA. Functional RNA elements have been identified in and adjacent to the genomic 5' and 3' UTRs and in and around the intergenic region. Here we describe an additional RNA element that is located in a central region of ORF2. The RNA element is predicted to fold into two highly conserved stem loop structures, ISL1 and ISL2. Mutations that disrupt the predicted structures, without altering the encoded amino acid sequence, result in a drastic reduction in capsid protein synthesis. This indicates that the RNA element plays an important role in one of the early steps of virus replication. The structures were further investigated using a replicon that expresses Gaussia luciferase in place of the capsid protein. Single mutations in ISL2 severely reduced luciferase expression, but a pair of compensatory mutations that were predicted to restore the ISL2 structure, restored luciferase expression to near-WT levels, thus lending experimental support to the predicted structure. Nonetheless the precise role of the ISL1+ISL2 element remains unknown. C1 [Emerson, Suzanne U.; Nguyen, Hanh T.; Torian, Udana; Mather, Karly] NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Emerson, Suzanne U.; Nguyen, Hanh T.; Torian, Udana; Mather, Karly] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Firth, Andrew E.] Univ Cambridge, Dept Pathol, Div Virol, Cambridge CB2 1QP, England. RP Firth, AE (reprint author), Univ Cambridge, Dept Pathol, Div Virol, Tennis Court Rd, Cambridge CB2 1QP, England. EM aef24@cam.ac.uk OI Firth, Andrew/0000-0002-7986-9520 FU Wellcome Trust [088789]; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX A. E. F. is supported by a grant from the Wellcome Trust (088789). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (S. U. E.). NR 37 TC 10 Z9 11 U1 0 U2 3 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD JUL PY 2013 VL 94 BP 1468 EP 1476 DI 10.1099/vir.0.051870-0 PN 7 PG 9 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 197MS UT WOS:000322855900004 PM 23515023 ER PT J AU Imayama, I Alfano, CM Mason, CE Wang, CC Xiao, LR Duggan, C Campbell, KL Foster-Schubert, KE Wang, CY McTiernan, A AF Imayama, Ikuyo Alfano, Catherine M. Mason, Caitlin E. Wang, Chiachi Xiao, Liren Duggan, Catherine Campbell, Kristin L. Foster-Schubert, Karen E. Wang, Ching-Yun McTiernan, Anne TI Exercise Adherence, Cardiopulmonary Fitness, and Anthropometric Changes Improve Exercise Self-Efficacy and Health-Related Quality of Life SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE intervention study; aerobic exercise; health-related quality of life ID RANDOMIZED CONTROLLED-TRIAL; BREAST-CANCER SURVIVORS; PHYSICAL-ACTIVITY; WEIGHT-LOSS; OLDER-ADULTS; WOMEN; OVERWEIGHT; PROGRAM; OBESE; MEN AB Background: Regular exercise increases exercise self-efficacy and health-related quality of life (HRQOL); however, the mechanisms are unknown. We examined the associations of exercise adherence and physiological improvements with changes in exercise self-efficacy and HRQOL. Methods: Middle-aged adults (N = 202) were randomized to 12 months aerobic exercise (360 minutes/week) or control. Weight, waist circumference, percent body fat, cardiopulmonary fitness, HRQOL (SF-36), and exercise self-efficacy were assessed at baseline and 12 months. Adherence was measured in minutes/day from activity logs. Results: Exercise adherence was associated with reduced bodily pain, improved general health and vitality, and reduced role-emotional scores (P-trend <= 0.05). Increased fitness was associated with improved physical functioning, bodily pain and general health scores (P-trend <= 0.04). Reduced weight and percent body fat were associated with improved physical functioning, general health, and bodily pain scores (P-trend < 0.05). Decreased waist circumference was associated with improved bodily pain and general health but with reduced role-emotional scores (P-trend <= 0.05). High exercise adherence, increased cardiopulmonary fitness and reduced weight, waist circumference and percent body fat were associated with increased exercise self-efficacy (P-trend < 0.02). Conclusions: Monitoring adherence and tailoring exercise programs to induce changes in cardiopulmonary fitness and body composition may lead to greater improvements in HRQOL and self-efficacy that could promote exercise maintenance. C1 [Imayama, Ikuyo; Mason, Caitlin E.; Wang, Chiachi; Xiao, Liren; Duggan, Catherine; Wang, Ching-Yun; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Dept Publ Hlth Sci, Seattle, WA 98104 USA. [Alfano, Catherine M.] NCI, Off Canc Survivors, Bethesda, MD 20892 USA. [Campbell, Kristin L.] Univ British Columbia, Dept Phys Therapy, Vancouver, BC V5Z 1M9, Canada. [Foster-Schubert, Karen E.] Univ Washington, Dept Med, Seattle, WA USA. RP Imayama, I (reprint author), Fred Hutchinson Canc Res Ctr, Dept Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. RI Duggan, Catherine/F-9414-2015 OI Duggan, Catherine/0000-0001-7369-4021 FU Canadian Institutes of Health Research; NCATS NIH HHS [KL2 TR000421]; NCI NIH HHS [P30 CA015704, R01 CA077572, R01 CA77572, U54 CA116847]; NCRR NIH HHS [M01 RR00037, 5KL2RR025015-03, KL2 RR025015, M01 RR000037]; NIA NIH HHS [AG1094] NR 39 TC 6 Z9 6 U1 1 U2 17 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD JUL PY 2013 VL 10 IS 5 BP 676 EP 689 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 192QX UT WOS:000322501500008 PM 23036856 ER PT J AU Shi, TJ Sun, XF Gao, YQ Fillmore, TL Schepmoes, AA Zhao, R He, JT Moore, RJ Kagan, J Rodland, KD Liu, T Liu, AY Smith, RD Tang, KQ Camp, DG Qian, WJ AF Shi, Tujin Sun, Xuefei Gao, Yiqian Fillmore, Thomas L. Schepmoes, Athena A. Zhao, Rui He, Jintang Moore, Ronald J. Kagan, Jacob Rodland, Karin D. Liu, Tao Liu, Alvin Y. Smith, Richard D. Tang, Keqi Camp, David G., II Qian, Wei-Jun TI Targeted Quantification of Low ng/mL Level Proteins in Human Serum without Immunoaffinity Depletion SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE SRM; PRISM; targeted quantification; low-abundance protein; human serum; sensitivity; reproducibility; immunoaffinity depletion ID MONITORING MASS-SPECTROMETRY; HUMAN PLASMA; CARDIOVASCULAR-DISEASE; CANCER PATIENTS; BIOMARKERS; PROTEOMICS; ASSAYS; ENRICHMENT; REPRODUCIBILITY; CHROMATOGRAPHY AB We recently reported an antibody-free targeted protein quantification strategy, termed high-pressure, high-resolution separations with intelligent selection and multiplexing (PRISM), for achieving significantly enhanced sensitivity using selected reaction monitoring (SRM) mass spectrometry. Integrating PRISM with front-end IgY14 immunoaffinity depletion, sensitive detection of targeted proteins at 50-100 pg/mL levels in human blood plasma/serum was demonstrated However, immunoaffinity depletion is often associated with undesired losses of target proteins of interest. Herein we report further evaluation of PRISM-SRM quantification of low abundance serum proteins without immunoaffinity depletion. Limits of quantification (LOW at low ng/mL levels with a median coefficient of variation (CV) of similar to 12% were achieved for proteins spiked into human female serum. PRISM-SRM provided >100 fold improvement in the LOQ when compared to conventional LC-SRM measurements. PRISM-SRM was then applied to measure several low abundance endogenous serum proteins, including prostate specific antigen (PSA), in clinical prostate cancer patient sera. PRISM-SRM enabled confident detection of all target endogenous serum proteins except the low pg/mL-level cardiac troponin T. A correlation coefficient >0.99 was observed for PSA between the results from PRISM-SRM and immunoassays. Our results demonstrate that PRISM-SRM can successfully quantify low ng/mL proteins in human plasma or serum without depletion. We anticipate broad applications for PRISM-SRM quantification of low abundance proteins in candidate biomarker verification and systems biology studies. C1 [Shi, Tujin; Sun, Xuefei; Gao, Yiqian; Schepmoes, Athena A.; He, Jintang; Moore, Ronald J.; Rodland, Karin D.; Liu, Tao; Smith, Richard D.; Tang, Keqi; Camp, David G., II; Qian, Wei-Jun] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Fillmore, Thomas L.; Zhao, Rui] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [Kagan, Jacob] NCI, Canc Prevent Div, Rockville, MD USA. [Liu, Alvin Y.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Liu, Alvin Y.] Univ Washington, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. RP Qian, WJ (reprint author), Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. EM weijun.qian@pnnl.gov RI He, Jintang/G-8671-2013; Smith, Richard/J-3664-2012; Shi, Tujin/O-1789-2014 OI Smith, Richard/0000-0002-2381-2349; FU NIH [DP2OD006668]; NCI Early Detection Research Network Interagency Agreement [Y01-CN-05013-29, R33CA155252, U01CA111244, U24CA160019, P41GM103493]; DOE; DOE [DE-AC05-76RL0 1830] FX We thank Drs. Lori Sokoll and Daniel Chan at the Johns Hopkins Medical Institutions for providing the clinical serum samples. Portions of this work were supported by the NIH New Innovator Award Program DP2OD006668, NCI Early Detection Research Network Interagency Agreement Y01-CN-05013-29, R33CA155252, U01CA111244, U24CA160019, and P41GM103493. The experimental work described herein was performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the DOE and located at Pacific Northwest National Laboratory, which is operated by Battelle Memorial Institute for the DOE under Contract DE-AC05-76RL0 1830. NR 47 TC 36 Z9 36 U1 1 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD JUL PY 2013 VL 12 IS 7 BP 3353 EP 3361 DI 10.1021/pr400178v PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 180OY UT WOS:000321605700026 PM 23763644 ER PT J AU Holl, AK Wilkinson, L Tabrizi, SJ Painold, A Jahanshahi, M AF Holl, Anna K. Wilkinson, Leonora Tabrizi, Sarah J. Painold, Annamaria Jahanshahi, Marjan TI Selective executive dysfunction but intact risky decision-making in early Huntington's disease SO MOVEMENT DISORDERS LA English DT Article DE Huntington's disease; executive function; Iowa Gambling Task; Stroop task; decision-making ID RELIABILITY; CORTEX AB Executive dysfunction, including problems with decision-making, inhibition of prepotent responses, and verbal fluency, are main features of Huntington's disease (HD). The decline of executive function in HD is related to the anatomical progression of HD pathology in the basal ganglia, where the earliest changes of neuronal cell death are seen in the dorsolateral caudate. To examine the specific pattern of executive dysfunction in early HD, 18 patients with early HD were assessed on: (1) the Iowa Gambling Task to measure risky decision making, (2) the Stroop test to measure inhibition of prepotent responses, and (3) the verbal fluency test to measure internally guided word search and production, necessitating suppression of retrieval/production of inappropriate words and monitoring of the output. Patients with early HD were significantly impaired on the Stroop and verbal fluency tests relative to controls. However, Iowa Gambling Task performance was comparable across the 2 groups. This pattern of selective executive dysfunction in early HD probably reflects the fact that inhibitory processing involved in both the Stroop and verbal fluency tests recruits the dorsolateral caudate and its cortical connections, which are dysfunctional in early HD, whereas risky decision-making during the Iowa Gambling Task recruits the ventromedial caudate and its connections, which remain spared early on in the disease. The current results demonstrate that the deterioration of executive functioning in HD is variable and that some types of executive processing might already be impaired in early HD, whereas others remain intact. (c) 2013 Movement Disorder Society C1 [Holl, Anna K.; Wilkinson, Leonora; Jahanshahi, Marjan] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. [Holl, Anna K.; Painold, Annamaria] Graz Med Univ, Dept Psychiat, Graz, Austria. [Wilkinson, Leonora] NINDS, Behav Neurol Unit, Bethesda, MD 20892 USA. [Tabrizi, Sarah J.] UCL, Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England. RP Jahanshahi, M (reprint author), UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, 33 Queen Sq, London WC1N 3BG, England. EM m.jahanshahi@ion.ucl.ac.uk OI Tabrizi, Sarah/0000-0003-2716-2045 FU Career Development Fellowship from Parkinson's UK FX This work was supported by a Career Development Fellowship from Parkinson's UK to Leonora Wilkinson. NR 24 TC 8 Z9 8 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 2013 VL 28 IS 8 BP 1104 EP 1109 DI 10.1002/mds.25388 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 198YS UT WOS:000322960800020 PM 23436289 ER PT J AU Kranick, SM Moore, JW Yusuf, N Martinez, VT LaFaver, K Edwards, MJ Mehta, AR Collins, P Harrison, NA Haggard, P Hallett, M Voon, V AF Kranick, Sarah M. Moore, James W. Yusuf, Nadia Martinez, Valeria T. LaFaver, Kathrin Edwards, Mark J. Mehta, Arpan R. Collins, Phoebe Harrison, Neil A. Haggard, Patrick Hallett, Mark Voon, Valerie TI Action-effect binding is decreased in motor conversion disorder: Implications for sense of agency SO MOVEMENT DISORDERS LA English DT Article DE agency; action-effect binding; conversion disorder; psychogenic movement disorder; forward model ID VOLUNTARY ACTION; EXPERIENCE; AWARENESS; INTENTION AB The abnormal movements seen in motor conversion disorder are affected by distraction and entrainment, similar to voluntary movement. Unlike voluntary movement, however, patients lack a sense of control for the abnormal movements, a failure of self-agency. The action-effect binding paradigm has been used to quantify the sense of self-agency, because subjective contraction of time between an action and its effect only occurs if the patient feels that they are the agent responsible for the action. We used this paradigm, coupled with emotional stimuli, to investigate the sense of agency with voluntary movements in patients with motor conversion disorder. Twenty patients with motor conversion disorder and 20 age-matched and sex-matched healthy volunteers used a rotating clock to judge the time of their own voluntary key presses (action) and a subsequent auditory tone (effect) after they completed conditioning blocks in which high, medium, and low tones were coupled to images of happy, fearful, and neutral faces. The results replicated those produced previously: it was reported that an effect after a voluntary action occurred earlier, and the preceding action occurred later, compared with trials that used only key presses or tones. Patients had reduced overall binding scores relative to healthy volunteers, suggesting a reduced sense of agency. There was no effect of the emotional stimuli (faces) or other interaction effects. Healthy volunteers with subclinical depressive symptoms had higher overall binding scores. We demonstrate that patients with motor conversion disorder have decreased action-effect binding for normal voluntary movements compared with healthy volunteers, consistent with the greater experience of lack of control. (c) 2013 Movement Disorder Society C1 [Kranick, Sarah M.; Yusuf, Nadia; Martinez, Valeria T.; LaFaver, Kathrin; Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Moore, James W.; Haggard, Patrick] UCL, Inst Cognit Neurosci, London, England. [Moore, James W.] Univ London, Dept Psychol Goldsmiths, London, England. [Edwards, Mark J.] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London, England. [Mehta, Arpan R.] Univ Cambridge, Dept Clin Neurosci, Neurol Unit, Cambridge, England. [Harrison, Neil A.] Univ Sussex, Ctr Imaging Sci, Falmer, England. [Collins, Phoebe; Voon, Valerie] Univ Cambridge, Dept Psychiat, Cambridge, England. [Voon, Valerie] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England. RP Voon, V (reprint author), Addenbrookes Hosp, Dept Psychiat, Level E4,Box 189, Cambridge CB2 0QQ, England. EM voonval@gmail.com OI Harrison, Neil/0000-0002-9584-3769 FU National Institute of Neurological Disorders and Stroke Intramural Program FX This study was supported by the National Institute of Neurological Disorders and Stroke Intramural Program. Dr. Voon is a Wellcome Trust Intermediate Clinical Fellow. NR 19 TC 12 Z9 12 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 2013 VL 28 IS 8 BP 1110 EP 1116 DI 10.1002/mds.25408 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 198YS UT WOS:000322960800021 PM 23494975 ER PT J AU Brenchley, JM AF Brenchley, J. M. TI Mucosal immunity in human and simian immunodeficiency lentivirus infections SO MUCOSAL IMMUNOLOGY LA English DT Review ID T-CELL DEPLETION; VIRUS TYPE-1 INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; HIV-1 DISEASE PROGRESSION; DEFICIENCY SYNDROME AIDS; MICROBIAL TRANSLOCATION; ULCERATIVE-COLITIS; CROHNS-DISEASE; GASTROINTESTINAL MUCOSA; INTESTINAL INFLAMMATION AB Overwhelming evidence indicates that distinct pathological phenomenon occurs within the gastrointestinal (GI) tract of progressively simian immunodeficiency virus (SIV)-infected Asian macaques and HIV-infected humans compared with other anatomical sites. Massive loss of GI tract lamina propria CD4 T cells, alteration in the profile of lymphocytic cytokine production, changes in the landscape of GI tract antigen-presenting cells, and variations to the structural barrier of the GI tract are hallmarks of progressive HIV/SIV infections. The pathology within the GI tract results in translocation of microbial products from the lumen of the intestine into peripheral circulation. These translocated microbial products directly stimulate the immune system and exacerbate immune activation and, thus, disease progression. Initiation of combination antiretroviral therapy (cART) does not restore completely the immunological abnormalities within the GI tract. This incomplete restoration within the GI tract may contribute to the increased mortality observed within HIV-infected individuals treated for decades with cART. Novel therapeutic interventions aimed at enhancing GI tract anatomy and physiology may improve the prognosis of HIV-infected individuals. C1 [Brenchley, J. M.] NIAID, Program Tissue Immun & Repair, NIH, Bethesda, MD 20892 USA. [Brenchley, J. M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Brenchley, JM (reprint author), NIAID, Program Tissue Immun & Repair, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov FU NIAID, US NIH program FX I thank the Cleveland Immunopathogenesis Consortium (BBC) for helpful discussions. This work was supported by the Intramural NIAID, US NIH program. The content of this publication does not necessarily reflect the views or policies of DHHS, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US NR 114 TC 25 Z9 25 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JUL PY 2013 VL 6 IS 4 BP 657 EP 665 DI 10.1038/mi.2013.15 PG 9 WC Immunology SC Immunology GA 193CU UT WOS:000322535800001 PM 23549448 ER PT J AU Nakano, H Burgents, JE Nakano, K Whitehead, GS Cheong, C Bortner, CD Cook, DN AF Nakano, H. Burgents, J. E. Nakano, K. Whitehead, G. S. Cheong, C. Bortner, C. D. Cook, D. N. TI Migratory properties of pulmonary dendritic cells are determined by their developmental lineage SO MUCOSAL IMMUNOLOGY LA English DT Article ID STEADY-STATE CONDITIONS; BRONCHIAL LYMPH-NODE; INHALED ANTIGEN; BONE-MARROW; FLOW-CYTOMETRY; T-CELLS; IN-VIVO; LUNG; INFECTION; CHEMOKINE AB The chemokine receptor, CCR7, directs the migration of dendritic cells (DCs) from peripheral tissue to draining lymph nodes (LNs). However, it is unknown whether all pulmonary DCs possess migratory potential. Using novel Ccr7(gfp) reporter mice, wefound that Ccr7 is expressed in CD103(+) and a CD14(med/Io) subset of CD11b(hi) classical (c) DCs but not in monocyte-derived (mo) DCs, including Ly-6C(hi) CD11b(hi) inflammatory DCs and CD14(hi) CD11b(hi) DCs. Consequently, cDCs migrated to lung-draining LNs but moDCs did not. Mice lacking the chemokine receptor, CCR2, also lacked inflammatory DCs in the lung after lipopolysaccharide inhalation but retained normal levels of migratory DCs. Conversely, the lungs of fms-like tyrosine kinase 3 ligand (Flt3L)-deficient mice lacked cDCs but retained moDCs, which were functionally mature but did not express Ccr7 and were uniformly non-migratory. Thus, the migratory properties of pulmonary DCs are determined by their developmental lineage. C1 [Nakano, H.; Burgents, J. E.; Nakano, K.; Whitehead, G. S.; Cook, D. N.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Cheong, C.] Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10021 USA. [Cheong, C.] Rockefeller Univ, Chris Browne Ctr Immunol & Immune Dis, New York, NY 10021 USA. [Bortner, C. D.] NIEHS, Lab Signal Transduct, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Cook, DN (reprint author), NIEHS, Lab Resp Biol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM cookd@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences FX We thank Maria Sifre for help with flow cytometry, Ligon Perrow for support with animal experiments, and Michael Fessler and Kym Gowdy (NIEHS) for critical reading of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. NR 47 TC 17 Z9 17 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD JUL PY 2013 VL 6 IS 4 BP 678 EP 691 DI 10.1038/mi.2012.106 PG 14 WC Immunology SC Immunology GA 193CU UT WOS:000322535800003 PM 23168837 ER PT J AU Rosen, CJ Taylor, CL AF Rosen, Clifford J. Taylor, Christine L. TI Common misconceptions about vitamin D-implications for clinicians SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Article ID D SUPPLEMENTATION; D DEFICIENCY; PREECLAMPSIA; PREVENTION; WOMEN; RISK; FRACTURES; CALCIUM; HEALTH AB Misconceptions about vitamin D continue to grow despite publications in the past few years that have attempted to clarify risk. We present our perspective, and offer several conclusions. Calcium and vitamin D supplementation can reduce fracture risk by similar to 10%. On the other hand, little evidence exists to support a threshold measure for vitamin D status (serum levels of 25-hydroxyvitamin D) above which fractures are reduced. The association of serum concentrations of 25-hydroxyvitamin D with other chronic diseases is confounded by multiple factors and conflicting outcomes that cannot be used to support a causal association. High doses of vitamin D supplements might not be completely harmless and should be avoided until additional data becomes available. Similarly, scant rationale exists for aggressive vitamin D supplementation for pregnant or lactating women. Dispelling misconceptions about vitamin D will ultimately benefit health-care providers and patients alike. C1 [Rosen, Clifford J.] Maine Med Ctr, Res Inst, Scarborough, ME 04074 USA. [Taylor, Christine L.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Rosen, CJ (reprint author), Maine Med Ctr, Res Inst, 81 Res Dr, Scarborough, ME 04074 USA. EM crofen@gmail.com NR 26 TC 13 Z9 13 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 EI 1759-5037 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD JUL PY 2013 VL 9 IS 7 BP 434 EP 438 DI 10.1038/nrendo.2013.75 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 170LJ UT WOS:000320851700013 PM 23609334 ER PT J AU Lev, O Wilfond, BS McBride, CM AF Lev, Ori Wilfond, Benjamin S. McBride, Colleen M. TI Enhancing Children against Unhealthy Behaviors-An Ethical and Policy Assessment of Using a Nicotine Vaccine SO PUBLIC HEALTH ETHICS LA English DT Article ID UNITED-STATES; CONJUGATE VACCINE; SMOKING; ENHANCEMENT; DEPENDENCE; CHILDHOOD; PROGRAM; OBESITY; HPV AB Health behaviors such as tobacco use contribute significantly to poor health. It is widely recognized that efforts to prevent poor health outcomes should begin in early childhood. Biomedical enhancements, such as a nicotine vaccine, are now emerging and have potential to be used for primary prevention of common diseases. In anticipation of such enhancements, it is important that we begin to consider the ethical and policy appropriateness of their use with children. The main ethical concerns raised by enhancing children relate to their impact on children's well-being and autonomy. These concerns are significant, however they do not appear to apply in the case of the nicotine vaccine; indeed the vaccine could even further these goals for children. Nevertheless, concerns about broadly applying this enhancement may be more challenging. The vaccine may be less cost-effective than alternative public efforts to prevent tobacco use, utilizing it could distract from addressing the foundational causes of smoking and it might not be publically acceptable. Empirical research about these concerns is needed to ascertain their likelihood and impact as well as how they could be minimized. This research could help determine whether behavior-related enhancements hold promise for improving children's health. C1 [Lev, Ori] Sapir Acad Coll, IL-79165 Dn Ashkelon, Israel. [Wilfond, Benjamin S.] Seattle Childrens Hosp, Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Wilfond, Benjamin S.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [McBride, Colleen M.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Lev, O (reprint author), Sapir Acad Coll, Dept Publ Policy & Adm, IL-79165 Dn Ashkelon, Israel. EM orilev22@mail.sapir.ac.il FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; National Center for Advancing Translational Sciences [UL1TR000423]; Center for Genomics and Health Care Equality, National Human Genome Research Institute [P50HG003374] FX The Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (grants to O.L. and C.M.); National Center for Advancing Translational Sciences (grant no. UL1TR000423 to B.W.); the Center for Genomics and Health Care Equality, National Human Genome Research Institute (grant no. P50HG003374 to B.W.). NR 42 TC 2 Z9 2 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1754-9973 J9 PUBLIC HEALTH ETH-UK JI Public Health Ethics PD JUL PY 2013 VL 6 IS 2 BP 197 EP 206 DI 10.1093/phe/pht006 PG 10 WC Ethics; Public, Environmental & Occupational Health; Medical Ethics SC Social Sciences - Other Topics; Public, Environmental & Occupational Health; Medical Ethics GA 196BU UT WOS:000322749200006 ER PT J AU Conde-Agudelo, A Nieto, A Rosas-Bermudez, A Romero, R AF Conde-Agudelo, Agustin Nieto, Anibal Rosas-Bermudez, Anyeli Romero, Roberto TI Misoprostol to reduce intraoperative and postoperative hemorrhage during cesarean delivery: a systematic review and metaanalysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE blood loss; oxytocin; postpartum hemorrhage; pregnancy; uterotonics ID POSTPARTUM HEMORRHAGE; BLOOD-LOSS; SUBLINGUAL MISOPROSTOL; RECTAL MISOPROSTOL; INTRAVENOUS OXYTOCIN; INTESTINAL MOTILITY; VAGINAL DELIVERY; ORAL MISOPROSTOL; CONTROLLED TRIAL; RISK-FACTORS AB OBJECTIVE: To evaluate the efficacy and safety of prophylactic misoprostol use at cesarean delivery for reducing intraoperative and postoperative hemorrhage. STUDY DESIGN: Systematic review and metaanalysis of randomized controlled trials. RESULTS: Seventeen studies (3174 women) were included of which 7 evaluated misoprostol vs oxytocin and 8 evaluated misoprostol plus oxytocin vs oxytocin alone. Overall, there were no significant differences in intraoperative and postoperative hemorrhage between sublingual or oral misoprostol and oxytocin. Rectal misoprostol, compared with oxytocin, was associated with a significant reduction in intraoperative and postoperative hemorrhage. The combined use of sublingual misoprostol and oxytocin, compared with the use of oxytocin alone, was associated with a significant reduction in the mean decrease in hematocrit (mean difference, -2.1%; 95% confidence interval, -3.4 to -0.8) and use of additional uterotonic agents (relative risk, 0.33; 95% confidence interval, 0.18-0.62). Compared with oxytocin alone, buccal misoprostol plus oxytocin reduced the use of additional uterotonic agents; rectal misoprostol plus oxytocin decreased intraoperative and postoperative blood loss, mean fall in hematocrit, and use of additional uterotonic agents; and intrauterine misoprostol plus oxytocin reduced the mean fall in hemoglobin and hematocrit. Women receiving misoprostol, alone or combined with oxytocin, had a higher risk of shivering and pyrexia. CONCLUSION: Misoprostol combined with oxytocin appears to be more effective than oxytocin alone in reducing intraoperative and postoperative hemorrhage during cesarean section. There were no significant differences in intraoperative and postoperative hemorrhage when misoprostol was compared to oxytocin. However, these findings were based on a few trials with methodological limitations. C1 [Conde-Agudelo, Agustin] Eunice Kennedy Shriver NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Conde-Agudelo, Agustin] Eunice Kennedy Shriver NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. [Nieto, Anibal] Univ Murcia, Dept Obstet & Gynecol, Murcia, Spain. [Rosas-Bermudez, Anyeli] Univ Valle, World Hlth Org Collaborating Ctr Human Reprod, Cali, Colombia. RP Conde-Agudelo, A (reprint author), Eunice Kennedy Shriver NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX This research was supported, in part, by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 66 TC 0 Z9 1 U1 2 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JUL PY 2013 VL 209 IS 1 AR 40.e1 DI 10.1016/j.ajog.2013.03.015 PG 17 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 181XL UT WOS:000321703700014 PM 23507545 ER PT J AU Groft, SC AF Groft, Stephen C. TI Rare Diseases Research Expanding Collaborative Translational Research Opportunities SO CHEST LA English DT Article ID CLINICAL-RESEARCH; REGISTRY AB Extensive public-private partnerships, including the National Institutes of Health (NIH) and the rare diseases community, which is seeing a renewed industry interest in smaller niche markets, have resulted in an increase of interventions for rare diseases. Significant collaborative efforts are required among the pharmaceutical industry, foundations, patient-advocacy groups, academic and government investigators and funding programs, regulatory scientists, and reimbursement agencies to meet the unmet diagnostic and treatment needs for approximately 25 million people in the United States with 7,000 rare diseases. The expanding role and outreach activities of patient-advocacy groups have increased public awareness. In the United States, a rare disease is defined as a disorder or condition with a prevalence of <200,000 people. In 2011, the NIH provided >$3.5 billion for rare diseases research, including $750 million for orphan product development activities, nearly 11.4% of the NIH research budget. Several research institutes and centers of the NIH, including the National Center for Advancing Translational Sciences, have initiated varied translational research efforts to address the absence of preclinical and clinical data required for regulatory review purposes. Clinicians can expect to see significant increases in requests from patients and their families to participate in patient registries and natural history or observational studies to gather specific information from a larger pool of patients on the progression of the disease or response to treatments. An expanding emphasis on rare diseases provides hope for the millions of patients with rare diseases. C1 NIH, Off Rare Dis Res, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Groft, SC (reprint author), NIH, Off Rare Dis Res, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. EM Stephen.Groft@nih.gov NR 18 TC 9 Z9 9 U1 1 U2 13 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 2013 VL 144 IS 1 BP 16 EP 23 DI 10.1378/chest.13-0606 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 180OW UT WOS:000321605500008 PM 23880676 ER PT J AU Grau, M Barr, RG Lima, JA Hoffman, EA Bluemke, DA Carr, JJ Chahal, H Enright, PL Jain, A Prince, MR Kawut, SM AF Grau, Maria Barr, R. Graham Lima, Joao A. Hoffman, Eric A. Bluemke, David A. Carr, J. Jeffrey Chahal, Harjit Enright, Paul L. Jain, Aditya Prince, Martin R. Kawut, Steven M. TI Percent Emphysema and Right Ventricular Structure and Function The Multi-Ethnic Study of Atherosclerosis-Lung and Multi-Ethnic Study of Atherosclerosis-Right Ventricle Studies SO CHEST LA English DT Article ID AIR-FLOW OBSTRUCTION; PULMONARY BLOOD-FLOW; QUANTIFIED EMPHYSEMA; FUNCTION DECLINE; COR-PULMONALE; CARDIAC CT; COPD; SMOKERS; DISEASE; SEX AB Background: Severe COPD can lead to cor pulmonale and emphysema and is associated with impaired left ventricular (LV) filling. We evaluated whether emphysema and airflow obstruction would be associated with changes in right ventricular (RV) structure and function and whether these associations would differ by smoking status. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac MRI on 5,098 participants without clinical cardiovascular disease aged 45 to 84 years. RV and emphysema measures were available for 4,188 participants. Percent emphysema was defined as the percentage of voxels below -910 Hounsfield units in the lung windows on cardiac CT scans. Generalized additive models were used to control for confounders and adjust for respective LV parameters. Results: Participants consisted of 13% current smokers, 36% former smokers, and 52% never smokers. Percent emphysema was inversely associated with RV end-diastolic volume, stroke volume, cardiac output, and mass prior to adjustment for LV measures. After adjustment for LV end-diastolic volume, greater percent emphysema was associated with greater RV end-diastolic volume (+1.5 mL, P=.03) among current smokers, smaller RV end-diastolic volume (-0.8 mL, P=.02) among former smokers, and similar changes among never smokers. Conclusions: Percent emphysema was associated with smaller RV volumes and lower mass. The relationship of emphysema to cardiac function is complex but likely involves increased pulmonary vascular resistance, predominantly with reduced cardiac output, pulmonary hyperinflation, and accelerated cardiopulmonary aging. C1 [Grau, Maria; Barr, R. Graham] Columbia Univ, Med Ctr, Dept Med, New York, NY 10032 USA. [Barr, R. Graham] Columbia Univ, Med Ctr, Dept Epidemiol, New York, NY 10032 USA. [Prince, Martin R.] Columbia Univ, Med Ctr, Dept Radiol, New York, NY 10032 USA. [Lima, Joao A.; Chahal, Harjit; Jain, Aditya] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Hoffman, Eric A.] Univ Iowa, Iowa City, IA USA. [Carr, J. Jeffrey] Wake Forest Univ, Winston Salem, NC 27109 USA. [Enright, Paul L.] Univ Arizona, Tucson, AZ USA. [Kawut, Steven M.] Univ Penn, Dept Med, Penn Cardiovasc Inst, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Grau, Maria] Hosp del Mar, Med Res Inst IMIM, Cardiovasc Epidemiol & Genet Grp, Barcelona, Spain. RP Barr, RG (reprint author), Columbia Univ, Med Ctr, Dept Med, 630 W 168th St,PH 9 E Room 105, New York, NY 10032 USA. EM rgb9@columbia.edu RI Grau, Maria/H-5572-2011; Carr, John/A-1938-2012; Prince, Martin/S-6850-2016; OI Grau, Maria/0000-0003-2807-8136; Prince, Martin/0000-0002-9883-0584; Carr, John/0000-0002-4398-8237; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-95159-N01-HC-95169, R01 HL077612, R01 HL086719, R01 HL075476, RC1 HL100543]; NHLBI [K24 HL103844]; Health Institute Carlos III-FEDER, Spain [Red HERACLES RD06/0009, CM08/00141, CP12/03287] FX The MESA, MESA-Lung, and MESA-Right Ventricle Studies are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) [Contracts N01-HC-95159-N01-HC-95169 and Grants R01 HL077612, R01 HL086719, R01 HL075476, and RC1 HL100543] in collaboration with the MESA, MESA-Lung, and MESA-Right Ventricle investigators. Dr Kawut was supported by the NHLBI [K24 HL103844]. Dr Grau was funded by grants from Health Institute Carlos III-FEDER, Spain [Red HERACLES RD06/0009, CM08/00141, and CP12/03287]. NR 32 TC 26 Z9 27 U1 1 U2 4 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 2013 VL 144 IS 1 BP 136 EP 144 DI 10.1378/chest.12-1779 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 180OW UT WOS:000321605500023 PM 23450302 ER PT J AU Edwards, E Mischoulon, D Rapaport, M Stussman, B Weber, W AF Edwards, Emmeline Mischoulon, David Rapaport, Mark Stussman, Barbara Weber, Wendy TI Building an Evidence Base in Complementary and Integrative Healthcare for Child and Adolescent Psychiatry SO CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Complementary medicine; Integrative medicine; Mind and body; Natural products; Child and adolescent psychiatry; Manipulative therapies; CAM research; Epidemiology ID MAJOR DEPRESSIVE DISORDER; ALTERNATIVE MEDICINE; HERBAL MEDICINE; UNITED-STATES; THERAPY; AUTISM; ACUPUNCTURE; PATTERNS; MEDICATIONS; INFANTS AB Complementary and integrative strategies are widely used by families with children who have mental health diagnoses. The therapies used by these children include herbs, dietary supplements, massage, acupuncture, meditation, and naturopathy. The literature on efficacy of complementary and alternative approaches is of limited value, and studies are needed to test efficacy and safety. Interpretation of complementary and integrative health care studies for symptomatic management of mental health conditions is hampered by study design and methodological limitations. Well-designed, adequately powered, and suitably controlled clinical trials on promising complementary and integrative modalities are needed for children and adolescents with psychiatric conditions. C1 [Edwards, Emmeline; Weber, Wendy] NIH, Div Extramural Res, NCCAM, Bethesda, MD 20892 USA. [Mischoulon, David] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Rapaport, Mark] Emory Univ, Dept Psychiat & Behav Sci, Sch Med, Atlanta, GA 30322 USA. [Stussman, Barbara] NIH, NCCAM, Bethesda, MD 20892 USA. RP Edwards, E (reprint author), NIH, Div Extramural Res, NCCAM, 6707 Democracy Blvd,Suite 401, Bethesda, MD 20892 USA. EM edwardse@mail.nih.gov FU Intramural NIH HHS [Z99 AT999999] NR 60 TC 0 Z9 0 U1 3 U2 16 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 J9 CHILD ADOL PSYCH CL JI Child Adolesc. Psychiatr. N. Am. PD JUL PY 2013 VL 22 IS 3 BP 509 EP + DI 10.1016/j.chc.2013.03.007 PG 22 WC Psychiatry SC Psychiatry GA 194BP UT WOS:000322606300009 PM 23806317 ER PT J AU Boshoff, H Tahlan, K AF Boshoff, H. Tahlan, K. TI SQ-109 Treatment of Tuberculosis Cell Wall Biosynthesis Inhibitor SO DRUGS OF THE FUTURE LA English DT Article DE Mycobacterium tuberculosis; Tuberculosis; HIV infection; Cell wall biosynthesis; SQ-109 ID MULTIDRUG-RESISTANT TUBERCULOSIS; KILL MYCOBACTERIUM-TUBERCULOSIS; IN-VITRO; ANTITUBERCULAR DRUG; SQ109; ETHAMBUTOL; CANDIDATES; DIAMINE; IDENTIFICATION; DERIVATIVES AB Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is the second leading cause of mortality worldwide due to an infectious agent following the human immunodeficiency virus (HIV). Co-infection with M. tuberculosis and HIV, and the emergence of drug-resistant forms of the disease, make the treatment of TB challenging and almost impossible in some cases. There has been great momentum for identifying and developing new agents for the treatment of TB, and SQ-109 is one such candidate currently under clinical development. SQ-109 inhibits cell wall biosynthesis in M. tuberculosis by a mechanism distinct from that of currently used first-line anti-TB drugs, and most importantly, it shows favorable interactions when used in combination with other approved drugs or those currently under development. SQ-109 accumulates in the lungs and spleens of test animals, is active against drug-resistant TB and is well tolerated at sufficient dosing in humans for further clinical development. This review discusses the strategies used for the chemical synthesis of SQ-109, its initial discovery and development, and concludes by providing a summary of some of the clinical trials already conducted or undergoing planning, to assess the safety and efficacy SQ-109 in humans. C1 [Boshoff, H.] NIH, TB Res Sect, Bethesda, MD 20892 USA. [Tahlan, K.] Mem Univ Newfoundland & Labrador, Dept Biol, St John, NF, Canada. RP Boshoff, H (reprint author), NIH, TB Res Sect, Rm 2W20G,Bldg 33,9000 Rockville Pike, Bethesda, MD 20892 USA. FU Intramural Research Program of the NIAID, NIH FX This work was funded in part by the Intramural Research Program of the NIAID, NIH. NR 44 TC 2 Z9 2 U1 2 U2 15 PU PROUS SCIENCE, SAU-THOMSON REUTERS PI BARCELONA PA 398 PROVENCA, 08025 BARCELONA, SPAIN SN 0377-8282 J9 DRUG FUTURE JI Drug Future PD JUL PY 2013 VL 38 IS 7 BP 467 EP 474 DI 10.1358/dof.2013.38.7.1970867 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 196KO UT WOS:000322773800003 ER PT J AU Kuniholm, MH Anastos, K Kovacs, A Gao, X Marti, D Sette, A Greenblatt, RM Peters, M Cohen, MH Minkoff, H Gange, SJ Thio, CL Young, MA Xue, X Carrington, M Strickler, HD AF Kuniholm, M. H. Anastos, K. Kovacs, A. Gao, X. Marti, D. Sette, A. Greenblatt, R. M. Peters, M. Cohen, M. H. Minkoff, H. Gange, S. J. Thio, C. L. Young, M. A. Xue, X. Carrington, M. Strickler, H. D. TI Relation of HLA class I and II supertypes with spontaneous clearance of hepatitis C virus SO GENES AND IMMUNITY LA English DT Article DE hepatitis C virus; human leukocyte antigen; supertype ID ANTIGEN CLASS-I; AFRICAN-AMERICANS; MHC SUPERTYPES; INFECTION; IDENTIFICATION; ALLELES; DEFINITION; MOLECULES AB Human leukocyte antigen (HLA) genotype has been associated with the probability of spontaneous clearance of hepatitis C virus (HCV). However, no prior studies have examined whether this relationship may be further characterized by grouping HLA alleles according to their supertypes, defined by their binding capacities. There is debate regarding the most appropriate method to define supertypes. Therefore, previously reported HLA supertypes (46 class I and 25 class II) were assessed for their relation with HCV clearance in a population of 758 HCV-seropositive women. Two HLA class II supertypes were significant in multivariable models that included: (i) supertypes with significant or borderline associations with HCV clearance after adjustment for multiple tests, and (ii) individual HLA alleles not part of these supertypes, but associated with HCV clearance in our prior study in this population. Specifically, supertype DRB3 (prevalence ratio (PR) = 0.4; P = 0.004) was associated with HCV persistence, whereas DR8 (PR = 1.8; P = 0.01) was associated with HCV clearance. Two individual alleles (B*57:01 and C*01:02) associated with HCV clearance in our prior study became nonsignificant in analysis that included supertypes, whereas B*57:03 (PR = 1.9; P = 0.008) and DRB1*07:01 (PR = 1.7; P = 0.005) retained their significance. These data provide epidemiologic support for the significance of HLA supertypes in relation to HCV clearance. C1 [Kuniholm, M. H.; Anastos, K.; Xue, X.; Strickler, H. D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Anastos, K.] Montefiore Med Ctr, Dept Med, Bronx, NY 10467 USA. [Kovacs, A.] Univ So Calif, Dept Pediat, Los Angeles, CA 90089 USA. [Gao, X.; Marti, D.; Carrington, M.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Gao, X.; Carrington, M.] MIT & Harvard, Ragon Inst, Charlestown, MA USA. [Sette, A.] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA USA. [Greenblatt, R. M.] Univ Calif San Francisco, Dept Clin Pharm, San Francisco, CA 94143 USA. [Peters, M.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Cohen, M. H.] Cook Cty Bur Hlth Serv, CORE Ctr, Chicago, IL USA. [Minkoff, H.] Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. [Gange, S. J.] Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. [Thio, C. L.] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Young, M. A.] Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. RP Kuniholm, MH (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Belfer Bldg,Room 1308C,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM mark.kuniholm@einstein.yu.edu OI Gange, Stephen/0000-0001-7842-512X FU National Center for Research Resources CTSA [UL1RR025750, KL2RR025749, TL1RR025748]; National Institute of Allergy and Infectious Diseases [R01A1052065, 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, the National Institutes of Health [HHSN261200800001E]; NIH, Frederick National Laboratory, Center for Cancer Research; Einstein-Montefiore Center for AIDS Research [5P30AI051519-08]; [R01AI057006] FX Funding for the current project was provided in part by R01AI057006 (HDS) in addition to the National Center for Research Resources CTSA grants UL1RR025750, KL2RR025749 and TL1RR025748, and from the National Institute of Allergy and Infectious Diseases grant R01A1052065 (AAK). Clinical data and specimens used in this study were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (principal investigators) at New York City/Bronx Consortium (KA); Brooklyn, NY (HM); Washington DC, Metropolitan Consortium (MY); The Connie Wofsy Study Consortium of Northern California (RG); Los Angeles County/Southern California Consortium (AL); Chicago Consortium (MC); Data Coordinating Center (SG). 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 co-funded 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, the National Institutes of Health under Contract No. HHSN261200800001E. This research was also supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research and by the Einstein-Montefiore Center for AIDS Research (5P30AI051519-08). NR 36 TC 5 Z9 5 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD JUL-AUG PY 2013 VL 14 IS 5 BP 330 EP 335 DI 10.1038/gene.2013.25 PG 6 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 190FO UT WOS:000322325000008 PM 23636221 ER PT J AU Townsley, DM Desmond, R Dunbar, CE Young, NS AF Townsley, Danielle M. Desmond, Ronan Dunbar, Cynthia E. Young, Neal S. TI Pathophysiology and management of thrombocytopenia in bone marrow failure: possible clinical applications of TPO receptor agonists in aplastic anemia and myelodysplastic syndromes SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Article DE Aplastic anemia; Eltrombopag; Thrombopoietin (TPO) mimetics; Bone marrow failure; Thrombocytopenia; Myelodysplastic syndromes (MDS) ID HEMATOPOIETIC GROWTH-FACTORS; COLONY-STIMULATING FACTOR; C-MPL LIGAND; HEALTHY-VOLUNTEERS; SUPPORTIVE CARE; MICE LACKING; STEM-CELLS; THROMBOPOIETIN; INTERMEDIATE; ROMIPLOSTIM AB Aplastic anemia is a bone marrow failure syndrome that causes pancytopenia and can lead to life-threatening complications. Bone marrow transplantation remains the standard of care for younger patients and those with a good performance status but many patients may not have a suitable donor. Immunosuppressive therapy is able to resolve cytopenias in a majority of patients with aplastic anemia but relapses are not uncommon and some patients remain refractory to this approach. Patients may require frequent blood and platelet transfusion support which is expensive and inconvenient. Life-threatening bleeding complications still occur despite prophylactic platelet transfusion. Thrombopoietin (TPO) mimetics, such as romiplostim and eltrombopag, were developed to treat patients with refractory immune thrombocytopenia but are now being investigated for the treatment of bone marrow failure syndromes. TPO is the main regulator for platelet production and its receptor (c-Mpl) is present on megakaryocytes and hematopoietic stem cells. Trilineage hematopoietic responses were observed in a recent clinical trial using eltrombopag in patients with severe aplastic anemia refractory to immunosuppression suggesting that these agents can provide a new therapeutic option for enhancing blood production. In this review, we discuss these recent results and ongoing investigation of TPO mimetics for aplastic anemia and other bone marrow failure states like myelodysplastic syndromes. Clonal evolution or progression to acute myeloid leukemia remains a concern when using these drugs in bone marrow failure and patients should only be treated in the setting of a clinical trial. C1 [Townsley, Danielle M.; Desmond, Ronan; Dunbar, Cynthia E.; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Townsley, DM (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,CRC 3-5140, Bethesda, MD 20892 USA. EM townsleydm@nhlbi.nih.gov FU Intramural NIH HHS [ZIA HL002315-31] NR 54 TC 9 Z9 11 U1 2 U2 9 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 0925-5710 J9 INT J HEMATOL JI Int. J. Hematol. PD JUL PY 2013 VL 98 IS 1 BP 48 EP 55 DI 10.1007/s12185-013-1352-6 PG 8 WC Hematology SC Hematology GA 182UF UT WOS:000321769400009 PM 23690288 ER PT J AU Li, LJ Khan, N Hurd, T Ghosh, AK Cheng, C Molday, R Heckenlively, JR Swaroop, A Khanna, H AF Li, Linjing Khan, Naheed Hurd, Toby Ghosh, Amiya Kumar Cheng, Christiana Molday, Robert Heckenlively, John R. Swaroop, Anand Khanna, Hemant TI Ablation of the X-Linked Retinitis Pigmentosa 2 (Rp2) Gene in Mice Results in Opsin Mislocalization and Photoreceptor Degeneration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE Rp2; retina; photoreceptor ID PROTEIN RP2; RETINAL DEGENERATION; OUTER SEGMENTS; RETINITIS-PIGMENTOSA-2 PROTEIN; MUTATION ANALYSIS; PRIMARY CILIUM; COLOR-VISION; COFACTOR-C; MOUSE; RPGR AB PURPOSE. Mutations in the RP2 gene are associated with 10% to 15% of X-linked retinitis pigmentosa (XLRP), a debilitating disorder characterized by the degeneration of retinal rod and cone photoreceptors. The molecular mechanism of pathogenesis of photoreceptor degeneration in XLRP-RP2 has not been elucidated, and no treatment is currently available. This study was undertaken to investigate the pathogenesis of RP2-associated retinal degeneration. METHODS. We introduced loxP sites that flank exon 2, a mutational hotspot in XLRP-RP2, in the mouse Rp2 gene. We then produced Rp2-null allele using transgenic mice that expressed Cre-recombinase under control of the ubiquitous CAG promoter. Electroretinography (ERG), histology, light microscopy, transmission electron microscopy, and immunofluorescence microscopy were performed to ascertain the effect of ablation of Rp2 on photoreceptor development, function, and protein trafficking. RESULTS. Although no gross abnormalities were detected in the Rp2(null) mice, photopic (cone) and scotopic (rod) function as measured by ERG showed a gradual decline starting as early as 1 month of age. We also detected slow progressive degeneration of the photoreceptor membrane discs in the mutant retina. These defects were associated with mislocalization of cone opsins to the nuclear and synaptic layers and reduced rhodopsin content in the outer segment of mutant retina prior to the onset of photoreceptor degeneration. CONCLUSIONS. Our studies suggest that RP2 contributes to the maintenance of photoreceptor function and that cone opsin mislocalization represents an early step in XLRP caused by RP2 mutations. The Rp2(null) mice should serve as a useful preclinical model for testing gene-and cell-based therapies. C1 [Li, Linjing; Khanna, Hemant] Univ Massachusetts, Sch Med, Dept Ophthalmol, Worcester, MA 01605 USA. [Khan, Naheed; Ghosh, Amiya Kumar; Heckenlively, John R.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Hurd, Toby] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Cheng, Christiana; Molday, Robert] Univ British Columbia, Ctr Macular Res, Dept Biochem & Mol Biol, Vancouver, BC V5Z 1M9, Canada. [Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Khanna, H (reprint author), Univ Massachusetts, Sch Med, Dept Ophthalmol, 368 Plantat St,AS6-2043, Worcester, MA 01605 USA. EM swaroopa@nei.nih.gov; hemant.khanna@umassmed.edu OI Swaroop, Anand/0000-0002-1975-1141 FU National Eye Institute (NEI)/National Institutes of Health [EY022372]; Foundation Fighting Blindness (FFB); Worcester Foundation; Canadian Institutes of Health Research (CIHR)/FFB [CIHR RMF-92101]; Intramural Research Program at NEI FX Supported by National Eye Institute (NEI)/National Institutes of Health Grant EY022372; Foundation Fighting Blindness (FFB); Worcester Foundation; Canadian Institutes of Health Research (CIHR)/FFB (CIHR RMF-92101); and the Intramural Research Program at NEI. NR 42 TC 20 Z9 20 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2013 VL 54 IS 7 BP 4503 EP 4511 DI 10.1167/iovs.13-12140 PG 9 WC Ophthalmology SC Ophthalmology GA 194MI UT WOS:000322637000013 PM 23745007 ER PT J AU Danis, RP Domalpally, A Chew, EY Clemons, TE Armstrong, J SanGiovanni, JP Ferris, FL AF Danis, Ronald P. Domalpally, Amitha Chew, Emily Y. Clemons, Traci E. Armstrong, Jane SanGiovanni, John Paul Ferris, Frederick L., III CA AREDS2 Study Grp TI Methods and Reproducibility of Grading Optimized Digital Color Fundus Photographs in the Age-Related Eye Disease Study 2 (AREDS2 Report Number 2) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE color photographic imaging; AMD; reproducibility ID OPTICAL COHERENCE TOMOGRAPHY; DIABETIC MACULAR EDEMA; AUTOFLUORESCENCE PATTERNS; GEOGRAPHIC ATROPHY; SEVERITY SCALE; CLINICAL-TRIAL; DEGENERATION; DRUSEN; FILM; CLASSIFICATION AB PURPOSE. To establish continuity with the grading procedures and outcomes from the historical data of the Age-Related Eye Disease Study (AREDS), color photographic imaging and evaluation procedures for the assessment of age-related macular degeneration (AMD) were modified for digital imaging in the AREDS2. The reproducibility of the grading of index AMD lesion components and for the AREDS severity scale was tested at the AREDS2 reading center. METHODS. Digital color stereoscopic fundus photographs from 4203 AREDS2 subjects collected at baseline and annual follow-up visits were optimized for tonal balance and graded according to a standard protocol slightly modified from AREDS. The reproducibility of digital grading of AREDS2 images was assessed by reproducibility exercises, temporal drift (regrading a subset of baseline annually, n = 88), and contemporaneous masked regrading (ongoing, monthly regrade on 5% of submissions, n = 1335 eyes). RESULTS. In AREDS2, 91% and 96% of images received replicate grades within two steps of the baseline value on the AREDS severity scale for temporal drift and contemporaneous assessment, respectively (weighted Kappa of 0.73 and 0.76). Historical data for temporal drift in replicate gradings on the AREDS film-based images were 88% within two steps (weighted Kappa 0.88). There was no difference in AREDS2-AREDS concordance for temporal drift (exact P = 0.57). CONCLUSIONS. Digital color grading has nearly the same reproducibility as historical film grading. There is substantial agreement for testing the predictive utility of the AREDS severity scale in AREDS2 as a clinical trial outcome. (ClinicalTrials.gov number, NCT00345176.) C1 [Danis, Ronald P.; Domalpally, Amitha; Armstrong, Jane] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI 53717 USA. [Chew, Emily Y.; SanGiovanni, John Paul; Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. RP Danis, RP (reprint author), Univ Wisconsin, Dept Ophthalmol & Visual Sci, 8010 Excelsior Dr, Madison, WI 53717 USA. EM rpdanis@wisc.edu RI Domalpally, Amitha/B-2367-2015; OI Klein, Ronald/0000-0002-4428-6237 FU National Eye Institute [HHS-N-260-2005-00007-C] FX Supported by National Eye Institute Grant HHS-N-260-2005-00007-C (TEC). NR 30 TC 18 Z9 18 U1 0 U2 47 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2013 VL 54 IS 7 BP 4548 EP 4554 DI 10.1167/iovs.13-11804 PG 7 WC Ophthalmology SC Ophthalmology GA 194MI UT WOS:000322637000018 PM 23620429 ER PT J AU Wright, CB Chrenek, MA Foster, SL Duncan, T Redmond, TM Pardue, MT Boatright, JH Nickerson, JM AF Wright, Charles B. Chrenek, Micah A. Foster, Stephanie L. Duncan, Todd Redmond, T. Michael Pardue, Machelle T. Boatright, Jeffrey H. Nickerson, John M. TI Complementation Test of Rpe65 Knockout and Tvrm148 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE RPE65/Rpe65; visual cycle; mutation ID LEBER CONGENITAL AMAUROSIS; PERFORMANCE LIQUID-CHROMATOGRAPHY; AMINO-ACID SUBSTITUTIONS; SUPPORT VECTOR MACHINES; MOUSE MODEL; PROTEIN FUNCTION; VISUAL CYCLE; ISOMEROHYDROLASE ACTIVITY; MISSENSE MUTATIONS; RETINAL DYSTROPHY AB PURPOSE. A mouse mutation, tvrm148, was previously reported as resulting in retinal degeneration. Tvrm148 and Rpe65 map between markers D3Mit147 and D3Mit19 on a genetic map, but the physical map places RPE65 outside the markers. We asked if Rpe65 or perhaps another nearby gene is mutated and if the mutant reduced 11-cis-retinal levels. We studied the impact of the tvrm148 mutation on visual function, morphology, and retinoid levels. METHODS. Normal phase HPLC was used to measure retinoid levels. Rpe65(+/+), tvrm148/+ (T+/-), tvrm148/ tvrm148 (T-/-), RPE65KO/KO (Rpe65(+/+)), and Rpe65(T/-) mice visual function was measured by optokinetic tracking (OKT) and electroretinography (ERG). Morphology was assessed by light microscopy and transmission electron microscopy (TEM). qRT-PCR was used to measure Rpe65 mRNA levels. Immunoblotting measured the size and amount of RPE65 protein. RESULTS. The knockout and tvrm148 alleles did not complement. No 11-cis-retinal was detected in T-/- or Rpe65(-/-) mice. Visual acuity in Rpe65(-/-) and T-/- mouse was similar to 0.382 c/d, but 0.037 c/d in T-/- mice at postnatal day 210 (P210). ERG response in T-/- mice was undetectable except at bright flash intensities. Outer nuclear layer (ONL) thickness in T-/- mice was similar to 70% of Rpe65(+/+) by P210. Rpe65 mRNA levels in T-/- mice were unchanged, yet 14.5% of Rpe65(+/+) protein levels was detected. Protein size was unchanged. CONCLUSIONS. A complementation test revealed the RPE65 knockout and tvrm148 alleles do not complement, proving that the tvrm148 mutation is in Rpe65. Behavioral, physiological, molecular, biochemical, and histological approaches indicate that tvrm148 is a null allele of Rpe65. C1 [Wright, Charles B.; Chrenek, Micah A.; Foster, Stephanie L.; Pardue, Machelle T.; Boatright, Jeffrey H.; Nickerson, John M.] Emory Univ, Dept Ophthalmol, Sch Med, Atlanta, GA 30322 USA. [Duncan, Todd; Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Pardue, Machelle T.] Atlanta VA Med Ctr, Rehabil Res & Dev Ctr Excellence, Decatur, GA USA. RP Nickerson, JM (reprint author), Emory Univ, Dept Ophthalmol, B5602,1365B Clifton Rd NE, Atlanta, GA 30322 USA. EM litjn@emory.edu OI Redmond, T. Michael/0000-0002-1813-5291 FU National Institutes of Health (NIH) [P30EY006360, R01EY016470, T32EY007092, R01EY014026, R01EY016435, R01EY021592]; Abraham J. & Phyllis Katz Foundation; Research to Prevent Blindness; Intramural Research Program of the National Eye Institute, NIH [Z01EY000444] FX Supported by National Institutes of Health (NIH) Grants P30EY006360, R01EY016470, T32EY007092, R01EY014026, R01EY016435, R01EY021592, and a grant from the Abraham J. & Phyllis Katz Foundation (JHB), an unrestricted Departmental Award from Research to Prevent Blindness, the Intramural Research Program of the National Eye Institute, NIH (Z01EY000444). The authors alone are responsible for the content and writing of the paper. NR 70 TC 6 Z9 6 U1 0 U2 7 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2013 VL 54 IS 7 BP 5111 EP 5122 DI 10.1167/iovs.13-12336 PG 12 WC Ophthalmology SC Ophthalmology GA 194MI UT WOS:000322637000088 PM 23778877 ER PT J AU Tice, JA OMeara, ES Weaver, DL Vachon, C Ballard-Barbash, R Kerlikowske, K AF Tice, Jeffrey A. OMeara, Ellen S. Weaver, Donald L. Vachon, Celine Ballard-Barbash, Rachel Kerlikowske, Karla TI Benign Breast Disease, Mammographic Breast Density, and the Risk of Breast Cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SCREENING MAMMOGRAPHY; ASSESSMENT MODELS; PREDICTION MODEL; WOMEN; LESIONS; TAMOXIFEN; CHEMOPREVENTION; INTEROBSERVER; VARIABILITY; PREVENTION AB Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk. We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided. Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR 5.34; 95% confidence interval [CI] 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR 1.37; 95% CI 1.11 to 1.69, P .003), high (HR 2.02; 95% CI 1.68 to 2.44, P < .001), or very high (HR 2.05; 95% CI 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs < 1) for all benign pathology diagnoses. Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis. C1 [Tice, Jeffrey A.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Gen Internal Med Sect, Dept Vet Affairs, Dept Med, San Francisco, CA 94143 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [OMeara, Ellen S.] Grp Hlth Res Inst, Seattle, WA USA. [Weaver, Donald L.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Weaver, Donald L.] Vermont Canc Ctr, Burlington, VT USA. [Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Tice, JA (reprint author), Univ Calif San Francisco, Dept Med, Div Gen Internal Med, 1545 Divisadero St,Ste 554, San Francisco, CA 94143 USA. EM jtice@medicine.ucsf.edu FU National Cancer Institute [P01CA154292]; Breast Cancer Surveillance Consortium [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, HHSN261201100031C]; [R01 CA140286] FX This work was supported by a National Cancer Institute-funded Program Project (P01CA154292), the Breast Cancer Surveillance Consortium (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, HHSN261201100031C), and the R01 CA140286. NR 43 TC 32 Z9 34 U1 1 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD JUL PY 2013 VL 105 IS 14 BP 1043 EP 1049 DI 10.1093/jnci/djt124 PG 7 WC Oncology SC Oncology GA 193OK UT WOS:000322569000011 PM 23744877 ER PT J AU Devine, K McCluskey, T Henne, M Armstrong, A Venkatesan, AM DeCherney, A AF Devine, Kate McCluskey, Tara Henne, Melinda Armstrong, Alicia Venkatesan, Aradhana M. DeCherney, Alan TI Is Magnetic Resonance Imaging Sufficient to Diagnose Rudimentary Uterine Horn? A Case Report and Review of the Literature SO JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY LA English DT Review DE Laparoscopy; Leiomyoma; Magnetic resonance imaging; Mullerian anomaly; Myomectomy; Unicornuate uterus ID MULLERIAN DUCT ANOMALIES; HYSTEROSALPINGOGRAPHY; ACCURACY; SONOHYSTEROGRAPHY; SONOGRAPHY AB Imaging is often part of the evaluation of gynecologic disorders, with transvaginal ultrasound being the most frequently used imaging modality. Although laparoscopy, hysterosalpingography, and hysteroscopy can add diagnostic accuracy, they are invasive and costly. Magnetic resonance imaging (MRI) has been increasingly used because it is both noninvasive and highly accurate. Although MRI is more expensive than ultrasound, it is less so than surgery. Given the demonstrated accuracy of MRI in assessing mullerian anomalies, additional imaging is not often sought once an MRI diagnosis is made. However, when imaging findings are not pathognomonic via MRI or otherwise, inaccurate diagnoses and their consequences may occur. We describe the case of a 21-year-old woman with unilateral dysmenorrhea whose MRI features suggested a unicornuate uterus with a hematometrous noncommunicating horn although laparoscopy ultimately revealed a necrotic myoma without an accompanying mullerian anomaly. Journal of Minimally Invasive Gynecology (2013) 20, 533-536 Published by Elsevier Inc. on behalf of AAGL. C1 [Devine, Kate; McCluskey, Tara; Henne, Melinda; Armstrong, Alicia; Venkatesan, Aradhana M.; DeCherney, Alan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Devine, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bldg 10,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM kate.devine@nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 12 TC 1 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1553-4650 J9 J MINIM INVAS GYN JI J. Mimim. Invasive Gynecol. PD JUL-AUG PY 2013 VL 20 IS 4 BP 533 EP 536 DI 10.1016/j.jmig.2013.01.012 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 196BL UT WOS:000322748300021 PM 23535077 ER PT J AU Lu, YY Dong, GL Gu, YX Ito, Y Wei, Y AF Lu, Yuanyuan Dong, Genlai Gu, Yanxiang Ito, Yoichiro Wei, Yun TI Separation of chlorogenic acid and concentration of trace caffeic acid from natural products by pH-zone-refining countercurrent chromatography SO JOURNAL OF SEPARATION SCIENCE LA English DT Article DE Caffeic acid; Chlorogenic acid; Flaveria bidentis (L.) Kuntze; Lonicerae; Flos; pH-zone-refining countercurrent chromatography ID BIDENTIS L. KUNTZE; PREPARATIVE SEPARATION; FLOS-LONICERAE AB Chlorogenic acid and caffeic acid were selected as test samples for separation by the pH-zone-refining countercurrent chromatography (CCC). The separation of these test samples was performed with a two-phase solvent system composed of methyl-tert-butyl-ether/acetonitrile/water at a volume ratio of 4:1:5 v/v/v where trifluoroacetic acid (TFA; 8 mM) was added to the organic stationary phase as a retainer and NH4OH (10 mM) to the aqueous mobile phase as an eluter. Chlorogenic acid was successfully separated from Flaveria bidentis (L.) Kuntze (F. bidentis) and Lonicerae Flos by pH-zone-refining CCC, a slightly polar two-phase solvent system composed of methyl-tert-butyl-ether/acetonitrile/n-butanol/water at a volume ratio of 4:1:1:5 v/v/v/v was selected where TFA (3 mM) was added to the organic stationary phase as a retainer and NH4OH (3 mM) to the aqueous mobile phase as an eluter. A 16.2 mg amount of chlorogenic acid with the purity of 92% from 1.4 g of F. bidentis, and 134 mg of chlorogenic acid at the purity of 99% from 1.3 g of crude extract of Lonicerae Flos have been obtained. These results suggest that pH-zone-refining CCC is suitable for the isolation of the chlorogenic acid from the crude extracts of F. bidentis and Lonicerae Flos. C1 [Lu, Yuanyuan; Dong, Genlai; Gu, Yanxiang; Wei, Yun] Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, Beijing 100029, Peoples R China. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Wei, Y (reprint author), Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, 15 Beisanhuan East Rd, Beijing 100029, Peoples R China. EM weiyun@mail.buct.edu.cn FU National Natural Science Foundation of China (NSFC) [21075007]; Program for New Century Excellent Talents in University [NCET-11-0563]; Special Fund for Agro-scientific Research in the Public Interest [200803022, 201103027]; Program for Changjiang Scholars and Innovative Research Team in University [PCSIRT1205] FX This work was supported by National Natural Science Foundation of China (NSFC, grant no. 21075007), Program for New Century Excellent Talents in University (NCET-11-0563), Special Fund for Agro-scientific Research in the Public Interest (project 200803022 and 201103027), and Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT1205). NR 19 TC 8 Z9 8 U1 4 U2 39 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1615-9306 EI 1615-9314 J9 J SEP SCI JI J. Sep. Sci. PD JUL PY 2013 VL 36 IS 13 BP 2210 EP 2215 DI 10.1002/jssc.201300260 PG 6 WC Chemistry, Analytical SC Chemistry GA 193NU UT WOS:000322567300020 PM 23625646 ER PT J AU Lukkahatai, N Majors, B Reddy, S Walitt, B Saligan, LN AF Lukkahatai, Nada Majors, Benjamin Reddy, Swarnalatha Walitt, Brian Saligan, Leorey N. TI Gene expression profiles of fatigued fibromyalgia patients with different categories of pain and catastrophizing: A preliminary report SO NURSING OUTLOOK LA English DT Article DE Catastrophizing; Fatigue; Fibromyalgia; Gene expression; Microarray; Pain AB Background: Fibromyalgia (FM) is a chronic condition characterized by diffused musculoskeletal pain and overwhelming fatigue. Purpose: To compare the gene expression profiles of fatigued FM women with different levels of pain and catastrophizing. Methods: Nine women with. FM enrolled in an active Medstar Research Institute protocol were included in the gene expression analyses of peripheral blood RNA via Affymetrix GeneChip Human Genome U133 Plus 2.0 array (Santa Clara, CA). Scores from Brief Pain Inventory, Pain Catastrophizing Scale, and Multidimensional Fatigue Inventory categorized the nine participants into pain (high, n = 3; low, n = 6) and catastrophizing groups (high, n = 5; low, n = 4). Discussion: Differential expression of 107 genes between the high and low pain groups and 139 genes between the high and low catastrophizing groups (over 2.0-fold change, p < .05) were observed. Network analyses showed interferon signaling and interferon regulatory activation factor pathways distinguished between the pain groups whereas dendritic cell maturation delineated between the catastrophizing groups. Conclusion: Findings provide preliminary evidence that specific physiological pathways may possibly delineate pain and catastrophizing mechanisms. Further investigation via the use of a larger and more homogenous sample is warranted. C1 [Lukkahatai, Nada; Majors, Benjamin; Reddy, Swarnalatha; Saligan, Leorey N.] NINR, NIH, Bethesda, MD 20892 USA. [Walitt, Brian] Washington Hosp Ctr, Medstar Res Inst, Washington, DC 20010 USA. RP Lukkahatai, N (reprint author), NINR, NIH, 9000 Rockville Pike,Bldg 10,Room 2-1339, Bethesda, MD 20892 USA. EM nada.dukkahatai@nih.gov RI Reddy, Swarna/G-5349-2013 FU NINR and from a Medstar grant FX This study is part of a collaborative activity of NINR and the MedStar Research Institute as approved by the Office of Human Subjects Research (OHSR) of the National Institutes of Health (OHSR IRB-Exempt #4966) and is funded in part by the Intramural Research Program of the NINR and from a Medstar grant. We would like to extend our gratitude to Joan K. Austin, PhD, RN, FAAN, for her guidance. NR 0 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 0029-6554 J9 NURS OUTLOOK JI Nurs. Outlook PD JUL-AUG PY 2013 VL 61 IS 4 BP 216 EP 224 DI 10.1016/j.outlook.2013.03.007 PG 9 WC Nursing SC Nursing GA 187UR UT WOS:000322147500005 PM 23684314 ER PT J AU Fojo, AT Bates, SE Chabner, BA AF Fojo, Antonio Tito Bates, Susan E. Chabner, Bruce A. TI Clinical Trial Results: Sharing Results, Speeding Discoveries SO ONCOLOGIST LA English DT Editorial Material C1 [Fojo, Antonio Tito; Bates, Susan E.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Chabner, Bruce A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Fojo, AT (reprint author), NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PD JUL PY 2013 VL 18 IS 7 BP 779 EP 779 PG 1 WC Oncology SC Oncology GA 192UE UT WOS:000322510100002 PM 23882019 ER PT J AU Madan, RA Tsang, KY Bilusic, M Vergati, M Poole, DJ Jochems, C Tucker, JA Schlom, J Giaccone, G Gulley, JL AF Madan, Ravi A. Tsang, Kwong-Yok Bilusic, Marijo Vergati, Matteo Poole, Diane J. Jochems, Caroline Tucker, Jo A. Schlom, Jeffrey Giaccone, Giuseppe Gulley, James L. TI Effect of Talactoferrin Alfa on the Immune System in Adults With Non-Small Cell Lung Cancer SO ONCOLOGIST LA English DT Article AB Background. Talactoferrin alfa (talactoferrin), an agent with immune-stimulating properties, has demonstrated safety and preliminary efficacy in clinical trials. Methods. Tenpatients (five males and five females) with stage IV non-small cell lung cancer (NSCLC) in a single-arm pilot study received orally administered talactoferrin (1.5 g, b.i.d.) for up to 24 weeks. Radiographic and immunologic studies were performed at baseline and at weeks 6 and 12. Circulating immune cells (natural killer cells [NKCs], CD4(+), CD8(+), and regulatory T cells) and systemic cytokine levels were measured to assess immune response. Results. Patients enrolled in the study had received a median of four prior chemotherapy regimens, and all patients were symptomatic. Talactoferrin was well tolerated, with no grade 3 or 4 toxicities. Median time to progression (TTP) and overall survival were 6 weeks and 14.5 weeks, respectively. The four patients with >= 9 weeks TTP had evidence of immunologic activity (three with increased NKC activity). Conclusions. The median of four previous chemotherapy regimens, with elevated levels of interleukin (IL) 6 and tumor necrosis factor-alfa in most patients, suggests these patients were poor candidates for immunotherapy. C1 [Madan, Ravi A.; Tsang, Kwong-Yok; Bilusic, Marijo; Vergati, Matteo; Poole, Diane J.; Jochems, Caroline; Tucker, Jo A.; Schlom, Jeffrey; Gulley, James L.] NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. [Madan, Ravi A.; Schlom, Jeffrey; Giaccone, Giuseppe; Gulley, James L.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Bilusic, Marijo] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Giaccone, Giuseppe] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Gulley, JL (reprint author), NCI, Bldg 10,Room 8B09, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016; Giaccone, Giuseppe/E-8297-2017 OI Gulley, James/0000-0002-6569-2912; Giaccone, Giuseppe/0000-0002-5023-7562 NR 4 TC 4 Z9 4 U1 0 U2 2 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PD JUL PY 2013 VL 18 IS 7 BP 821 EP 822 DI 10.1634/theoncologist.2013-0199 PG 2 WC Oncology SC Oncology GA 192UE UT WOS:000322510100010 PM 23847257 ER PT J AU Beebe, K Mollapour, M Scroggins, B Prodromou, C Xu, WP Tokita, M Taldone, T Pullen, L Zierer, BK Lee, MJ Trepel, J Buchner, J Bolon, D Chiosis, G Neckers, L AF Beebe, Kristin Mollapour, Mehdi Scroggins, Bradley Prodromou, Chrisostomos Xu, Wanping Tokita, Mari Taldone, Tony Pullen, Lester Zierer, Bettina K. Lee, Min-Jung Trepel, Jane Buchner, Johannes Bolon, Daniel Chiosis, Gabriela Neckers, Leonard TI Post-translational modification and conformational state of Heat Shock Protein 90 differentially affect binding of chemically diverse small molecule inhibitors SO ONCOTARGET LA English DT Article DE Hsp90; posttranslational modification; phosphorylation; drug binding; Hsp90 inhibitor ID HSP90 ATPASE ACTIVITY; CHAPERONE FUNCTION; BREAST-CANCER; TYROSINE PHOSPHORYLATION; TANESPIMYCIN 17-AAG; TERMINAL DOMAIN; CO-CHAPERONE; KINASE; MACHINERY; COMPLEX AB Heat shock protein 90 (Hsp90) is an essential molecular chaperone in eukaryotes that facilitates the conformational maturation and function of a diverse protein clientele, including aberrant and/or over-expressed proteins that are involved in cancer growth and survival. A role for Hsp90 in supporting the protein homeostasis of cancer cells has buoyed interest in the utility of Hsp90 inhibitors as anti-cancer drugs. Despite the fact that all clinically evaluated Hsp90 inhibitors target an identical nucleotide-binding pocket in the N domain of the chaperone, the precise determinants that affect drug binding in the cellular environment remain unclear, and it is possible that chemically distinct inhibitors may not share similar binding preferences. Here we demonstrate that two chemically unrelated Hsp90 inhibitors, the benzoquinone ansamycin geldanamycin and the purine analog PU-H71, select for overlapping but not identical subpopulations of total cellular Hsp90, even though both inhibitors bind to an amino terminal nucleotide pocket and prevent N domain dimerization. Our data also suggest that PU-H71 is able to access a broader range of N domain undimerized Hsp90 conformations than is geldanamycin and is less affected by Hsp90 phosphorylation, consistent with its broader and more potent anti-tumor activity. A more complete understanding of the impact of the cellular milieu on small molecule inhibitor binding to Hsp90 should facilitate their more effective use in the clinic. C1 [Beebe, Kristin; Mollapour, Mehdi; Scroggins, Bradley; Xu, Wanping; Tokita, Mari; Neckers, Leonard] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Prodromou, Chrisostomos] Univ Sussex, Brighton, E Sussex, England. [Taldone, Tony; Chiosis, Gabriela] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10021 USA. [Pullen, Lester; Bolon, Daniel] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA USA. [Zierer, Bettina K.; Buchner, Johannes] Tech Univ Munich, Dept Chem, D-80290 Munich, Germany. [Lee, Min-Jung; Trepel, Jane] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Mollapour, Mehdi] SUNY Upstate Med Univ, Dept Biochem & Mol Biol, Syracuse, NY 13210 USA. [Mollapour, Mehdi] SUNY Upstate Med Univ, Dept Urol, Syracuse, NY 13210 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM len@helix.nih.gov OI Prodromou, Chrisostomos/0000-0003-4320-1147 FU NCATS NIH HHS [UL1 TR000457]; NCI NIH HHS [R21 CA158609, R01 CA172546, R01 CA155226, P30 CA008748]; NCRR NIH HHS [UL1 RR024996] NR 45 TC 19 Z9 19 U1 0 U2 8 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL PY 2013 VL 4 IS 7 BP 1065 EP 1074 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 193UW UT WOS:000322588000013 PM 23867252 ER PT J AU Balla, T AF Balla, Tamas TI PHOSPHOINOSITIDES: TINY LIPIDS WITH GIANT IMPACT ON CELL REGULATION SO PHYSIOLOGICAL REVIEWS LA English DT Review ID PHOSPHATIDYLINOSITOL-TRANSFER PROTEIN; INOSITOL-POLYPHOSPHATE 5-PHOSPHATASE; PLECKSTRIN-HOMOLOGY-DOMAIN; PHOSPHOLIPASE-C-EPSILON; GROWTH-FACTOR RECEPTOR; TRANS-GOLGI NETWORK; G-BETA-GAMMA; OXYSTEROL-BINDING-PROTEIN; RETINAL-DEGENERATION-B; TUMOR-SUPPRESSOR PTEN AB Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease. C1 [Balla, Tamas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD USA. RP Balla, T (reprint author), NIH, Bldg 49,Rm 5A22,49 Convent Dr, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov OI Balla, Tamas/0000-0002-9077-3335 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX The author's research is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. NR 1832 TC 263 Z9 274 U1 15 U2 145 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 2013 VL 93 IS 3 BP 1019 EP 1137 DI 10.1152/physrev.00028.2012 PG 119 WC Physiology SC Physiology GA 192UV UT WOS:000322512400003 PM 23899561 ER PT J AU Harris, ML Buac, K Shakhova, O Hakami, RM Wegner, M Sommer, L Pavan, WJ AF Harris, Melissa L. Buac, Kristina Shakhova, Olga Hakami, Ramin M. Wegner, Michael Sommer, Lukas Pavan, William J. TI A Dual Role for SOX10 in the Maintenance of the Postnatal Melanocyte Lineage and the Differentiation of Melanocyte Stem Cell Progenitors SO PLOS GENETICS LA English DT Article ID TRANSCRIPTION FACTOR SOX10; FOLLICLE PIGMENTARY UNIT; NEURAL CREST DEVELOPMENT; HAIR-FOLLICLES; DOPACHROME-TAUTOMERASE; WAARDENBURG-SYNDROME; COMPREHENSIVE GUIDE; GENOTOXIC STRESS; MOUSE MODEL; EXPRESSION AB During embryogenesis, the transcription factor, Sox10, drives the survival and differentiation of the melanocyte lineage. However, the role that Sox10 plays in postnatal melanocytes is not established. We show in vivo that melanocyte stem cells (McSCs) and more differentiated melanocytes express SOX10 but that McSCs remain undifferentiated. Sox10 knockout (Sox10(fl); Tg(Tyr::CreER)) results in loss of both McSCs and differentiated melanocytes, while overexpression of Sox10 (Tg(DctSox10)) causes premature differentiation and loss of McSCs, leading to hair graying. This suggests that levels of SOX10 are key to normal McSC function and Sox10 must be downregulated for McSC establishment and maintenance. We examined whether the mechanism of Tg(DctSox10) hair graying is through increased expression of Mitf, a target of SOX10, by asking if haploinsufficiency for Mitf (Mitf(vga9)) can rescue hair graying in Tg(DctSox10) animals. Surprisingly, Mitf(vga9) does not mitigate but exacerbates Tg(DctSox10) hair graying suggesting that MITF participates in the negative regulation of Sox10 in McSCs. These observations demonstrate that while SOX10 is necessary to maintain the postnatal melanocyte lineage it is simultaneously prevented from driving differentiation in the McSCs. This data illustrates how tissue-specific stem cells can arise from lineage-specified precursors through the regulation of the very transcription factors important in defining that lineage. C1 [Harris, Melissa L.; Pavan, William J.] Natl Human Genome Inst, Genet Dis Res Branch, NIH, Bethesda, MD USA. [Buac, Kristina] Univ Georgia, Dept Genet, Athens, GA 30602 USA. [Shakhova, Olga; Sommer, Lukas] Univ Zurich, Inst Anat, Zurich, Switzerland. [Hakami, Ramin M.] George Mason Univ, Natl Ctr Biodef & Infect Dis, Sch Syst Biol, Manassas, VA USA. [Wegner, Michael] Univ Erlangen Nurnberg, Emil Fischer Zentrum, Inst Biochem, D-91054 Erlangen, Germany. RP Harris, ML (reprint author), Natl Human Genome Inst, Genet Dis Res Branch, NIH, Bethesda, MD USA. EM bpavan@mail.nih.gov OI Wegner, Michael/0000-0002-4586-3294 FU National Human Genome Research Institute's Intramural Research Program at the National Institutes of Health; Swiss National Science Foundation; National Research Program (NRP) 63; Promedica Foundation Chur; Swiss Cancer League FX Funding for the work presented in this study was provided by the National Human Genome Research Institute's Intramural Research Program at the National Institutes of Health (to WJP), and the Swiss National Science Foundation, National Research Program (NRP) 63, Promedica Foundation Chur, and the Swiss Cancer League (to OS, and LS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 14 Z9 15 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2013 VL 9 IS 7 AR e1003644 DI 10.1371/journal.pgen.1003644 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 190EG UT WOS:000322321100043 PM 23935512 ER PT J AU Inbar, E Akopyants, NS Charmoy, M Romano, A Lawyer, P Elnaiem, DEA Kauffmann, F Barhoumi, M Grigg, M Owens, K Fay, M Dobson, DE Shaik, J Beverley, SM Sacks, D AF Inbar, Ehud Akopyants, Natalia S. Charmoy, Melanie Romano, Audrey Lawyer, Phillip Elnaiem, Dia-Eldin A. Kauffmann, Florence Barhoumi, Mourad Grigg, Michael Owens, Katherine Fay, Michael Dobson, Deborah E. Shaik, Jahangheer Beverley, Stephen M. Sacks, David TI The Mating Competence of Geographically Diverse Leishmania major Strains in Their Natural and Unnatural Sand Fly Vectors SO PLOS GENETICS LA English DT Article ID TRYPANOSOMA-BRUCEI; GENETIC EXCHANGE; LIFE-CYCLE; TRANSMISSION; ANEUPLOIDY; SEX; BRAZILIENSIS; PLASTICITY; EVOLUTION; PATHOGENS AB Invertebrate stages of Leishmania are capable of genetic exchange during their extracellular growth and development in the sand fly vector. Here we explore two variables: the ability of diverse L. major strains from across its natural range to undergo mating in pairwise tests; and the timing of the appearance of hybrids and their developmental stage associations within both natural (Phlebotomus duboscqi) and unnatural (Lutzomyia longipalpis) sand fly vectors. Following co-infection of flies with parental lines bearing independent drug markers, doubly-drug resistant hybrid progeny were selected, from which 96 clonal lines were analyzed for DNA content and genotyped for parent alleles at 4-6 unlinked nuclear loci as well as the maxicircle DNA. As seen previously, the majority of hybrids showed '2n' DNA contents, but with a significant number of '3n' and one '4n' offspring. In the natural vector, 97% of the nuclear loci showed both parental alleles; however, 3% (4/150) showed only one parental allele. In the unnatural vector, the frequency of uniparental inheritance rose to 10% (27/275). We attribute this to loss of heterozygosity after mating, most likely arising from aneuploidy which is both common and temporally variable in Leishmania. As seen previously, only uniparental inheritance of maxicircle kDNA was observed. Hybrids were recovered at similar efficiencies in all pairwise crosses tested, suggesting that L. major lacks detectable 'mating types' that limit free genetic exchange. In the natural vector, comparisons of the timing of hybrid formation with the presence of developmental stages suggest nectomonads as the most likely sexually competent stage, with hybrids emerging well before the first appearance of metacyclic promastigotes. These studies provide an important perspective on the prevalence of genetic exchange in natural populations of L. major and a guide for experimental studies to understand the biology of mating. C1 [Inbar, Ehud; Charmoy, Melanie; Romano, Audrey; Lawyer, Phillip; Elnaiem, Dia-Eldin A.; Kauffmann, Florence; Barhoumi, Mourad; Grigg, Michael; Sacks, David] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Akopyants, Natalia S.; Owens, Katherine; Dobson, Deborah E.; Shaik, Jahangheer; Beverley, Stephen M.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Fay, Michael] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Inbar, E (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM dsacks@nih.gov OI Fay, Michael P./0000-0002-8643-9625; Beverley, Stephen/0000-0001-5319-0811 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; NIH [AI-RO129646] FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by NIH grant AI-RO129646 (SMB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 20 Z9 20 U1 2 U2 14 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 2013 VL 9 IS 7 AR e1003672 DI 10.1371/journal.pgen.1003672 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 190EG UT WOS:000322321100058 PM 23935521 ER PT J AU Li, XM Sanneman, JD Harbidge, DG Zhou, F Ito, T Nelson, R Picard, N Chambrey, R Eladari, D Miesner, T Griffith, AJ Marcus, DC Wangemann, P AF Li, Xiangming Sanneman, Joel D. Harbidge, Donald G. Zhou, Fei Ito, Taku Nelson, Raoul Picard, Nicolas Chambrey, Regine Eladari, Dominique Miesner, Tracy Griffith, Andrew J. Marcus, Daniel C. Wangemann, Philine TI SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice SO PLOS GENETICS LA English DT Article ID VESTIBULAR AQUEDUCT SYNDROME; PROMOTER DRIVES EXPRESSION; TRANSCRIPTION FACTOR FOXI1; MOUSE INNER-EAR; PENDRED-SYNDROME; H+-ATPASE; INTERCALATED CELLS; STARTLE REFLEX; B1 SUBUNIT; KIDNEY AB Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the vestibular labyrinth and the endolymphatic sac. Slc26a4(Delta/Delta) mice are devoid of pendrin and develop a severe enlargement of the membranous labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4(Delta/Delta) line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the vestibular labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy will restore normal hearing in human patients carrying a variety of mutations of SLC26A4. C1 [Li, Xiangming; Sanneman, Joel D.; Harbidge, Donald G.; Zhou, Fei; Marcus, Daniel C.; Wangemann, Philine] Kansas State Univ, Dept Anat & Physiol, Manhattan, KS 66506 USA. [Ito, Taku; Griffith, Andrew J.] Natl Inst Deafness & Other Commun Disorders, Otolaryngol Branch, NIH, Rockville, MD USA. [Nelson, Raoul] Univ Utah, Sch Med, Dept Pediat, Div Nephrol, Salt Lake City, UT USA. [Picard, Nicolas; Chambrey, Regine; Eladari, Dominique] Fac Med Paris Descartes, Ctr Rech PARCC, Paris Ctr Rech Cardiovasc, Inserm,UMRS 970,Sorbonne Paris Cite, Paris, France. [Eladari, Dominique] AP HP, HEGP, Dept Physiol, Paris, France. [Miesner, Tracy] Kansas State Univ, Comparat Med Grp, Manhattan, KS 66506 USA. RP Li, XM (reprint author), Kansas State Univ, Dept Anat & Physiol, Manhattan, KS 66506 USA. EM wange@vet.ksu.edu RI Wangemann, Philine/N-2826-2013; Picard, Nicolas/B-6677-2012 OI Picard, Nicolas/0000-0002-1695-3389 FU National Institutes on Deafness and Other Communication Disorders [NIH-R01-DC012151]; KINBRE grant; National Center for Research Resources [P20 RR016475]; National Institute of General Medical Sciences [P20 GM103418]; grant HYPERCLO BLANC from l'Agence Nationale de la Recherche [2010-R10164DD]; INSERM grant from the association pour l'information et la recherche sur les maladies renales genetiques (AIRG); Societe Francaise d'Hypertension (SFHTA); grant "RENPAR'' ANR BLANC from l'Agence Nationale de la Recherche [2012-BSV1-0017]; NIH [DC-000060-10]; Kansas State University - College of Veterinary Medicine; National Institutes of Health [NIH-P20-RR017686] FX This work was supported by a grant from the National Institutes on Deafness and Other Communication Disorders, NIH-R01-DC012151 (to PW), a KINBRE grant (to PW) that in turn was funded by grants from the National Center for Research Resources (P20 RR016475) and the National Institute of General Medical Sciences (P20 GM103418), by a grant HYPERCLO BLANC 2010-R10164DD from l'Agence Nationale de la Recherche (to DE), by an INSERM grant "subvention de recherche'' from the association pour l'information et la recherche sur les maladies renales genetiques (AIRG) 2011 (to DE), by a grant Subvention de Recherche 2012 from the Societe Francaise d'Hypertension (SFHTA) (to DE), and by a grant "RENPAR'' ANR BLANC 2012-BSV1-0017 from l'Agence Nationale de la Recherche (to RC and DE), and by NIH intramural research funds DC-000060-10 (to AJG). The Confocal Microscopy Core facility at Kansas State University was supported by Kansas State University - College of Veterinary Medicine and a grant from the National Institutes of Health, NIH-P20-RR017686 (to DCM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 17 Z9 17 U1 0 U2 2 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 2013 VL 9 IS 7 AR e1003641 DI 10.1371/journal.pgen.1003641 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA 190EG UT WOS:000322321100040 PM 23874234 ER PT J AU Vallabhaneni, H O'Callaghan, N Sidorova, J Liu, Y AF Vallabhaneni, Haritha O'Callaghan, Nathan Sidorova, Julia Liu, Yie TI Defective Repair of Oxidative Base Lesions by the DNA Glycosylase Nth1 Associates with Multiple Telomere Defects SO PLOS GENETICS LA English DT Article ID EXCISION-REPAIR; DAMAGE-RESPONSE; REPLICATIVE SENESCENCE; HUMAN FIBROBLASTS; MOUSE TELOMERASE; MAMMALIAN-CELLS; THYMINE GLYCOL; FRAGILE SITES; GGG SEQUENCE; LENGTH AB Telomeres are chromosome end structures and are essential for maintenance of genome stability. Highly repetitive telomere sequences appear to be susceptible to oxidative stress-induced damage. Oxidation may therefore have a severe impact on telomere integrity and function. A wide spectrum of oxidative pyrimidine-derivatives has been reported, including thymine glycol (Tg), that are primarily removed by a DNA glycosylase, Endonuclease III-like protein 1 (Nth1). Here, we investigate the effect of Nth1 deficiency on telomere integrity in mice. Nth1 null (Nth1(-/-)) mouse tissues and primary MEFs harbor higher levels of Endonuclease III-sensitive DNA lesions at telomeric repeats, in comparison to a non-telomeric locus. Furthermore, oxidative DNA damage induced by acute exposure to an oxidant is repaired slowly at telomeres in Nth1(-/-) MEFs. Although telomere length is not affected in the hematopoietic tissues of Nth(-/-) adult mice, telomeres suffer from attrition and increased recombination and DNA damage foci formation in Nth1(-/-) bone marrow cells that are stimulated ex vivo in the presence of 20% oxygen. Nth1 deficiency also enhances telomere fragility in mice. Lastly, in a telomerase null background, Nth1(-/-) bone marrow cells undergo severe telomere loss at some chromosome ends and cell apoptosis upon replicative stress. These results suggest that Nth1 plays an important role in telomere maintenance and base repair against oxidative stress-induced base modifications. The fact that telomerase deficiency can exacerbate telomere shortening in Nth1 deficient mouse cells supports that base excision repair cooperates with telomerase to maintain telomere integrity. C1 [Vallabhaneni, Haritha; Liu, Yie] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [O'Callaghan, Nathan] CSIRO, Anim Food & Hlth Sci, Adelaide, SA, Australia. [Sidorova, Julia] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP Vallabhaneni, H (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM liuyie@mail.nih.gov RI o'callaghan, nathan/E-8363-2011; OI Sidorova, Julia/0000-0001-5502-4323 FU NIA, National Institutes of Health FX This work was supported by funds from the Intramural Research Program of the NIA, 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 57 TC 16 Z9 16 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2013 VL 9 IS 7 AR e1003639 DI 10.1371/journal.pgen.1003639 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 190EG UT WOS:000322321100038 PM 23874233 ER PT J AU Luoto, J Maglione, MA Johnsen, B Chang, C Higgs, ES Perry, T Shekelle, PG AF Luoto, Jill Maglione, Margaret A. Johnsen, Breanne Chang, Christine Higgs, Elizabeth S. Perry, Tanja Shekelle, Paul G. TI A Comparison of Frameworks Evaluating Evidence for Global Health Interventions SO PLOS MEDICINE LA English DT Editorial Material ID RADICAL-RETHINKING; ABHIJIT BANERJEE; POOR-ECONOMICS; QUALITY; RECOMMENDATIONS; METAANALYSIS; STRENGTH; POVERTY; TRIALS; GRADE C1 [Luoto, Jill; Maglione, Margaret A.; Johnsen, Breanne; Perry, Tanja; Shekelle, Paul G.] Rand Hlth, Southern Calif Evidence Based Practice Ctr, Santa Monica, CA USA. [Chang, Christine] Agcy Healthcare Res & Qual, Rockville, MD USA. [Higgs, Elizabeth S.] NIAID, NIH, Bethesda, MD 20892 USA. [Shekelle, Paul G.] West Los Angeles VA Med Ctr, Los Angeles, CA USA. RP Luoto, J (reprint author), Rand Hlth, Southern Calif Evidence Based Practice Ctr, Santa Monica, CA USA. EM jluoto@rand.org FU PHS HHS [HHSA290200710062I] NR 31 TC 5 Z9 5 U1 1 U2 3 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 2013 VL 10 IS 7 AR e1001469 DI 10.1371/journal.pmed.1001469 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 193VY UT WOS:000322590800001 PM 23874159 ER PT J AU Pfeiffer, RM Park, Y Kreimer, AR Lacey, JV Pee, D Greenlee, RT Buys, SS Hollenbeck, A Rosner, B Gail, MH Hartge, P AF Pfeiffer, Ruth M. Park, Yikyung Kreimer, Aimee R. Lacey, James V., Jr. Pee, David Greenlee, Robert T. Buys, Saundra S. Hollenbeck, Albert Rosner, Bernard Gail, Mitchell H. Hartge, Patricia TI Risk Prediction for Breast, Endometrial, and Ovarian Cancer in White Women Aged 50 y or Older: Derivation and Validation from Population-Based Cohort Studies SO PLOS MEDICINE LA English DT Article ID SCREENING MAMMOGRAPHY; NURSES HEALTH; TAMOXIFEN; MODEL; RALOXIFENE; DENSITY; BENEFITS; DESIGN; TRIAL AB Background: Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer. Methods and Findings: Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health-AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96-1.04) for breast cancer and 1.08 (95% CI: 0.97-1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11-1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57-0.59), 0.59 (95% CI: 0.56-0.63), and 0.68 (95% CI: 0.66-0.70) for the breast, ovarian, and endometrial models, respectively. Conclusions: These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races. C1 [Pfeiffer, Ruth M.; Park, Yikyung; Kreimer, Aimee R.; Gail, Mitchell H.; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lacey, James V., Jr.] City Hope Natl Med Ctr, Duarte, CA USA. [Pee, David] Informat Management Syst, Rockville, MD USA. [Greenlee, Robert T.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Buys, Saundra S.] Univ Utah, Dept Internal Med, Hlth Sci Ctr, Salt Lake City, UT 84112 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. [Rosner, Bernard] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Rosner, Bernard] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Pfeiffer, RM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM Pfeiffer@mail.nih.gov RI Kreimer, Aimee/H-1687-2015; OI Park, Yikyung/0000-0002-6281-489X FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX The manuscript was developed with support from the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 34 Z9 34 U1 1 U2 20 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 2013 VL 10 IS 7 AR e1001492 DI 10.1371/journal.pmed.1001492 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 193VY UT WOS:000322590800018 PM 23935463 ER PT J AU Balzarini, J Andrei, G Balestra, E Huskens, D Vanpouille, C Introini, A Zicari, S Liekens, S Snoeck, R Holy, A Perno, CF Margolis, L Schols, D AF Balzarini, Jan Andrei, Graciela Balestra, Emanuela Huskens, Dana Vanpouille, Christophe Introini, Andrea Zicari, Sonia Liekens, Sandra Snoeck, Robert Holy, Antonin Perno, Carlo-Federico Margolis, Leonid Schols, Dominique TI A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity SO PLOS PATHOGENS LA English DT Article ID HERPES-SIMPLEX-VIRUS; SIMIAN IMMUNODEFICIENCY VIRUS; BETA-CHEMOKINES; IN-VITRO; PHOSPHONYLMETHOXYALKYL DERIVATIVES; NUCLEOSIDE PHOSPHONATES; TYPE-1 REPLICATION; ANTIVIRAL ACTIVITY; DOWN-REGULATION; UP-REGULATION AB Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4(+) T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing beta-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1 beta, MIP-1 alpha and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific beta-chemokine upregulation required new mRNA synthesis. The upregulation of beta-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i. e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i. e. CCR5 receptor down regulation). C1 [Balzarini, Jan; Andrei, Graciela; Huskens, Dana; Liekens, Sandra; Snoeck, Robert; Schols, Dominique] Katholieke Univ Leuven, Rega Inst Med Res, Louvain, Belgium. [Balestra, Emanuela; Perno, Carlo-Federico] Univ Roma Tor Vergata, Dept Expt Med & Biochem Sci, Rome, Italy. [Vanpouille, Christophe; Introini, Andrea; Zicari, Sonia; Margolis, Leonid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. [Holy, Antonin] Acad Sci Czech Republic, Inst Organ Chem & Biochem, Prague, Czech Republic. RP Balzarini, J (reprint author), Katholieke Univ Leuven, Rega Inst Med Res, Louvain, Belgium. EM jan.balzarini@rega.kuleuven.be RI perno, carlo federico/O-1544-2016; OI Introini, Andrea/0000-0002-9929-8964 FU KU Leuven [10/014, 10/18]; European Community (CHAARM); Belgian Federal Public Service; NICHD FX The work of AI, CV, LM and SZ was supported by the NICHD Intramural Program. The research of JB, DS, DH, SL, GA, and RS was supported by the KU Leuven (GOA no. 10/014 and PF no. 10/18), by the European Community (CHAARM) for JB and DS, and by the Belgian Federal Public Service "Public Health, Food Chain Safety and Environment, action 29 of the National Cancer Plan" for GA and RS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 6 Z9 6 U1 2 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2013 VL 9 IS 7 AR e1003456 DI 10.1371/journal.ppat.1003456 PG 18 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 190CX UT WOS:000322316700015 PM 23935482 ER PT J AU McLaren, PJ Coulonges, C Ripke, S van den Berg, L Buchbinder, S Carrington, M Cossarizza, A Dalmau, J Deeks, SG Delaneau, O De Luca, A Goedert, JJ Haas, D Herbeck, JT Kathiresan, S Kirk, GD Lambotte, O Luo, M Mallal, S van Manen, D Martinez-Picado, J Meyer, L Miro, JM Mullins, JI Obel, N O'Brien, SJ Pereyra, F Plummer, FA Poli, G Qi, Y Rucart, P Sandhu, MS Shea, PR Schuitemaker, H Theodorou, I Vannberg, F Veldink, J Walker, BD Weintrob, A Winkler, CA Wolinsky, S Telenti, A Goldstein, DB de Bakker, PIW Zagury, JF Fellay, J AF McLaren, Paul J. Coulonges, Cedric Ripke, Stephan van den Berg, Leonard Buchbinder, Susan Carrington, Mary Cossarizza, Andrea Dalmau, Judith Deeks, Steven G. Delaneau, Olivier De Luca, Andrea Goedert, James J. Haas, David Herbeck, Joshua T. Kathiresan, Sekar Kirk, Gregory D. Lambotte, Olivier Luo, Ma Mallal, Simon van Manen, Danielle Martinez-Picado, Javier Meyer, Laurence Miro, Jose M. Mullins, James I. Obel, Niels O'Brien, Stephen J. Pereyra, Florencia Plummer, Francis A. Poli, Guido Qi, Ying Rucart, Pierre Sandhu, Manj S. Shea, Patrick R. Schuitemaker, Hanneke Theodorou, Ioannis Vannberg, Fredrik Veldink, Jan Walker, Bruce D. Weintrob, Amy Winkler, Cheryl A. Wolinsky, Steven Telenti, Amalio Goldstein, David B. de Bakker, Paul I. W. Zagury, Jean-Francois Fellay, Jacques TI Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls SO PLOS PATHOGENS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENOTYPE IMPUTATION; AFRICAN-AMERICANS; HOST CONTROL; AIDS; PROGRESSION; ALLELE; POLYMORPHISMS; DETERMINANTS; TRANSMISSION AB Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p=3.6x10(-11)). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5 Delta 32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size. C1 [McLaren, Paul J.; Fellay, Jacques] Ecole Polytech Fed Lausanne, Sch Life Sci, Lausanne, Switzerland. [McLaren, Paul J.; Fellay, Jacques] Univ Lausanne, Lausanne, Switzerland. [McLaren, Paul J.; Fellay, Jacques] Univ Hosp Ctr, Inst Microbiol, Lausanne, Switzerland. [McLaren, Paul J.; Ripke, Stephan; Kathiresan, Sekar; de Bakker, Paul I. W.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Coulonges, Cedric; Zagury, Jean-Francois] Chaire Bioinformat Conservatoire Natl Arts & Meti, EA4627, Lab Genom Bioinformat, Paris, France. [Coulonges, Cedric; Meyer, Laurence; Rucart, Pierre; Theodorou, Ioannis; Zagury, Jean-Francois] ANRS Genom Grp, French Agcy Res AIDS & Hepatitis, Paris, France. [Ripke, Stephan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [van den Berg, Leonard] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, Utrecht, Netherlands. [Buchbinder, Susan] Bridge HIV, San Francisco Dept Publ Hlth, San Francisco, CA USA. [Carrington, Mary] SAIC Frederick Inc, Expt Immunol Lab, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Carrington, Mary; Walker, Bruce D.] MIT & Harvard, Ragon Inst MGH, Boston, MA USA. [Cossarizza, Andrea] Univ Modena, Dept Surg Med Dent & Morphol Sci, I-41100 Modena, Italy. [Cossarizza, Andrea] Reggio Emilia Sch Med, Modena, Italy. [Dalmau, Judith] Univ Autonoma Barcelona, Inst Investigacio Ciencies Salut Germans Trias &, AIDS Res Inst IrsiCaixa, Badalona, Spain. [Deeks, Steven G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Delaneau, Olivier] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [De Luca, Andrea] Siena Univ Hosp, Univers Div Infect Dis, Siena, Italy. [De Luca, Andrea] Univ Cattolica Sacro Cuore, Inst Clin Infect Dis, Rome, Italy. [Goedert, James J.] Natl Canc Inst, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD USA. [Haas, David] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Herbeck, Joshua T.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Kirk, Gregory D.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Delaneau, Olivier] INSERM U1012, Le Kremlin Bicetre, France. [Lambotte, Olivier] Univ Paris Sud, Le Kremlin Bicetre, France. [Lambotte, Olivier] Hop Bicetre, AP HP, Dept Internal Med & Infect Dis, Le Kremlin Bicetre, France. [Luo, Ma] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Luo, Ma] Natl Microbiol Lab, Winnipeg, MB, Canada. [Mallal, Simon] Murdoch Univ & Pathwest, Inst Immunol & Infect Dis, Perth, WA, Australia. [van Manen, Danielle] Univ Amsterdam, Dept Expt Immunol, Sanquin Res Landsteiner Lab, Amsterdam, Netherlands. [van Manen, Danielle] Univ Amsterdam, Acad Med Ctr, Ctr Infect Dis & Immun Amster