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 Amsterdam, Amsterdam, Netherlands. [Martinez-Picado, Javier] ICREA, Barcelona, Spain. [Meyer, Laurence] Univ Paris Sud, UMRS 1018, Fac Med, INSERM,CESP U1018, Paris, France. [Meyer, Laurence] AP HP, Hopital Bicetre, Epidemiol & Publ Hlth Serv, Le Kremlin Bicetre, France. [Miro, Jose M.] Univ Barcelona, IDIBAPS, Hosp Clin, Infect Dis Serv, Barcelona, Spain. [Obel, Niels] Rigshosp, Natl Univ Hosp, Dept Infect Dis, Copenhagen, Denmark. [O'Brien, Stephen J.] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg 199034, Russia. [Pereyra, Florencia] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Infect Dis, Boston, MA 02115 USA. [Poli, Guido] Univ Vita Salute San Raffaele, Div Immunol Transplantat & Infect Dis, Milan, Italy. [Poli, Guido] Ist Sci San Raffaele, I-20132 Milan, Italy. [Sandhu, Manj S.] Wellcome Trust Sanger Inst, Genet Epidemiol Grp, Hinxton, England. [Sandhu, Manj S.] Univ Cambridge, Dept Publ Hlth & Primary Care, Non Communicable Dis Res Grp, Cambridge, England. [Shea, Patrick R.] Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC USA. [Theodorou, Ioannis] INSERM, UMRS 945, Paris, France. [Vannberg, Fredrik] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Weintrob, Amy] Univ Hlth Sci, Uniformed Serv, Infect Dis Clin Res Program, Bethesda, MD USA. [Winkler, Cheryl A.] Frederick Natl Lab, SAIC Frederick Inc, NCI,Basic Res Lab, Ctr Canc Res,Mol Genetic Epidemiol Sect, Frederick, MD USA. [Wolinsky, Steven] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. [de Bakker, Paul I. W.] Harvard Univ, Sch Med, Div Genet Brigham, Boston, MA USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, Utrecht, Netherlands. RP Fellay, J (reprint author), Ecole Polytech Fed Lausanne, Sch Life Sci, Lausanne, Switzerland. EM jacques.fellay@epfl.ch RI de Bakker, Paul/B-8730-2009; SHCS, int. coll. A/G-4083-2011; De Luca, Andrea/G-8810-2011; Fellay, Jacques/A-6681-2009; SHCS, all/G-4072-2011; Martinez-Picado, Javier/G-5507-2012 OI de Bakker, Paul/0000-0001-7735-7858; Wolinsky, Steven/0000-0002-9625-6697; O'Brien, Stephen J./0000-0001-7353-8301; Fellay, Jacques/0000-0002-8240-939X; Cossarizza, Andrea/0000-0002-5381-1558; Shea, Patrick/0000-0001-6804-5131; Martinez-Picado, Javier/0000-0002-4916-2129 FU NIH Office of AIDS Research; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; US NIH National Heart, Lung, and Blood Institute's STAMPEED genomics research program [R01 HL087676]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX Initial funding for the International Collaboration for the Genomics of HIV was provided by the NIH Office of AIDS Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The MIGen study was funded by the US NIH National Heart, Lung, and Blood Institute's STAMPEED genomics research program through grant R01 HL087676. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. A full statement of funding for the contributing cohorts is listed in the supplementary materials. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 35 Z9 36 U1 2 U2 23 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 e1003515 DI 10.1371/journal.ppat.1003515 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 190CX UT WOS:000322316700050 PM 23935489 ER PT J AU Morens, DM Fauci, AS AF Morens, David M. Fauci, Anthony S. TI Emerging Infectious Diseases: Threats to Human Health and Global Stability SO PLOS PATHOGENS LA English DT Article ID PERPETUAL CHALLENGE; EMERGENCE; HIV/AIDS; VIRUS C1 [Morens, David M.; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dm270q@nih.gov FU NIH FX Both authors are employees of NIH and as such our work is funded by NIH from operating funds rather than grants or other awards. NR 23 TC 49 Z9 51 U1 1 U2 39 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2013 VL 9 IS 7 AR e1003467 DI 10.1371/journal.ppat.1003467 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 190CX UT WOS:000322316700020 PM 23853589 ER PT J AU Pallikkuth, S Micci, L Ende, ZS Iriele, RI Cervasi, B Lawson, B McGary, CS Rogers, KA Else, JG Silvestri, G Easley, K Estes, JD Villinger, F Pahwa, S Paiardini, M AF Pallikkuth, Suresh Micci, Luca Ende, Zachary S. Iriele, Robin I. Cervasi, Barbara Lawson, Benton McGary, Colleen S. Rogers, Kenneth A. Else, James G. Silvestri, Guido Easley, Kirk Estes, Jacob D. Villinger, Francois Pahwa, Savita Paiardini, Mirko TI Maintenance of Intestinal Th17 Cells and Reduced Microbial Translocation in SIV-infected Rhesus Macaques Treated with Interleukin (IL)-21 SO PLOS PATHOGENS LA English DT Article ID CHRONIC VIRAL-INFECTION; CD8 T-CELLS; VIRUS TYPE-1 INFECTION; IMMUNE ACTIVATION; ANTIRETROVIRAL THERAPY; GASTROINTESTINAL-TRACT; METASTATIC MELANOMA; LENTIVIRAL INFECTIONS; SOOTY MANGABEYS; HIV-INFECTION AB In pathogenic HIV and SIV infections of humans and rhesus macaques (RMs), preferential depletion of CD4(+) Th17 cells correlates with mucosal immune dysfunction and disease progression. Interleukin (IL)-21 promotes differentiation of Th17 cells, long-term maintenance of functional CD8(+) T cells, and differentiation of memory B cells and antibody-secreting plasma cells. We hypothesized that administration of IL-21 will improve mucosal function in the context of pathogenic HIV/SIV infections. To test this hypothesis, we infected 12 RMs with SIVmac239 and at day 14 post-infection treated six of them with rhesus rIL-21-IgFc. IL-21-treatment was safe and did not increase plasma viral load or systemic immune activation. Compared to untreated animals, IL-21-treated RMs showed (i) higher expression of perforin and granzyme B in total and SIV-specific CD8(+) T cells and (ii) higher levels of intestinal Th17 cells. Remarkably, increased levels of Th17 cells were associated with reduced levels of intestinal T cell proliferation, microbial translocation and systemic activation/inflammation in the chronic infection. In conclusion, IL-21-treatment in SIV-infected RMs improved mucosal immune function through enhanced preservation of Th17 cells. Further preclinical studies of IL-21 may be warranted to test its potential use during chronic infection in conjunction with antiretroviral therapy. C1 [Pallikkuth, Suresh; Pahwa, Savita] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Micci, Luca; Ende, Zachary S.; Iriele, Robin I.; Cervasi, Barbara; Lawson, Benton; McGary, Colleen S.; Rogers, Kenneth A.; Else, James G.; Silvestri, Guido; Villinger, Francois; Paiardini, Mirko] Emory Univ, Div Microbiol & Immunol, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Silvestri, Guido; Paiardini, Mirko] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Easley, Kirk] Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA USA. [Estes, Jacob D.] SAIC Frederick, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Paiardini, M (reprint author), Emory Univ, Div Microbiol & Immunol, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. EM mirko.paiardini@emory.edu RI Easley, Kirk/K-6910-2015 OI Easley, Kirk/0000-0003-4419-2617 FU NIH [R01-AI084836, R56-AI087186, P01-AI076174, A1077501]; ORIP [8R24OD010947, P30-AI050409]; National Center for Research Resources [P51RR165]; Office of Research Infrastructure Programs [OD P51OD11132] FX Research reported in this publication was supported by NIH grants R01-AI084836 and R56-AI087186 (to M. Paiardini), P01-AI076174 (to G. Silvestri), A1077501 (to S. Pahwa), ORIP grant 8R24OD010947 (to F. Villinger), P30-AI050409 (Emory CFAR) as well as the National Center for Research Resources P51RR165, and is currently supported by the Office of Research Infrastructure Programs/OD P51OD11132. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 41 Z9 41 U1 0 U2 5 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 e1003471 DI 10.1371/journal.ppat.1003471 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 190CX UT WOS:000322316700024 PM 23853592 ER PT J AU Sakakibara, N Chen, D McBride, AA AF Sakakibara, Nozomi Chen, Dan McBride, Alison A. TI Papillomaviruses Use Recombination-Dependent Replication to Vegetatively Amplify Their Genomes in Differentiated Cells SO PLOS PATHOGENS LA English DT Editorial Material ID DNA-DAMAGE RESPONSE; FANCONI-ANEMIA PATHWAY; LIFE-CYCLE; VIRAL GENOME; EPITHELIAL DIFFERENTIATION; E1 PROTEIN; MAINTENANCE; REPAIR; INITIATION; HELICASE C1 [Sakakibara, Nozomi; Chen, Dan; McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Sakakibara, N (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM amcbride@nih.gov OI McBride, Alison/0000-0001-5607-5157 FU Intramural NIH HHS; NIAID NIH HHS [1 ZIA AI001073--05] NR 52 TC 25 Z9 26 U1 0 U2 5 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 e1003321 DI 10.1371/journal.ppat.1003321 PG 6 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 190CX UT WOS:000322316700001 PM 23853576 ER PT J AU Taylor, SL Wahl-Jensen, V Copeland, AM Jahrling, PB Schmaljohn, CS AF Taylor, Shannon L. Wahl-Jensen, Victoria Copeland, Anna Maria Jahrling, Peter B. Schmaljohn, Connie S. TI Endothelial Cell Permeability during Hantavirus Infection Involves Factor XII-Dependent Increased Activation of the Kallikrein-Kinin System SO PLOS PATHOGENS LA English DT Article ID SYRIAN-HAMSTER MODEL; PULMONARY SYNDROME; ANDES VIRUS; HEMORRHAGIC-FEVER; GROWTH-FACTOR; NITRIC-OXIDE; VE-CADHERIN; HEREDITARY ANGIOEDEMA; INTRINSIC PATHWAY; VESSEL FORMATION AB Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) are diseases caused by hantavirus infections and are characterized by vascular leakage due to alterations of the endothelial barrier. Hantavirus-infected endothelial cells (EC) display no overt cytopathology; consequently, pathogenesis models have focused either on the influx of immune cells and release of cytokines or on increased degradation of the adherens junction protein, vascular endothelial (VE)-cadherin, due to hantavirus-mediated hypersensitization of EC to vascular endothelial growth factor (VEGF). To examine endothelial leakage in a relevant in vitro system, we co-cultured endothelial and vascular smooth muscle cells (vSMC) to generate capillary blood vessel-like structures. In contrast to results obtained in monolayers of cultured EC, we found that despite viral replication in both cell types as well as the presence of VEGF, infected in vitro vessels neither lost integrity nor displayed evidence of VE-cadherin degradation. Here, we present evidence for a novel mechanism of hantavirus-induced vascular leakage involving activation of the plasma kallikrein-kinin system (KKS). We show that incubation of factor XII (FXII), prekallikrein (PK), and high molecular weight kininogen (HK) plasma proteins with hantavirus-infected EC results in increased cleavage of HK, higher enzymatic activities of FXIIa/kallikrein (KAL) and increased liberation of bradykinin (BK). Measuring cell permeability in real-time using electric cell-substrate impedance sensing (ECIS), we identified dramatic increases in endothelial cell permeability after KKS activation and liberation of BK. Furthermore, the alterations in permeability could be prevented using inhibitors that directly block BK binding, the activity of FXIIa, or the activity of KAL. Lastly, FXII binding and autoactivation is increased on the surface of hantavirus-infected EC. These data are the first to demonstrate KKS activation during hantavirus infection and could have profound implications for treatment of hantavirus infections. C1 [Taylor, Shannon L.; Copeland, Anna Maria; Schmaljohn, Connie S.] US Army Med Res Inst Infect Dis, Ft Detrick, MD USA. [Wahl-Jensen, Victoria; Jahrling, Peter B.] NIAID, Integrated Res Facil Ft Detrick, NIH, Ft Detrick, MD USA. RP Schmaljohn, CS (reprint author), US Army Med Res Inst Infect Dis, Ft Detrick, MD USA. EM Connie.Schmaljohn@us.army.mil FU Independent Laboratory In-House Research (ILIR) [1591244] FX This work was sponsored by an Independent Laboratory In-House Research (ILIR) grant, project number 1591244. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 25 Z9 25 U1 0 U2 10 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 e1003470 DI 10.1371/journal.ppat.1003470 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 190CX UT WOS:000322316700023 PM 23874198 ER PT J AU Wolff, L Humeniuk, R AF Wolff, Linda Humeniuk, Rita TI Concise Review: Erythroid Versus Myeloid Lineage Commitment: Regulating the Master Regulators SO STEM CELLS LA English DT Review DE Acute leukemia; Hematopoietic progenitors; Differentiation; Erythroid differentiation; Myeloid cells; Transcription factors; Signal transduction ID HEMATOPOIETIC STEM-CELLS; TRANSCRIPTION FACTOR GATA-1; CHROMATIN OCCUPANCY ANALYSIS; METHYLTRANSFERASE GENE EZH2; COLONY-STIMULATING FACTOR; BINDING-PROTEIN-ALPHA; C/EBP-ALPHA; MYELODYSPLASTIC SYNDROMES; PROGENITOR CELLS; FACTOR COMPLEXES AB Developmental processes, like blood formation, are orchestrated by transcriptional networks. Those transcriptional networks are highly responsive to various environmental stimuli and affect common precursors resulting in increased production of cells of the erythroid lineage or myeloid lineage (granulocytes, neutrophils, and macrophages). A significant body of knowledge has accumulated describing transcription factors that drive differentiation of these two major cellular pathways, in particular the antagonistic master regulators such as GATA-1 and PU.1. However, little is known about factors that work upstream of master regulators to enhance differentiation toward one lineage. These functions become especially important under various stress conditions like sudden loss of red blood cells or pathogen infection. This review describes recent studies that begin to provide evidence for such factors. An increased understanding of factors regulating cellular commitment will advance our understanding of the etiology of diseases like anemia, cancer, and possibly other blood related disorders. STEM Cells2013;31:1237-1244 C1 [Wolff, Linda; Humeniuk, Rita] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wolff, L (reprint author), 37 Convent Dr, Bethesda, MD 20892 USA. EM wolffl@mail.nih.gov NR 111 TC 13 Z9 13 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD JUL PY 2013 VL 31 IS 7 BP 1237 EP 1244 DI 10.1002/stem.1379 PG 8 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 176XB UT WOS:000321339000003 PM 23559316 ER PT J AU Liu, OS Xu, JJ Ding, G Liu, DY Fan, ZP Zhang, CM Chen, WJ Ding, YZ Tang, ZG Wang, SL AF Liu, Ousheng Xu, Junji Ding, Gang Liu, Dayong Fan, Zhipeng Zhang, Chunmei Chen, Wanjun Ding, Yaozhong Tang, Zhangui Wang, Songlin TI Periodontal Ligament Stem Cells Regulate B Lymphocyte Function via Programmed Cell Death Protein 1 SO STEM CELLS LA English DT Article DE Immunoregulation; Mesenchymal stem cells; Periodontal ligament stem cells; Periodontitis; B lymphocyte; Humoral immunity; Programmed cell death protein 1 ID MESENCHYMAL STROMAL CELLS; BONE-MARROW; MULTIPOTENT CELLS; IN-VITRO; ACTIVATION; TRANSPLANTATION; INTERLEUKIN-6; RESPONSES; RECEPTOR; SWINE AB Periodontal ligament stem cells (PDLSCs) have provided novel cell sources for tooth and periodontal tissue regeneration. Allogeneic PDLSCs can reconstruct periodontal ligament tissue that has been damaged by periodontal diseases and regulate T-cell immunity. However, the effect of PDLSCs on B cells remains unknown. Here, we treated periodontitis in a miniature pig model using allogeneic PDLSCs and showed a reduction in humoral immunity in the animals. When cocultured with normal B cells, human PDLSCs (hPDLSCs) had similar effects as bone marrow mesenchymal stem cells in suppressing B cell proliferation, differentiation, and migration, while intriguingly, hPDLSCs increased B cell viability by secreting interleukin-6. Mechanistically, hPDLSCs suppressed B cell activation through cell-to-cell contact mostly mediated by programmed cell death protein 1 and programmed cell death 1 ligand 1. Our data revealed a previously unrecognized function of PDLSCs in regulating humoral immune responses, which may represent a novel therapeutic strategy for immune-related disorders. STEM Cells2013;31:1371-1382 C1 [Liu, Ousheng; Xu, Junji; Ding, Gang; Liu, Dayong; Fan, Zhipeng; Zhang, Chunmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Salivary Gland Dis Ctr, Beijing 100050, Peoples R China. [Liu, Ousheng; Xu, Junji; Ding, Gang; Liu, Dayong; Fan, Zhipeng; Zhang, Chunmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Beijing Key Lab Tooth Regenerat & Funct Reconstru, Beijing 100050, Peoples R China. [Liu, Ousheng; Tang, Zhangui] Cent S Univ, Xiangya Hosp, Dept Oral & Maxillofacial Surg, Changsha, Hunan, Peoples R China. [Chen, Wanjun] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Ding, Yaozhong] Capital Med Univ, Dept Immunol, Beijing 100050, Peoples R China. [Wang, Songlin] Capital Med Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Beijing 100050, Peoples R China. RP Wang, SL (reprint author), Capital Med Univ, Sch Stomatol, Tian Tan Xi Li 4, Beijing 100050, Peoples R China. EM slwang@ccmu.edu.cn OI Liu, Dayong/0000-0001-8511-2658 FU Beijing Municipal Committee for Science and Technology [Z121100005212004]; National Basic Research Program of China [2010CB944801]; Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality [PHR20090510]; National Natural Science Foundation of China (NSFC) [81070799]; Funding Project to Science Facility in Institutions of Higher Learning Under the jurisdiction of Beijing Municipality [PXM 2009-014226-074691]; Intramural Research program of the National Institute of Dental and Craniofacial Research, National Institutes of Health FX This work was supported by the grant from Beijing Municipal Committee for Science and Technology (Z121100005212004; to S. W.); the National Basic Research Program of China (2010CB944801; to S. W.), the Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (PHR20090510; to S. W.), National Natural Science Foundation of China (NSFC NO. 81070799; to G. D.), and the Funding Project to Science Facility in Institutions of Higher Learning Under the jurisdiction of Beijing Municipality (PXM 2009-014226-074691; to S. W.). W. C. was supported by the Intramural Research program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 49 TC 16 Z9 17 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD JUL PY 2013 VL 31 IS 7 BP 1371 EP 1382 DI 10.1002/stem.1387 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 176XB UT WOS:000321339000016 PM 23553748 ER PT J AU Walsh, RK Aguilar, CL Facchinelli, L Valerio, L Ramsey, JM Scott, TW Lloyd, AL Gould, F AF Walsh, Rachael K. Aguilar, Cristobal L. Facchinelli, Luca Valerio, Laura Ramsey, Janine M. Scott, Thomas W. Lloyd, Alun L. Gould, Fred TI Regulation of Aedes aegypti Population Dynamics in Field Systems: Quantifying Direct and Delayed Density Dependence SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID WATER-STORAGE CONTAINERS; GENE DRIVE SYSTEMS; CULICIDAE; MOSQUITOS; DIPTERA; DENGUE; COMPETITION; STRATEGIES; THAILAND; TRANSMISSION AB Transgenic strains of Aedes aegypti have been engineered to help control transmission of dengue virus. Although resources have been invested in developing the strains, we lack data on the ecology of mosquitoes that could impact the success of this approach. Although studies of intra-specific competition have been conducted using Ae. aegypti larvae, none of these studies examine mixed age cohorts at densities that occur in the field, with natural nutrient levels. Experiments were conducted in Mexico to determine the impact of direct and delayed density dependence on Ae. aegypti populations. Natural water, food, and larval densities were used to estimate the impacts of density dependence on larval survival, development, and adult body size. Direct and delayed density-dependent factors had a significant impact on larval survival, larval development, and adult body size. These results indicate that control methods attempting to reduce mosquito populations may be counteracted by density-dependent population regulation. C1 [Walsh, Rachael K.; Gould, Fred] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Lloyd, Alun L.] N Carolina State Univ, Biomath Grad Program, Raleigh, NC 27695 USA. [Lloyd, Alun L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Aguilar, Cristobal L.; Ramsey, Janine M.] Inst Nacl Salud Publ, Ctr Reg Invest Salud Publ, CISEI3, Tapachula, Chiapas, Mexico. [Facchinelli, Luca; Valerio, Laura; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Valerio, Laura] Univ Rome, Inst Pasteur, Cenci Bolognetti Fdn, Rome, Italy. [Scott, Thomas W.; Lloyd, Alun L.; Gould, Fred] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Walsh, RK (reprint author), N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. EM rachael_katz@ncsu.edu; cris_loagui@hotmail.com; lucafacchinelli@yahoo.it; scarablaura@yahoo.it; jramsey@insp.mx; twscott@ucdavis.edu; alun_lloyd@ncsu.edu; fred_gould@ncsu.edu RI Lloyd, Alun/H-4944-2012; OI Facchinelli, Luca/0000-0002-8987-1472 FU National Institutes of Health [R01-AI54954-0IA2]; Foundation for the National Institutes of Health through the Grand Challenges in Global Health initiative FX This work was supported by National Institutes of Health grant R01-AI54954-0IA2 and a grant to the Regents of the University of California from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health initiative. NR 44 TC 5 Z9 5 U1 3 U2 25 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD JUL PY 2013 VL 89 IS 1 BP 68 EP 77 DI 10.4269/ajtmh.12-0378 PG 10 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 185BG UT WOS:000321939600013 PM 23669230 ER PT J AU Shah, M Targoff, IN Rice, MM Miller, FW Rider, LG AF Shah, Mona Targoff, Ira N. Rice, Madeline M. Miller, Frederick W. Rider, Lisa G. CA Childhood Myositis Heterogeneity TI Ultraviolet Radiation Exposure Is Associated With Clinical and Autoantibody Phenotypes in Juvenile Myositis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; SYSTEMIC-LUPUS-ERYTHEMATOSUS; ENVIRONMENTAL EXPOSURES; VITAMIN-D; PREVALENCE; INTENSITY; ONSET AB ObjectiveGenetic and environmental factors may contribute to the etiology of the juvenile idiopathic inflammatory myopathies (IIMs), which are systemic autoimmune diseases that are characterized by muscle and skin inflammation. We undertook this study to investigate the association between ultraviolet radiation (UVR) exposure and the clinical and autoantibody expression of juvenile IIM. MethodsThe relationship between UVR exposure in the month before symptom onset and the prevalence of juvenile dermatomyositis (DM), compared to juvenile polymyositis (PM), was assessed in 298 juvenile IIM patients. Among the patients with juvenile DM, the association between UVR exposure and presence of myositis autoantibodies was assessed. Regression models were stratified by sex and race. The association between the regional UV index in US geoclimatic zones and the clinical and autoantibody subgroups was examined by weighted least squares regression analysis. ResultsAmong girls in this population, the odds of having juvenile DM, compared to juvenile PM, increased per unit increase in the patients' highest UV index in the month before symptom onset (odds ratio [OR] 1.18, 95% confidence interval 1.00-1.40). Moreover, both the mean and highest UV indices were associated with increasing odds of having anti-p155/140 autoantibodies, with the strongest odds in white males (ORs of 1.30 and 1.23, respectively). No association was observed between the UV index and presence of anti-MJ autoantibodies or lack of any myositis autoantibodies. Across all 9 US geoclimatic regions, the mean UV index was associated with increasing odds of having juvenile DM and anti-p155/140 autoantibodies, but decreasing odds of having anti-MJ autoantibodies. ConclusionShort-term UVR exposure prior to illness onset may have a role in the clinical and serologic expression of juvenile myositis. Further research examining the mechanisms of action of UVR in the pathogenesis of juvenile IIM is suggested from these findings. C1 [Shah, Mona; Miller, Frederick W.; Rider, Lisa G.] NIEHS, NIH, Bethesda, MD 20892 USA. [Shah, Mona; Rice, Madeline M.] George Washington Univ, Sch Med, Washington, DC USA. [Targoff, Ira N.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City VA Med Ctr, Oklahoma City, OK USA. [Targoff, Ira N.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. 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 NIH (Intramural Research Programs of the National Institute of Environmental Health Sciences) [ES-101074]; NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases); Food and Drug Administration Center for Biologics Evaluation and Research, Office of Biostatistics and Epidemiology FX Supported in part by the NIH (Intramural Research Programs of the National Institute of Environmental Health Sciences [project number ES-101074] and the National Institute of Arthritis and Musculoskeletal and Skin Diseases) and the Food and Drug Administration Center for Biologics Evaluation and Research, Office of Biostatistics and Epidemiology. NR 16 TC 15 Z9 15 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD JUL PY 2013 VL 65 IS 7 BP 1934 EP 1941 DI 10.1002/art.37985 PG 8 WC Rheumatology SC Rheumatology GA 187XM UT WOS:000322155000029 PM 23658122 ER PT J AU Yue, XY Kiesewetter, DO Guo, JX Sun, ZC Zhang, XX Zhu, L Niu, G Ma, Y Lang, LX Chen, XY AF Yue, Xuyi Kiesewetter, Dale O. Guo, Jinxia Sun, Zhongchan Zhang, Xiaoxiang Zhu, Lei Niu, Gang Ma, Ying Lang, Lixin Chen, Xiaoyuan TI Development of a New Thiol Site-Specific Prosthetic Group and Its Conjugation with [Cys(40)]-exendin-4 for in Vivo Targeting of Insulinomas SO BIOCONJUGATE CHEMISTRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; REACTIVE F-18-LABELING AGENT; LOW-DENSITY LIPOPROTEINS; N-SUCCINIMIDYL; GLP-1 RECEPTOR; PEPTIDES; PROTEINS; PET; F-18; ANALOGS AB A new tracer, N-5-[F-18]fluoropentylmaleimide ([F-18]FPenM), for site-specific labeling of free thiol group in proteins and peptides was developed. The tracer was synthesized in three steps (F-18 displacement of the aliphatic tosylate, di-Boc removal by TFA to expose free amine, and incorporation of the free amine into a maleimide). The radiosynthesis was completed in 110 min with 11-17% radiochemical yield (uncorrected), and specific activity of 20-49 GBq/mu mol. [F-18]FPenM showed comparable labeling efficiency with N-[2-(4-[F-18]-fluorobenzamido)ethyl]maleimide ([F-18]FBEM). Its application was demonstrated by conjugation with glucagon-like peptide type 1 (GLP-1) analogue [cys(40)]-exendin-4. The cell uptake, binding affinity, imaging properties, biodistribution, and metabolic stability of the radiolabeled [F-18]FPenM-[cys(40)]-exendin-4 were studied using INS-1 tumor cells and INS-1 xenograft model. Positron emission tomography (PET) results showed that the new thiol-specific tracer, [F-18]FPenM-[cys(40)]-exendin-4, had high tumor uptake (20.32 +/- 4.36%ID/g at 60 min postinjection) and rapid liver and kidney clearance, which was comparable to the imaging results with [F-18]FBEM-[cys(40)]-exendin-4 reported by our group. C1 [Yue, Xuyi; Kiesewetter, Dale O.; Guo, Jinxia; Sun, Zhongchan; Zhang, Xiaoxiang; Zhu, Lei; Niu, Gang; Ma, Ying; Lang, Lixin; Chen, Xiaoyuan] NIBIB, NIH, Bethesda, MD 20892 USA. [Yue, Xuyi; Guo, Jinxia; Zhu, Lei] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Chen, XY (reprint author), NIBIB, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM Shawn.Chen@nih.gov RI Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health; Center for Neuroscience and Regenerative Medicine (CNRM) through Henry Jackson Foundation FX This work was supported by the intramural research program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. The authors acknowledge the NIH Warren Grant Magnuson Clinical Center's PET Department for radioisotope production. Lei Zhu was partially supported by the Center for Neuroscience and Regenerative Medicine (CNRM) through Henry Jackson Foundation. NR 49 TC 8 Z9 8 U1 3 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 EI 1520-4812 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JUL PY 2013 VL 24 IS 7 BP 1191 EP 1200 DI 10.1021/bc400084u PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 187FV UT WOS:000322103200008 PM 23750453 ER PT J AU Hafez, D Ni, T Mukherjee, S Zhu, J Ohler, U AF Hafez, Dina Ni, Ting Mukherjee, Sayan Zhu, Jun Ohler, Uwe TI Genome-wide identification and predictive modeling of tissue-specific alternative polyadenylation SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT Joint 21st Annual Meeting of Intelligent Systems for Molecular Biology (ISMB) / 12th European Conference on Computational Biology (ECCB) CY JUL 21-23, 2013 CL Berlin, GERMANY ID MESSENGER-RNA POLYADENYLATION; HUMAN DNA-SEQUENCES; SIGNALS; SITES; TRANSCRIPTION; CLEAVAGE; COMPLEX; CELLS; DETERMINANTS; RECOGNITION AB Motivation: Pre-mRNA cleavage and polyadenylation are essential steps for 30-end maturation and subsequent stability and degradation of mRNAs. This process is highly controlled by cis-regulatory elements surrounding the cleavage/polyadenylation sites (polyA sites), which are frequently constrained by sequence content and position. More than 50% of human transcripts have multiple functional polyA sites, and the specific use of alternative polyA sites (APA) results in isoforms with variable 30-untranslated regions, thus potentially affecting gene regulation. Elucidating the regulatory mechanisms underlying differential polyA preferences in multiple cell types has been hindered both by the lack of suitable data on the precise location of cleavage sites, as well as of appropriate tests for determining APAs with significant differences across multiple libraries. Results: We applied a tailored paired-end RNA-seq protocol to specifically probe the position of polyA sites in three human adult tissue types. We specified a linear-effects regression model to identify tissue-specific biases indicating regulated APA; the significance of differences between tissue types was assessed by an appropriately designed permutation test. This combination allowed to identify highly specific subsets of APA events in the individual tissue types. Predictive models successfully classified constitutive polyA sites from a biologically relevant background (auROC = 99.6%), as well as tissue-specific regulated sets from each other. We found that the main cis-regulatory elements described for polyadenylation are a strong, and highly informative, hallmark for constitutive sites only. Tissue-specific regulated sites were found to contain other regulatory motifs, with the canonical polyadenylation signal being nearly absent at brain-specific polyA sites. Together, our results contribute to the understanding of the diversity of post-transcriptional gene regulation. C1 [Hafez, Dina; Mukherjee, Sayan; Ohler, Uwe] Duke Univ, Dept Comp Sci, Durham, NC 27708 USA. [Hafez, Dina; Ohler, Uwe] Max Delbruck Ctr, Berlin Inst Med Syst Biol, D-13125 Berlin, Germany. [Ni, Ting; Zhu, Jun] NHLBI, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [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. [Mukherjee, Sayan; Ohler, Uwe] Duke Univ, Med Ctr, Inst Genome Sci & Policy, Durham, NC 27708 USA. [Mukherjee, Sayan] Duke Univ, Dept Stat Sci, Durham, NC 27708 USA. RP Ohler, U (reprint author), Duke Univ, Dept Comp Sci, Durham, NC 27708 USA. EM uwe.ohler@duke.edu OI Mukherjee, Sayan/0000-0002-6715-3920 NR 51 TC 9 Z9 9 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUL 1 PY 2013 VL 29 IS 13 BP 108 EP 116 DI 10.1093/bioinformatics/btt233 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 182MD UT WOS:000321746100013 ER PT J AU Chowdhury, SA Shackney, SE Heselmeyer-Haddad, K Ried, T Schafer, AA Schwartz, R AF Chowdhury, Salim Akhter Shackney, Stanley E. Heselmeyer-Haddad, Kerstin Ried, Thomas Schaeffer, Alejandro A. Schwartz, Russell TI Phylogenetic analysis of multiprobe fluorescence in situ hybridization data from tumor cell populations SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT Joint 21st Annual Meeting of Intelligent Systems for Molecular Biology (ISMB) / 12th European Conference on Computational Biology (ECCB) CY JUL 21-23, 2013 CL Berlin, GERMANY ID BREAST-CANCER; CERVICAL-CANCER; TREE MODELS; GENE; HETEROGENEITY; PROGRESSION; EVOLUTION; MYC; METASTASIS; CARCINOMAS AB Motivation: Development and progression of solid tumors can be attributed to a process of mutations, which typically includes changes in the number of copies of genes or genomic regions. Although comparisons of cells within single tumors show extensive heterogeneity, recurring features of their evolutionary process may be discerned by comparing multiple regions or cells of a tumor. A useful source of data for studying likely progression of individual tumors is fluorescence in situ hybridization (FISH), which allows one to count copy numbers of several genes in hundreds of single cells. Novel algorithms for interpreting such data phylogenetically are needed, however, to reconstruct likely evolutionary trajectories from states of single cells and facilitate analysis of tumor evolution. Results: In this article, we develop phylogenetic methods to infer likely models of tumor progression using FISH copy number data and apply them to a study of FISH data from two cancer types. Statistical analyses of topological characteristics of the tree-based model provide insights into likely tumor progression pathways consistent with the prior literature. Furthermore, tree statistics from the resulting phylogenies can be used as features for prediction methods. This results in improved accuracy, relative to unstructured gene copy number data, at predicting tumor state and future metastasis. C1 [Chowdhury, Salim Akhter] Joint Carnegie Mellon Univ Pittsburgh PhD Program, Pittsburgh, PA 15213 USA. [Chowdhury, Salim Akhter; Schwartz, Russell] Carnegie Mellon Univ, Lane Ctr Computat Biol, Pittsburgh, PA 15213 USA. [Shackney, Stanley E.] Intelligent Oncotherapeut, Pittsburgh, PA 15243 USA. [Heselmeyer-Haddad, Kerstin; Ried, Thomas] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Schaeffer, Alejandro A.] NIH, Computat Biol Branch, NCBI, Bethesda, MD 20892 USA. [Schwartz, Russell] Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. RP Schwartz, R (reprint author), Carnegie Mellon Univ, Lane Ctr Computat Biol, Pittsburgh, PA 15213 USA. EM sachowdh@andrew.cmu.edu RI Schwartz, Russell/A-1998-2016 OI Schwartz, Russell/0000-0002-4970-2252 NR 44 TC 20 Z9 20 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUL 1 PY 2013 VL 29 IS 13 BP 189 EP 198 DI 10.1093/bioinformatics/btt205 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 182MD UT WOS:000321746100021 ER PT J AU Koh, DS Moody, M Jo, J AF Koh, Duk-Su Moody, Mark Jo, Junghyo TI Collection of islets of Langerhans using an equilibrium method SO BIOTECHNIQUES LA English DT Article DE islets; tissue; isolation; purification; equilibrium ID INSULIN-SECRETION; PANCREATIC-ISLETS; DYNAMICS; GLUCOSE; RELEASE; CELLS AB Here we present a convenient method for easy hand selection of enzymatically isolated small tissues such as islets of Langerhans. Islets are continuously collected in a micropipette tip connected to a peristaltic pump. After entering the conical micropipette tip, the islets are quickly dragged up by solution flow, but this movement subsequently decreases as the flow rate decreases. Thus, the islets are trapped at a specific height where downward gravitation balances upward buoyancy and the drag provided by solution flow. Our device allows more efficient isolation of islets compared to conventional manual collection methods. C1 [Koh, Duk-Su; Moody, Mark] Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA. [Koh, Duk-Su] POSTECH, Dept Phys, Pohang, South Korea. [Jo, Junghyo] Natl Inst Diabet & Digest & Kidney Dis, Lab Biol Modeling, NIH, Bethesda, MD USA. RP Koh, DS (reprint author), Univ Washington, Sch Med, Dept Physiol & Biophys, Seattle, WA 98195 USA. EM koh@uw.edu FU KOSEF [R01-2002-000-00285-0]; NIH [DK080840, GM83913]; Diabetes Endocrinology Research Center of the University of Washington [DX017047] FX We thank M. Gilbert, B. Hille, and I. Sweet for comments on the manuscript and J. Willard for providing mouse pancreatic tissues. This work was supported by grants from the KOSEF (R01-2002-000-00285-0 to D.S.K.), from the NIH (DK080840 to D.S.K and GM83913 to Bertil Hille), and from the Diabetes Endocrinology Research Center of the University of Washington (DX017047). This paper is subject to the NIH Public Access Policy. NR 10 TC 1 Z9 1 U1 0 U2 3 PU BIOTECHNIQUES OFFICE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUL PY 2013 VL 55 IS 1 BP 34 EP 37 DI 10.2144/000114053 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 188PW UT WOS:000322207000007 PM 23834383 ER PT J AU Patterson, AD Carlson, BA Li, F Bonzo, JA Yoo, MH Krausz, KW Conrad, M Chen, C Gonzalez, FJ Hatfield, DL AF Patterson, Andrew D. Carlson, Bradley A. Li, Fei Bonzo, Jessica A. Yoo, Min-Hyuk Krausz, Kristopher W. Conrad, Marcus Chen, Chi Gonzalez, Frank J. Hatfield, Dolph L. TI Disruption of Thioredoxin Reductase 1 Protects Mice from Acute Acetaminophen-Induced Hepatotoxicity through Enhanced NRF2 Activity SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID INDUCED LIVER-INJURY; TERMINAL KINASE; GLUTATHIONE PEROXIDASE-1; MAMMALIAN THIOREDOXIN; REDOX HOMEOSTASIS; ACTIVATION; CANCER; MOUSE; RESISTANCE; EXPRESSION AB The critical importance of glutathione in mitigating the deleterious effects of electrophile generating drugs such as acetaminophen (APAP) is well established. However, the role of other antioxidant systems, such as that provided by thioredoxin, has not been extensively studied. Selenoprotein thioredoxin reductase 1 (Third!) is important for attenuating activation of the apoptosis signaling-regulating kinase 1 (ASK1) and the c-Jun N-terminal kinase (JNK) pathway caused by high doses of APAP. Therefore, a detailed investigation of the role of Txnrd1 in APAP-induced hepatotoxicity was conducted. Liver-specific Txnrd1 knockout mice (Txnrd1(Delta Liv)) were generated and treated with a hepatotoxic dose (400 mg/kg) of APAP for 1 or 6 h. Liver toxicity was assessed by measuring the activities of liver enzymes aspartate aminotransferase and alanine aminotransferase in serum, in addition to histopathological analysis of liver sections and analysis of glutathione levels. At 1 h post-APAP treatment, total and mitochondrial glutathione levels in control and Txnrd1(Delta Liv) mice were similarly depleted. However, at 6 h post-APAP treatment, Txnrd1(Delta Liv) mice were resistant to APAP toxicity as liver enzymes and histology were not significantly different from the corresponding untreated mice. Analyses revealed the compensatory up-regulation of many of the nuclear factor erythroid 2-related factor 2 (NRF2) target genes and proteins in Txnrd1(Delta Liv) mice with and without APAP treatment. Yet, JNK was phosphorylated to a similar extent in APAP-treated control mice. The results suggest that Txnrd1(Delta Liv) mice are primed for xenobiotic detoxication primarily through NRF2 activation. C1 [Patterson, Andrew D.; Li, Fei; Bonzo, Jessica A.; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Patterson, Andrew D.; Carlson, Bradley A.; Yoo, Min-Hyuk; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, NIH, Bethesda, MD 20892 USA. [Conrad, Marcus] Helmholtz Zentrum Munchen, Inst Dev Genet, D-85764 Neuherberg, Germany. [Chen, Chi] Univ Minnesota, Dept Food Sci & Nutr, St Paul, MN 55108 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov; hatfield@mail.nih.gov RI Li, Fei/F-6849-2013; Patterson, Andrew/G-3852-2012; OI Patterson, Andrew/0000-0003-2073-0070; Conrad, Marcus/0000-0003-1140-5612 FU Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health (to D.L.H. and F.J.G.). NR 45 TC 20 Z9 20 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD JUL PY 2013 VL 26 IS 7 BP 1088 EP 1096 DI 10.1021/tx4001013 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 187AD UT WOS:000322086800014 PM 23697945 ER PT J AU Ganini, D Hollnagel, HC Colepicolo, P Barros, MP AF Ganini, D. Hollnagel, H. C. Colepicolo, P. Barros, M. P. TI Hydrogen peroxide and nitric oxide trigger redox-related cyst formation in cultures of the dinoflagellate Lingulodinium polyedrum SO HARMFUL ALGAE LA English DT Article DE Carotenoid; Gonyaulax; Harmful algal blooms; Oxidative stress; Peridinin; Photosynthesis ID NITRATE REDUCTASE-ACTIVITY; GONYAULAX-POLYEDRA; SUPEROXIDE-DISMUTASE; ALEXANDRIUM-MINUTUM; LIPID-PEROXIDATION; PRODUCTION PATHWAY; OXIDATIVE DAMAGE; CHLOROPHYLL-A; ENCYSTMENT; PERIDININ AB The dinoflagellate Lingulodinium polyedrum is a toxin producer that shows the ability of turning to resting cysts as a survival strategy when exposed to environmental unfavorable conditions, such as nitrogen and phosphorus depletion, abrupt changes in temperature or light, and chemical or mechanical stress. Algal adaptation to all these conditions involves hydrogen peroxide (H2O2) and nitric oxide (NO center dot) as key redox signals for housekeeping cellular processes. Thus, we aim here to shed light on the role of H2O2 and NO center dot (from aqueous decomposition of sodium nitroprusside, SNP)- as prooxidant agents and putative redox signals for encystment of the dinoflagellate L. polyedrum. Harsh oxidative stress imposed by 500 mu M H2O2 treatment forced L. polyedrum cells to rapidly encyst, in less than 30 min, whereas slower cyst formation was observed upon lower H2O2 doses. L. polyedrum encystment was marked by a significant increase in the antioxidant carotenoid peridinin, although other photosynthetic pigments (chlorophyll a and beta-carotene) and light-harvesting complexes (peridinin complex protein, PCP) were all diminished in cyst forms. Although SOD activity (a frontline antioxidant enzyme) was severely inhibited by increasing doses of H2O2, a theoretical compensatory effect was provided by the dose-dependent increase of ascorbate peroxidase activity (APX), which resulted in significant lower levels of lipid peroxidation during cyst formation. Although SNP data cannot be fully compared to those found with H2O2 treatments, changes in APX activity and in biomarkers of lipid and protein oxidation matched the dose-responses found in H2O2 experiments, revealing similar biochemical and morphological responses against increasing oxidative conditions during cyst formation. Our data significantly contribute to a better understanding of the relationship between encystment, photosynthesis, and antioxidant responses triggered by H2O2 and NO center dot in L. polyedrum, a harmful diarrhetic shellfish poisoning toxin (DSPs) producer. (C) 2013 Elsevier B.V. All rights reserved. C1 [Ganini, D.; Barros, M. P.] Univ Cruzeiro Sul, CBS, Postgrad Program Hlth Sci Environm Chem, BR-08060070 Sao Paulo, Brazil. [Ganini, D.] NIEHS, Free Radical Metab Grp, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Hollnagel, H. C.] Fac Mario Schenberg, Postgrad Program Environm Management, Cotia, SP, Brazil. [Colepicolo, P.] Univ Sao Paulo IQ USP, Dept Biochem, Inst Quim, Sao Paulo, Brazil. RP Barros, MP (reprint author), Univ Cruzeiro Sul, CBS, Av Ussiel Cirilo 225, BR-08060070 Sao Paulo, Brazil. EM marcelo.barros@cruzeirodosul.edu.br RI Barros, Marcelo/K-1410-2013; Colepicolo, Pio/C-1349-2013; CEPID, Redoxoma/J-2971-2015 OI Barros, Marcelo/0000-0003-3565-8331; FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Programa de Suporte a Pos-graduacao de Instituicoes de Ensino Particulares; da Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (PROSUP/CAPES, Brazil); Projeto Redoxoma, and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Bolsa Produtividade em Pesquisa, Nivel 2 [307474/2012-7]; CNPq, Brazil FX The authors are indebted to Dr. Chrislaine O. Soares and B.Sc. Aline B. Glavina for technical support in dinoflagellate cultures, and to Prof. David Morse, at Institut de Recherche en Biologie Vegetale, Departement de Sciences Biologiques, Universite de Montreal, Montreal, Canada, for providing specific rabbit antibodies against dinoflagellate Rubisco and PCP proteins. This research was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Programa de Suporte a Pos-graduacao de Instituicoes de Ensino Particulares, da Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (PROSUP/CAPES, Brazil), "Red iberoamericana para el estudio de nuevos carotenoides bioactivos como ingredientes de alimentos" (112RT0445; IBER-CAROT/CYTED), Projeto Redoxoma, and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Bolsa Produtividade em Pesquisa, Nivel 2, #307474/2012-7, CNPq, Brazil).[SS] NR 56 TC 4 Z9 5 U1 0 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9883 J9 HARMFUL ALGAE JI Harmful Algae PD JUL PY 2013 VL 27 BP 121 EP 129 DI 10.1016/j.hal.2013.05.002 PG 9 WC Marine & Freshwater Biology SC Marine & Freshwater Biology GA 189WG UT WOS:000322298400011 ER PT J AU Cortez, KJ Proschan, MA Barrett, L Brust, DG Formentini, E Davey, RT Masur, H Polis, MA Neumann, AU Kottilil, S AF Cortez, K. J. Proschan, M. A. Barrett, L. Brust, D. G. Formentini, E. Davey, R. T. Masur, H. Polis, M. A. Neumann, A. U. Kottilil, S. TI Baseline CD4+T-Cell Counts Predict HBV Viral Kinetics to Adefovir Treatment in Lamivudine-Resistant HBV-Infected Patients with or without HIV Infection SO HIV CLINICAL TRIALS LA English DT Article DE CD4; HBV; HIV; viral kinetics ID HEPATITIS-B-VIRUS; ANTIRETROVIRAL THERAPY; ANTIVIRAL THERAPY; AIDS; INDIVIDUALS; PROGRESSION; MORTALITY; COHORT; IMPACT AB Background: Coinfection with HIV and hepatitis B virus (HBV) substantially alters the course of HBV. Directly acting anti-HBV agents suppress HBV viral levels; however, the kinetics of HBV decline in mono- and coinfected persons have not been evaluated. We investigated the role of baseline CD4+ T-cell counts as a predictor of HBV response to adefovir (ADV) therapy in chronic HBV with and without HIV coinfection. Methods: We conducted a double-blind, randomized, placebo-controlled study of HIV-infected (n = 12) and uninfected (n = 5) chronic HBV patients treated with ADV. Five HIV uninfected patients received ADV; the HIV+ patients received ADV or placebo for a total of 48 weeks. At the end of 48 weeks, all patients received open-label ADV for an additional 48 weeks. HBV, HIV viral loads, CD4+ T-cell counts, and safety labs were performed on days 0, 1, 3, 5, 7, 10, 14, and 28 and then every 4 weeks. Results: Lower HBV slopes were observed among coinfected compared to monoinfected patients (P=.027 at 4 weeks, P=.019 at 24 weeks, and P=.045 at 48 weeks). Using a mixed model analysis, we found a significant difference between the slopes of the 2 groups at 48 weeks (P=.045). Baseline CD4+ T-cell count was the only independent predictor of HBV decline in all patients. Conclusion: HIV coinfection is associated with slower HBV response to ADV. Baseline CD4+ T-cell count and not IL28B genotype is an independent predictor of HBV decline in all patients, emphasizing the role of immune status on clearance of HBV. C1 [Cortez, K. J.] US FDA, Div Human Tissues, Off Cell Therapy & Gene Therapies, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Proschan, M. A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Barrett, L.; Davey, R. T.; Polis, M. A.; Kottilil, S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Brust, D. G.] Lee Mem Hlth Syst, Div Infect Dis, Ft Myers, FL USA. [Formentini, E.] NIH, Div Microbiol & Infect Dis, Bethesda, MD 20892 USA. [Masur, H.] NIH, Dept Crit Care Med, Ctr Clin, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Neumann, A. U.] Bar Ilan Univ, Ramat Dan, Israel. RP Kottilil, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10 Rm 11N 204, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268 FU NIH (National Institute of Allergy and Infectious Diseases) FX This research was supported in part by the Intramural Research Program of the NIH (National Institute of Allergy and Infectious Diseases). NR 16 TC 2 Z9 2 U1 0 U2 4 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119-3627 USA SN 1528-4336 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD JUL-AUG PY 2013 VL 14 IS 4 BP 149 EP 159 DI 10.1310/hct1404-149 PG 11 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 185UA UT WOS:000321994600003 PM 23924587 ER PT J AU Pellicano, C Kane, RL Gallo, A Li, XB Stern, SK Ikonomidou, VN Evangelou, IE Ohayon, JM Ehrmantraut, M Cantor, FK Bagnato, F AF Pellicano, Clelia Kane, Robert L. Gallo, Antonio Li Xiaobai Stern, Susan K. Ikonomidou, Vasiliki N. Evangelou, Iordanis E. Ohayon, Joan M. Ehrmantraut, Mary Cantor, Fredric K. Bagnato, Francesca TI Cognitive Impairment and Its Relation to Imaging Measures in Multiple Sclerosis: A Study Using a Computerized Battery SO JOURNAL OF NEUROIMAGING LA English DT Article DE Multiple sclerosis; 3TMRI; cognitive impairment; ANAM; computerized batteries ID TRAUMATIC BRAIN-INJURY; NEUROPSYCHOLOGICAL ASSESSMENT; PROCESSING SPEED; CORTICAL ATROPHY; GREY-MATTER; LESION; REGISTRATION; DYSFUNCTION; DISABILITY; DISEASE AB BACKGROUND AND PURPOSE Cognitive impairment (CI) is an important component of multiple sclerosis (MS) disability. A complex biological interplay between white matter (WM) and gray matter (GM) disease likely sustains CI. This study aims to address this issue by exploring the association between the extent of normal WM and GM disease and CI. METHODS Cognitive function of 24 MS patients and 24 healthy volunteers (HVs) was studied using the Automated Neuropsychological Assessment Metrics (ANAM) battery. WM focal lesions and normal appearing WM (NAWM) volume in patients, cortical thickness (CTh) and deep GM structure volumes in both patients and HVs were measured by high field strength (3.0-Tesla; 3T) imaging. RESULTS An analysis of covariance showed that patients performed worse than HVs on Code Substitution Delayed Memory (P = .04) and Procedural Reaction Time (P =.05) indicative of reduced performance in memory, cognitive flexibility, and processing speed. A summary score (Index of Cognitive Efficiency) indicating global test battery performance was also lower for the patient group (P =.04). Significant associations, as determined by the Spearman rank correlation tests, were noted between each of these 3 cognitive scores and measures of NAWM volume [CDD-TP1(r =.609; P =.0035), PRO-TP1 (r =.456; P = .029) and ICE (r =.489; P =.0129)], CTh (r =.5; P <= .05) and volume of subcortical normal appearing GM (NAGM) structures (r =.4; P <= .04), but not WM lesions. CONCLUSIONS Both NAWM and NAGM volumes are related to CI in MS. The results highlight once again the urgent need to develop pharmacological strategies protecting patients from widespread neurodegeneration as possible preventive strategies of CI development. C1 [Pellicano, Clelia; Gallo, Antonio; Stern, Susan K.; Ikonomidou, Vasiliki N.; Evangelou, Iordanis E.; Ohayon, Joan M.; Ehrmantraut, Mary; Cantor, Fredric K.; Bagnato, Francesca] NINDS, Neuroimmunol Branch NIB, NIH, Bethesda, MD 20892 USA. [Kane, Robert L.] VA Maryland Healthcare Syst, Baltimore, MD USA. [Li Xiaobai] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Bagnato, F (reprint author), Vanderbilt Univ, Inst Imaging Sci, Dept Radiol & Radiol Sci, 1161 21st Ave S,AA 1105 MCN, Nashville, TN 37232 USA. EM francesca.r.bagnato@vanderbilt.edu RI Pellicano, Clelia/K-1062-2016 OI Pellicano, Clelia/0000-0002-3272-1094 FU NINDS, NIH FX This research was supported by the Intramural Research Program of the NINDS, NIH. NR 45 TC 2 Z9 2 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1051-2284 J9 J NEUROIMAGING JI J. Neuroimaging PD JUL PY 2013 VL 23 IS 3 BP 445 EP 452 DI 10.1111/j.1552-6569.2011.00687.x PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 175EN UT WOS:000321213500024 PM 23227967 ER PT J AU Saira, K Lin, XD DePasse, JV Halpin, R Twaddle, A Stockwell, T Angus, B Cozzi-Lepri, A Delfino, M Dugan, V Dwyer, DE Freiberg, M Horban, A Losso, M Lynfield, R Wentworth, DN Holmes, EC Davey, R Wentworth, DE Ghedin, E AF Saira, Kazima Lin, Xudong DePasse, Jay V. Halpin, Rebecca Twaddle, Alan Stockwell, Timothy Angus, Brian Cozzi-Lepri, Alessandro Delfino, Marina Dugan, Vivien Dwyer, Dominic E. Freiberg, Matthew Horban, Andrzej Losso, Marcelo Lynfield, Ruth Wentworth, Deborah N. Holmes, Edward C. Davey, Richard Wentworth, David E. Ghedin, Elodie CA INSIGHT FLU002 Study Grp INSIGHT FLU003 Study Grp TI Sequence Analysis of In Vivo Defective Interfering-Like RNA of Influenza A H1N1 Pandemic Virus SO JOURNAL OF VIROLOGY LA English DT Article ID INFECTED-CELLS; VIRAL-RNA; INTERNAL DELETION; DI RNAS; SINGLE; EXPRESSION; GENERATION; PROTECTION; PARTICLES; INOCULUM AB Influenza virus defective interfering (DI) particles are naturally occurring noninfectious virions typically generated during in vitro serial passages in cell culture of the virus at a high multiplicity of infection. DI particles are recognized for the role they play in inhibiting viral replication and for the impact they have on the production of infectious virions. To date, influenza virus DI particles have been reported primarily as a phenomenon of cell culture and in experimentally infected embryonated chicken eggs. They have also been isolated from a respiratory infection of chickens. Using a sequencing approach, we characterize several subgenomic viral RNAs from human nasopharyngeal specimens infected with the influenza A(H1N1)pdm09 virus. The distribution of these in vivo-derived DI-like RNAs was similar to that of in vitro DIs, with the majority of the defective RNAs generated from the PB2 (segment 1) of the polymerase complex, followed by PB1 and PA. The lengths of the in vivo-derived DI-like segments also are similar to those of known in vitro DIs, and the in vivo-derived DI-like segments share internal deletions of the same segments. The presence of identical DI-like RNAs in patients linked by direct contact is compatible with transmission between them. The functional role of DI-like RNAs in natural infections remains to be established. C1 [Saira, Kazima; DePasse, Jay V.; Twaddle, Alan; Ghedin, Elodie] Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Ctr Vaccine Res, Pittsburgh, PA 15260 USA. [Lin, Xudong; Halpin, Rebecca; Stockwell, Timothy; Dugan, Vivien; Wentworth, David E.] J Craig Venter Inst, Rockville, MD USA. [Angus, Brian] Univ Oxford, Nuffield Dept Med, Oxford, England. [Cozzi-Lepri, Alessandro] UCL, Res Dept Infect & Populat Hlth, London, England. [Delfino, Marina] Clin Res Coordinat Latin Amer CICAL, Buenos Aires, DF, Argentina. [Dwyer, Dominic E.] Univ Sydney, Westmead Hosp, Ctr Infect Dis & Microbiol, Sydney, NSW 2006, Australia. [Freiberg, Matthew] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. [Horban, Andrzej] Med Univ Warsaw, Warsaw, Poland. [Horban, Andrzej] Hosp Infect Dis, Warsaw, Poland. [Losso, Marcelo] Hosp Gen Agudos Jose Maria Ramos Mejia, Serv Inmunocomprometidos, Buenos Aires, DF, Argentina. [Lynfield, Ruth] Minnesota Dept Hlth, St Paul, MN USA. [Wentworth, Deborah N.] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Davey, Richard] NIAID, NIH, Bethesda, MD 20892 USA. RP Ghedin, E (reprint author), Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Ctr Vaccine Res, Pittsburgh, PA 15260 USA. EM elg21@pitt.edu OI Twaddle, Alan/0000-0001-9293-7607; Angus, Brian/0000-0003-3598-7784; Wentworth, David/0000-0002-5190-980X; Holmes, Edward/0000-0001-9596-3552 FU NIH [UOI-AI068641]; SAIC Prime Contract [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services [HHSN272200900007C] FX INSIGHT is funded by NIH grant UOI-AI068641, and the FLU 002 and FLU 003 studies are funded by SAIC Prime Contract HHSN261200800001E, NCI/NIAID. This research was supported with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services, under contract number HHSN272200900007C (D.E.W., E.G., E.C.H., R.H., and X.L.). NR 38 TC 29 Z9 29 U1 0 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2013 VL 87 IS 14 BP 8064 EP 8074 DI 10.1128/JVI.00240-13 PG 11 WC Virology SC Virology GA 172PX UT WOS:000321017700026 PM 23678180 ER PT J AU Chang, KO Sosnovtsev, SV Belliot, G Wang, QH Saif, LJ Green, KY AF Chang, Kyeong-Ok Sosnovtsev, Stanislav V. Belliot, Gael Wang, Qiuhong Saif, Linda J. Green, Kim Y. TI Reverse Genetics System for Porcine Enteric Calicivirus, a Prototype Sapovirus in the Caliciviridae (vol 79, pg 1409, 2005) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Chang, Kyeong-Ok; Sosnovtsev, Stanislav V.; Belliot, Gael; Green, Kim Y.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wang, Qiuhong; Saif, Linda J.] Ohio State Univ, Dept Vet Prevent Med, Food Anim Hlth Res Program, Wooster, OH USA. RP Chang, KO (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2013 VL 87 IS 14 BP 8266 EP 8266 DI 10.1128/JVI.01364-13 PG 1 WC Virology SC Virology GA 172PX UT WOS:000321017700047 ER PT J AU Brooke, CB Ince, WL Wrammert, J Ahmed, R Wilson, PC Bennink, JR Yewdell, JW AF Brooke, Christopher B. Ince, William L. Wrammert, Jens Ahmed, Rafi Wilson, Patrick C. Bennink, Jack R. Yewdell, Jonathan W. TI Most Influenza A Virions Fail To Express at Least One Essential Viral Protein (vol 87, pg 3155, 2013) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Brooke, Christopher B.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Microbiol & Immunol, Div Infect Dis,Dept Med, Atlanta, GA 30322 USA. Univ Chicago, Dept Med, Rheumatol Sect, Comm Immunol,Knapp Ctr Lupus & Immunol Res, Chicago, IL 60637 USA. RP Brooke, CB (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2013 VL 87 IS 14 BP 8267 EP 8267 DI 10.1128/JVI.01308-13 PG 1 WC Virology SC Virology GA 172PX UT WOS:000321017700048 ER PT J AU Schrouff, J Rosa, MJ Rondina, JM Marquand, AF Chu, C Ashburner, J Phillips, C Richiardi, J Mourao-Miranda, J AF Schrouff, J. Rosa, M. J. Rondina, J. M. Marquand, A. F. Chu, C. Ashburner, J. Phillips, C. Richiardi, J. Mourao-Miranda, J. TI PRoNTo: Pattern Recognition for Neuroimaging Toolbox SO NEUROINFORMATICS LA English DT Article DE Neuroimaging software; Pattern recognition; Machine learning; Image analysis; MVPA ID RELEVANCE VECTOR MACHINE; VENTRAL TEMPORAL CORTEX; ALZHEIMERS-DISEASE; BRAIN ACTIVATION; SINGLE-SUBJECT; VISUAL-CORTEX; FMRI; CLASSIFICATION; SELECTION; FACES AB In the past years, mass univariate statistical analyses of neuroimaging data have been complemented by the use of multivariate pattern analyses, especially based on machine learning models. While these allow an increased sensitivity for the detection of spatially distributed effects compared to univariate techniques, they lack an established and accessible software framework. The goal of this work was to build a toolbox comprising all the necessary functionalities for multivariate analyses of neuroimaging data, based on machine learning models. The "Pattern Recognition for Neuroimaging Toolbox" (PRoNTo) is open-source, cross-platform, MATLAB-based and SPM compatible, therefore being suitable for both cognitive and clinical neuroscience research. In addition, it is designed to facilitate novel contributions from developers, aiming to improve the interaction between the neuroimaging and machine learning communities. Here, we introduce PRoNTo by presenting examples of possible research questions that can be addressed with the machine learning framework implemented in PRoNTo, and cannot be easily investigated with mass univariate statistical analysis. C1 [Schrouff, J.; Phillips, C.] Univ Liege, Cyclotron Res Ctr, Liege, Belgium. [Rosa, M. J.; Rondina, J. M.; Mourao-Miranda, J.] UCL, Dept Comp Sci, Ctr Computat Stat & Machine Learning, London WC1E 6BT, England. [Marquand, A. F.; Mourao-Miranda, J.] Kings Coll London, Dept Neuroimaging, Ctr Neuroimaging Sci, Inst Psychiat, London, England. [Chu, C.] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Ashburner, J.] UCL, Wellcome Trust Ctr NeuroImaging, London WC1E 6BT, England. [Phillips, C.] Univ Liege, Dept Elect Engn & Comp Sci, Liege, Belgium. [Richiardi, J.] Stanford Univ, Dept Neurol & Neurol Sci, Funct Imaging Neuropsychiat Disorders Lab, Stanford, CA 94305 USA. [Richiardi, J.] Univ Geneva, Lab Neurol & Imaging Cognit, Dept Neurosci, Geneva, Switzerland. [Richiardi, J.] Univ Geneva, Dept Clin Neurol, Geneva, Switzerland. [Rondina, J. M.] Univ Sao Paulo, Fac Med, Neuroimaging Lab, Dept & Inst Psychiat, Sao Paulo, Brazil. RP Rosa, MJ (reprint author), UCL, Dept Comp Sci, Ctr Computat Stat & Machine Learning, Gower St, London WC1E 6BT, England. EM m.rosa@ucl.ac.uk RI Centre d'imagerie Biomedicale, CIBM/B-5740-2012; Marquand, Andre/B-6050-2012; Rosa, Maria J./K-3185-2015; Ashburner, John/I-3757-2013; OI Marquand, Andre/0000-0001-5903-203X; Rosa, Maria J./0000-0001-9822-3752; Ashburner, John/0000-0001-7605-2518; Richiardi, Jonas/0000-0002-6975-5634; Phillips, Christophe/0000-0002-4990-425X; Schrouff, Jessica/0000-0003-4992-3183 FU Department of Computer Science, University College London; Wellcome Trust [WT086565/Z/08/Z]; PASCAL2; HARVEST programme; Fonds de la Recherche Scientifique-FNRS, Belgium; Portuguese Foundation for Science and Technology, Portugal; Swiss National Science Foundation [PP00P2-123438]; Center for Biomedical Imaging (CIBM) of the EPFL; University and Hospital of Lausanne; University and Hospital Geneva; King's College London Centre of Excellence in Medical Engineering; Wellcome Trust; EPSRC [WT088641/Z/09/Z]; Marie Curie Actions [299500] FX PRoNTo is the deliverable of a Pascal Harvest project coordinated by Dr. J. Mourao-Miranda and its development was possible with the financial and logistic support of:; the Department of Computer Science, University College London (http://www.cs.ucl.ac.uk);; the Wellcome Trust support under grant no. WT086565/Z/08/Z (http://www.wellcome.ac.uk/);; PASCAL2 (http://www.pascal-network.org) and its HARVEST programme;; the Fonds de la Recherche Scientifique-FNRS (http://www.fnrs.be), Belgium;; the Portuguese Foundation for Science and Technology (http://www.fct.pt), Portugal;; Swiss National Science Foundation (PP00P2-123438) and Center for Biomedical Imaging (CIBM) of the EPFL and Universities and Hospitals of Lausanne and Geneva.; The King's College London Centre of Excellence in Medical Engineering, funded by the Wellcome Trust and EPSRC under grant no. WT088641/Z/09/Z; Marie Curie Actions (project #299500). NR 60 TC 59 Z9 59 U1 3 U2 24 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1539-2791 J9 NEUROINFORMATICS JI Neuroinformatics PD JUL PY 2013 VL 11 IS 3 BP 319 EP 337 DI 10.1007/s12021-013-9178-1 PG 19 WC Computer Science, Interdisciplinary Applications; Neurosciences SC Computer Science; Neurosciences & Neurology GA 189HY UT WOS:000322259300005 PM 23417655 ER PT J AU Semsey, S Jauffred, L Csiszovszki, Z Erdossy, J Steger, V Hansen, S Krishna, S AF Semsey, Szabolcs Jauffred, Liselotte Csiszovszki, Zsolt Erdossy, Janos Steger, Viktor Hansen, Sabine Krishna, Sandeep TI The effect of LacI autoregulation on the performance of the lactose utilization system in Escherichia coli SO NUCLEIC ACIDS RESEARCH LA English DT Article ID REPRESSOR CAP INTERACTION; GENE-EXPRESSION; CATABOLITE REPRESSION; TRANSCRIPTION FACTORS; AUXILIARY OPERATORS; PROTEIN EXPRESSION; INDUCER EXCLUSION; BISTABLE BEHAVIOR; INTRINSIC NOISE; CONTROL REGION AB The lactose operon of Escherichia coli is a paradigm system for quantitative understanding of gene regulation in prokaryotes. Yet, none of the many mathematical models built so far to study the dynamics of this system considered the fact that the Lac repressor regulates its own transcription by forming a transcriptional roadblock at the O3 operator site. Here we study the effect of autoregulation on intracellular LacI levels and also show that cAMP-CRP binding does not affect the efficiency of autoregulation. We built a mathematical model to study the role of LacI autoregulation in the lactose utilization system. Previously, it has been argued that negative autoregulation can significantly reduce noise as well as increase the speed of response. We show that the particular molecular mechanism, a transcriptional roadblock, used to achieve self-repression in the lac system does neither. Instead, LacI autoregulation balances two opposing states, one that allows quicker response to smaller pulses of external lactose, and the other that minimizes production costs in the absence of lactose. C1 [Semsey, Szabolcs; Jauffred, Liselotte; Hansen, Sabine] Univ Copenhagen, Niels Bohr Inst, Ctr Models Life, DK-2100 Copenhagen, Denmark. [Csiszovszki, Zsolt] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Erdossy, Janos] Eotvos Lorand Univ, Dept Genet, H-1117 Budapest, Hungary. [Steger, Viktor] Agr Biotechnol Ctr, H-2100 Godollo, Hungary. [Krishna, Sandeep] Natl Ctr Biol Sci, Bangalore 560065, Karnataka, India. RP Semsey, S (reprint author), Univ Copenhagen, Niels Bohr Inst, Ctr Models Life, Blegdamsvej 17, DK-2100 Copenhagen, Denmark. EM semsey@nbi.dk; sandeep@ncbs.res.in RI Semsey, Szabolcs/L-6329-2013; Jauffred, Liselotte/E-3662-2015; OI Jauffred, Liselotte/0000-0002-2223-9464; Semsey, Szabolcs/0000-0002-4522-5495 FU Danish Council for Independent Research\Natural Sciences; National Institutes of Health; National Cancer Institute; Center for Cancer Research; Danish National Research Foundation FX Danish Council for Independent Research vertical bar Natural Sciences; the Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research and the Danish National Research Foundation. Funding for open access charge: Danish National Research Foundation. NR 54 TC 5 Z9 5 U1 5 U2 44 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 13 BP 6381 EP 6390 DI 10.1093/nar/gkt351 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 192BK UT WOS:000322458800011 PM 23658223 ER PT J AU Liu, S Wang, J Su, YJ Guerrero, C Zeng, YX Mitra, D Brooks, PJ Fisher, DE Song, HJ Wang, YS AF Liu, Shuo Wang, Jin Su, Yijing Guerrero, Candace Zeng, Yaxue Mitra, Devarati Brooks, Philip J. Fisher, David E. Song, Hongjun Wang, Yinsheng TI Quantitative assessment of Tet-induced oxidation products of 5-methylcytosine in cellular and tissue DNA SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CROSS-LINK LESION; THYMINE DNA; MAMMALIAN DNA; DEMETHYLATION; 5-HYDROXYMETHYLCYTOSINE; GLYCOSYLASE; 5-CARBOXYLCYTOSINE; PROTEIN; BASE AB Recent studies showed that Ten-eleven translocation (Tet) family dioxygenases can oxidize 5-methyl-2'-deoxycytidine (5-mdC) in DNA to yield the 5-hydroxymethyl, 5-formyl and 5-carboxyl derivatives of 2'-deoxycytidine (5-HmdC, 5-FodC and 5-CadC). 5-HmdC in DNA may be enzymatically deaminated to yield 5-hydroxymethyl-2'-deoxyuridine (5-HmdU). After their formation at CpG dinucleotide sites, these oxidized pyrimidine nucleosides, particularly 5-FodC, 5-CadC, and 5-HmdU, may be cleaved from DNA by thymine DNA glycosylase, and subsequent action of base-excision repair machinery restores unmethylated cytosine. These processes are proposed to be important in active DNA cytosine demethylation in mammals. Here we used a reversed-phase HPLC coupled with tandem mass spectrometry (LC-MS/MS/MS) method, along with the use of stable isotope-labeled standards, for accurate measurements of 5-HmdC, 5-FodC, 5-CadC and 5-HmdU in genomic DNA of cultured human cells and multiple mammalian tissues. We found that overexpression of the catalytic domain of human Tet1 led to marked increases in the levels of 5-HmdC, 5-FodC and 5-CadC, but only a modest increase in 5-HmdU, in genomic DNA of HEK293T cells. Moreover, 5-HmdC is present at a level that is approximately 2-3 and 3-4 orders of magnitude greater than 5-FodC and 5-CadC, respectively, and 35-400 times greater than 5-HmdU in the mouse brain and skin, and human brain. The robust analytical method built a solid foundation for dissecting the molecular mechanisms of active cytosine demethylation, for measuring these 5-mdC derivatives and assessing their involvement in epigenetic regulation in other organisms and for examining whether these 5-mdC derivatives can be used as biomarkers for human diseases. C1 [Liu, Shuo; Wang, Yinsheng] Univ Calif Riverside, Environm Toxicol Grad Program, Riverside, CA 92521 USA. [Wang, Jin; Guerrero, Candace; Wang, Yinsheng] Univ Calif Riverside, Dept Chem, Riverside, CA 92521 USA. [Su, Yijing; Zeng, Yaxue; Song, Hongjun] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA. [Su, Yijing; Zeng, Yaxue; Song, Hongjun] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Su, Yijing; Zeng, Yaxue; Song, Hongjun] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Mitra, Devarati; Fisher, David E.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Brooks, Philip J.] NIAAA, Neurogenet Lab, Bethesda, MD 20892 USA. [Brooks, Philip J.] NIAAA, Div Metab & Hlth Effects, Bethesda, MD 20892 USA. [Brooks, Philip J.] NIH, Off Rare Dis Res, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Wang, YS (reprint author), Univ Calif Riverside, Environm Toxicol Grad Program, Riverside, CA 92521 USA. EM yinsheng.wang@ucr.edu FU National Institutes of Health (NIH) [DK082779, NS047344, ES021957, AR043369]; Maryland Stem Cell Research Fund postdoctoral fellowship; NIH [DK082779] FX National Institutes of Health (NIH) [DK082779 to Y.W., NS047344 and ES021957 to H. S. and AR043369 to D. E. F.]; Maryland Stem Cell Research Fund postdoctoral fellowship (to Y.S and Y.Z). Funding for open access charge: NIH [DK082779]. NR 34 TC 53 Z9 53 U1 4 U2 34 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 13 BP 6421 EP 6429 DI 10.1093/nar/gkt360 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 192BK UT WOS:000322458800014 PM 23658232 ER PT J AU Dong, B Moore, AR Dai, JH Roberts, S Chu, K Kapranov, P Moss, B Xiao, WD AF Dong, Biao Moore, Andrea R. Dai, Jihong Roberts, Sean Chu, Kirk Kapranov, Philipp Moss, Bernard Xiao, Weidong TI A concept of eliminating nonhomologous recombination for scalable and safe AAV vector generation for human gene therapy SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ADENOASSOCIATED VIRAL VECTORS; PACKAGING CELL-LINES; VIRUS VECTORS; INSECT CELLS; EXPRESSION; REP; ADENOVIRUS; SYSTEM; CAP; PURIFICATION AB Scalable and efficient production of high-quality recombinant adeno-associated virus (rAAV) for gene therapy remains a challenge despite recent clinical successes. We developed a new strategy for scalable and efficient rAAV production by sequestering the AAV helper genes and the rAAV vector DNA in two different subcellular compartments, made possible by using cytoplasmic vaccinia virus as a carrier for the AAV helper genes. For the first time, the contamination of replication-competent AAV particles (rcAAV) can be completely eliminated in theory by avoiding ubiquitous nonhomologous recombination. Vector DNA can be integrated into the host genomes or delivered by a nuclear targeting vector such as adenovirus. In suspension HeLa cells, the achieved vector yield per cell is similar to that from traditional triple-plasmid transfection method. The rcAAV contamination was undetectable at the limit of our assay. Furthermore, this new concept can be used not only for production of rAAV, but also for other DNA vectors. C1 [Dong, Biao; Moore, Andrea R.; Dai, Jihong; Roberts, Sean; Chu, Kirk; Xiao, Weidong] Temple Univ, Dept Microbiol & Immunol, Sol Sherry Thrombosis Res Ctr, Philadelphia, PA 19140 USA. [Kapranov, Philipp] St Laurent Inst, Cambridge, MA 02139 USA. [Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20814 USA. RP Xiao, WD (reprint author), Temple Univ, Dept Microbiol & Immunol, Sol Sherry Thrombosis Res Ctr, Philadelphia, PA 19140 USA. EM wxiao@temple.edu FU National Institutes of Health (NIH) [R01HL080789, R01HL084381]; NIH under Ruth L. Kirschstein National Research Service from the National Heart Lung and Blood Institute [T32-HL-007777]; NIAID FX National Institutes of Health (NIH) [R01HL080789 and R01HL084381 to W. X.]; NIH under Ruth L. Kirschstein National Research Service Award T32-HL-007777 from the National Heart Lung and Blood Institute (to A. R. M.). NIAID intramural program (in part). Funding for open access charge: NIH. NR 41 TC 10 Z9 12 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2013 VL 41 IS 13 BP 6609 EP 6617 DI 10.1093/nar/gkt404 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 192BK UT WOS:000322458800028 PM 23677609 ER PT J AU Lusvarghi, S Sztuba-Solinska, J Purzycka, KJ Pauly, GT Rausch, JW Le Grice, SFJ AF Lusvarghi, Sabrina Sztuba-Solinska, Joanna Purzycka, Katarzyna J. Pauly, Gary T. Rausch, Jason W. Le Grice, Stuart F. J. TI The HIV-2 Rev-response element: determining secondary structure and defining folding intermediates SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SELECTIVE 2'-HYDROXYL ACYLATION; SINGLE NUCLEOTIDE RESOLUTION; PRIMER EXTENSION SHAPE; RNA STRUCTURE-ANALYSIS; STRUCTURE PREDICTION; GENE-EXPRESSION; MESSENGER-RNA; BINDING; RRE AB Interaction between the viral protein Rev and the RNA motifs known as Rev response elements (RREs) is required for transport of unspliced and partially spliced human immunodeficiency virus (HIV)-1 and HIV-2 RNAs from the nucleus to the cytoplasm during the later stages of virus replication. A more detailed understanding of these nucleoprotein complexes and the host factors with which they interact should accelerate the development of new antiviral drugs targeting cis-acting RNA regulatory signals. In this communication, the secondary structures of the HIV-2 RRE and two RNA folding precursors have been identified using the SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) chemical probing methodology together with a novel mathematical approach for determining the secondary structures of RNA conformers present in a mixture. A complementary chemical probing technique was also used to support these secondary structure models, to confirm that the RRE2 RNA undergoes a folding transition and to obtain information about the relative positioning of RRE2 substructures in three dimensions. Our analysis collectively suggests that the HIV-2 RRE undergoes two conformational transitions before assuming the energetically most favorable conformer. The 3D models for the HIV-2 RRE and folding intermediates are also presented, wherein the Rev-binding stem-loops (IIB and I) are located coaxially in the former, which is in agreement with previous models for HIV-1 Rev-RRE binding. C1 [Lusvarghi, Sabrina; Sztuba-Solinska, Joanna; Purzycka, Katarzyna J.; Rausch, Jason W.; Le Grice, Stuart F. J.] Frederick Natl Lab Canc Res, Reverse Transcriptase Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Pauly, Gary T.] Frederick Natl Lab Canc Res, Biol Chem Lab, Frederick, MD 21702 USA. RP Rausch, JW (reprint author), Frederick Natl Lab Canc Res, Reverse Transcriptase Biochem Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM rauschj@mail.nih.gov; legrices@mail.nih.gov FU Center for Cancer Research; National Cancer Institute; National Institutes of Health; Frederick National Laboratory for Cancer Research FX Intramural Research Program of the Center for Cancer Research; National Cancer Institute and National Institutes of Health (to S. L. G.). Funding for open access charge: Frederick National Laboratory for Cancer Research. NR 45 TC 10 Z9 10 U1 0 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2013 VL 41 IS 13 BP 6637 EP 6649 DI 10.1093/nar/gkt353 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 192BK UT WOS:000322458800030 PM 23640333 ER PT J AU Gardner, EL Goldberg, S Robles, JM de Fonseca, FR AF Gardner, E. L. Goldberg, S. Manzanares Robles, J. Rodriguez de Fonseca, F. TI The Endocannabinoid Systems: Useful Targets For Anti-Addiction Treatments? SO SUBSTANCE ABUSE LA English DT Meeting Abstract C1 [Gardner, E. L.; Goldberg, S.] NIDA, Intramural Res Program, Baltimore, MD USA. [Manzanares Robles, J.] Univ Miguel Hernandez, CSIC, Inst Neurociencias, Alicante, Spain. [Rodriguez de Fonseca, F.] Hosp Carlos Haya Malaga, Fdn IMABIS, Lab Med Regenerat, Malaga, Spain. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0889-7077 J9 SUBST ABUS JI Subst. Abus. PD JUL 1 PY 2013 VL 34 IS 3 BP 324 EP 324 PG 1 WC Substance Abuse SC Substance Abuse GA 181SF UT WOS:000321688100020 ER PT J AU Gardner, EL AF Gardner, E. L. TI CB2 Agonist and Antagonist Effects on Cocaine Self-Administration and Other Cocaine-Induced Actions. SO SUBSTANCE ABUSE LA English DT Meeting Abstract C1 [Gardner, E. L.] NIDA, Intramural Res Program, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0889-7077 J9 SUBST ABUS JI Subst. Abus. PD JUL 1 PY 2013 VL 34 IS 3 BP 324 EP 325 PG 2 WC Substance Abuse SC Substance Abuse GA 181SF UT WOS:000321688100021 ER PT J AU Khalsa, J Bunt, G AF Khalsa, J. Bunt, G. TI Legalization of Marijuana: Where Addiction Medicine Stands. SO SUBSTANCE ABUSE LA English DT Meeting Abstract C1 [Khalsa, J.] NIDA, Div Pharmacotherapies, NIH, Bethesda, MD 20892 USA. [Bunt, G.] DayTop Village Inc, New York, NY USA. NR 0 TC 0 Z9 0 U1 2 U2 25 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0889-7077 J9 SUBST ABUS JI Subst. Abus. PD JUL 1 PY 2013 VL 34 IS 3 BP 324 EP 324 PG 1 WC Substance Abuse SC Substance Abuse GA 181SF UT WOS:000321688100019 ER PT J AU Gardner, EL AF Gardner, E. L. TI Neurobiological Circuits in Addiction. SO SUBSTANCE ABUSE LA English DT Meeting Abstract C1 [Gardner, E. L.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0889-7077 J9 SUBST ABUS JI Subst. Abus. PD JUL 1 PY 2013 VL 34 IS 3 BP 331 EP 331 PG 1 WC Substance Abuse SC Substance Abuse GA 181SF UT WOS:000321688100042 ER PT J AU Montoya, I Carra, G Khalsa, J AF Montoya, I. Carra, G. Khalsa, J. TI Advances in the Development of Medications to Treat Addictions. SO SUBSTANCE ABUSE LA English DT Meeting Abstract C1 [Montoya, I.] NIDA, NIH, Bethesda, MD 20892 USA. [Carra, G.] Mental Hlth Univ Trust, Milan, Italy. [Khalsa, J.] NIDA, Div Pharmacotherapies, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0889-7077 J9 SUBST ABUS JI Subst. Abus. PD JUL 1 PY 2013 VL 34 IS 3 BP 331 EP 331 PG 1 WC Substance Abuse SC Substance Abuse GA 181SF UT WOS:000321688100043 ER PT J AU Hou, LP Faraci, G Chen, DTW Kassem, L Schulze, TG Shugart, YY McMahon, FJ AF Hou, Liping Faraci, Gloria Chen, David T. W. Kassem, Layla Schulze, Thomas G. Shugart, Yin Yao McMahon, Francis J. TI Amish revisited: next-generation sequencing studies of psychiatric disorders among the Plain people SO TRENDS IN GENETICS LA English DT Review DE bipolar disorder; identity by descent; homozygosity; Mennonite; Anabaptist ID OLD ORDER AMISH; BIPOLAR AFFECTIVE-DISORDER; RARE VARIANTS; GENOME; DISEASE; ASSOCIATION; MUTATIONS; DESCENT; LOCI; RELATIVES AB The rapid development of next-generation sequencing (NGS) technology has led to renewed interest in the potential contribution of rarer forms of genetic variation to complex non-mendelian phenotypes such as psychiatric illnesses. Although challenging, family-based studies offer some advantages, especially in communities with large families and a limited number of founders. Here we revisit family-based studies of mental illnesses in traditional Amish and Mennonite communities - known collectively as the Plain people. We discuss the new opportunities for NGS in these populations, with particular emphasis on investigating psychiatric disorders. We also address some of the challenges facing NGS-based studies of complex phenotypes in founder populations. C1 [Hou, Liping; Faraci, Gloria; Chen, David T. W.; Kassem, Layla; McMahon, Francis J.] NIMH, Human Genet Branch, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Schulze, Thomas G.] Univ Gottingen, Dept Psychiat & Psychotherapy, D-37073 Gottingen, Germany. [Shugart, Yin Yao] NIMH, Unit Stat Genom, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP McMahon, FJ (reprint author), NIMH, Human Genet Branch, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. EM mcmahonf@mail.nih.gov RI Hou, Liping/G-1648-2011; OI Hou, Liping/0000-0003-3972-245X; McMahon, Francis/0000-0002-9469-305X FU NIMH Intramural Research Program FX Supported by the NIMH Intramural Research Program. We thank Daniel Weaver (Holmes County, OH) and Dr Richard Stevick (Messiah College, Lebanon, PA) for critical review of the manuscript. NR 41 TC 8 Z9 8 U1 4 U2 17 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JUL PY 2013 VL 29 IS 7 BP 412 EP 418 DI 10.1016/j.tig.2013.01.007 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 191NK UT WOS:000322419600006 PM 23422049 ER PT J AU Moraski, GC Markley, LD Cramer, J Hipskind, PA Boshoff, H Bailey, MA Aing, T Ollinger, J Parish, T Miller, MJ AF Moraski, Garrett C. Markley, Lowell D. Cramer, Jeffrey Hipskind, Philip A. Boshoff, Helena Bailey, Mai A. Aing, Torey Ollinger, Juliane Parish, Tanya Miller, Marvin J. TI Advancement of Imidazo[1,2-a]pyridines with Improved Pharmacokinetics and nM Activity vs. Mycobacterium tuberculosis SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Mycobacterium tuberculosis; imidazo[1,2-a]pyridine-3-carboxamides; MDR-TB; XDR-TB; pharmacokinetics AB A set of 14 imidazo[1,2-a]pyridine-3-carboxamides was synthesized and screened against Mycobacterium tuberculosis H(37)Rv. The minimum inhibitory concentrations of 12 of these agents were <= 1 mu M against replicating bacteria and 5 compounds (9, 12, 16, 17, and 18) had MIC values <= 0.006 mu M. Compounds 13 and 18 were screened against a panel of MDR and XDR drug resistant clinical Mtb strains with the potency of 18 surpassing that of clinical candidate PA-824 by nearly 10-fold. The in vivo pharmacokinetics of compounds 13 and 18 were evaluated in male mice by oral (PO) and intravenous (IV) routes. These results indicate that readily synthesized imidazo[1,2-a]pyridine-3-carboxamides are an exciting new class of potent, selective anti-TB agents that merit additional development opportunities. C1 [Moraski, Garrett C.; Markley, Lowell D.; Miller, Marvin J.] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. [Cramer, Jeffrey; Hipskind, Philip A.] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. [Boshoff, Helena] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Bailey, Mai A.; Aing, Torey; Ollinger, Juliane; Parish, Tanya] Infect Dis Res Inst, Seattle, WA 09810 USA. RP Miller, MJ (reprint author), Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. EM mmiller1@nd.edu OI Moraski, Garrett/0000-0002-6992-5584 FU NIH [AI054193]; Dow AgroSciences; NSF [CHE-0741793] FX Funding was provided by NIH Grant AI054193, Dow AgroSciences, and NSF Grant CHE-0741793. NR 12 TC 7 Z9 7 U1 1 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD JUL PY 2013 VL 4 IS 7 BP 110 EP 114 DI 10.1021/ml400088y PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 184IR UT WOS:000321883800024 PM 23930153 ER PT J AU Gleich, GJ Klion, AD Lee, JJ Weller, PF AF Gleich, G. J. Klion, A. D. Lee, J. J. Weller, P. F. TI The consequences of not having eosinophils SO ALLERGY LA English DT Review DE anti-interleukin 5; deficiency; eosinophil; thymoma ID ALLERGIC PULMONARY INFLAMMATION; HYPEREOSINOPHILIC SYNDROMES; FACTOR INTERLEUKIN-5; TOTAL ABSENCE; GUINEA-PIG; ASTHMA; MEPOLIZUMAB; ANTIBODY; PATIENT; CELLS AB Several lines of evidence suggest that deficiency of eosinophils is not associated with any characteristic abnormality. Patients lacking eosinophils, in the setting of immunodeficiency or as a consequence of IgG-mediated eosinophil precursor destruction, do not display any distinguishing abnormalities related to eosinophil reduction. The observation that eosinophil-deficient mice do not display any distinctive syndrome or failure of their health is evidence that, under ordinary laboratory conditions, the eosinophil does not play a critical role in the well-being of mammals. Observations that monoclonal antibodies to interleukin-5 (IL-5) are well tolerated appear unsurprising in light of these findings. For example, patients with the hypereosinophilic syndrome have received mepolizumab, an anti-IL-5 monoclonal antibody, for as long as 6years and have not developed any characteristic set of adverse events. Safety data for reslizumab, another anti-IL-5 monoclonal antibody, and benralizumab, a monoclonal antibody to the IL-5 receptor -chain, are comparatively limited, especially for benralizumab, although reports of administration of these antibodies to humans suggest that they are well tolerated. Thus, data to the present suggest that reduction of eosinophils appears to have no characteristic ill effects on normal health, and monoclonal antibodies that deplete eosinophils have the potential to be widely employed in the treatment of eosinophil-associated diseases. C1 [Gleich, G. J.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT 84132 USA. [Klion, A. D.] NIAID, NIH, Bethesda, MD 20892 USA. [Lee, J. J.] Mayo Clin Arizona, Dept Biochem & Mol Biol, Scottsdale, AZ USA. [Weller, P. F.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Gleich, GJ (reprint author), Univ Utah, Sch Med 4A330, Dept Dermatol, 30 North 1900 East, Salt Lake City, UT 84132 USA. EM gerald.gleich@hsc.utah.edu OI Klion, Amy/0000-0002-4986-5326 FU Division of Intramural Research, NIAID, NIH; NIH [R37-020241, HL065228]; Mayo Foundation FX This work was funded in part by the Division of Intramural Research, NIAID, NIH. PFW was supported by the NIH (R37-020241). JJL was supported by the Mayo Foundation and the NIH (HL065228). NR 54 TC 19 Z9 20 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-4538 J9 ALLERGY JI Allergy PD JUL PY 2013 VL 68 IS 7 BP 829 EP 835 DI 10.1111/all.12169 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 182QT UT WOS:000321759500003 PM 23742015 ER PT J AU Crende, O Sabatino, M Valcarcel, M Carrascal, T Riestra, P Lopez-Guerrero, JA Nagore, E Mandruzzato, S Wang, E Marincola, FM Vidal-Vanaclocha, F AF Crende, Olatz Sabatino, Marianna Valcarcel, Maria Carrascal, Teresa Riestra, Pia Lopez-Guerrero, Jose A. Nagore, Eduardo Mandruzzato, Susanna Wang, Ena Marincola, Francesco M. Vidal-Vanaclocha, Fernando TI Metastatic Lesions with and without Interleukin-18-Dependent Genes in Advanced-Stage Melanoma Patients SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CELL-ADHESION MOLECULE-1; HUMAN-MALIGNANT MELANOMA; DIFFERENTIAL EXPRESSION; SINUSOIDAL ENDOTHELIUM; COLORECTAL-CANCER; INDUCED APOPTOSIS; TUMOR-METASTASIS; PROGRESSION; GROWTH; RECEPTOR AB IL-18 is an immune-stimulating cytokine that promotes experimental melanoma metastasis via vascular endothelial growth factor (VEGF)-induced very late antigen (VLA)-4. We studied genes associated with the ability of melanoma cells to allow metastasis under IL-18 effects, and we verified their expression in metastatic lesions from patients with melanoma. Human melanoma cell Lines with and without the IL-18 receptor (IL-18R)/VEGF/VLA-4-expressing phenotype were identified, and their metastatic potential was studied in nude mice. RNA from untreated and IL-18-treated melanoma phenotypes was hybridized to a cDNA microarray, and their signature genes were studied. RNA from primary and metastatic lesions from patients with melanoma was hybridized to a cDNA microarray to identify lesions with the transcript patterns of melanoma cells with and without the IL-18R/VEGF/VLA-4 phenotype. IL-18R/VEGF/VLA-4-expressing A375 and 1182 melanoma cells produced a higher metastasis number than 526 and 624.28 melanoma cells, not using this prometastatic pathway. Melanoma cells with and without the IL-18R/VEGF/VLA-4 phenotype had distinct transcript patterns. However, the type I transcriptional cluster, including cutaneous and lymph node metastases, but not the type II cluster, not including cutaneous metastases, had signature genes from IL-18-treated melanoma cells with, but not without, the IL-18R/VEGF/VLA-4 phenotype. Metastatic melanoma lesions with and without IL-18-dependent genes were identified, suggesting that melanoma metastasis developed via inflammation-dependent and inflammation-independent mechanisms. Signature genes from melanomas with and without the IL-18R/VEGF/VLA-4 phenotype may serve as diagnostic biomarkers of melanoma predisposition to prometastatic effects of IL-18. C1 [Crende, Olatz; Carrascal, Teresa] Univ Basque Country, Dept Cellular Biol & Histol, Sch Med & Dent, Leioa, Spain. [Sabatino, Marianna; Wang, Ena] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Bethesda, MD 20892 USA. [Valcarcel, Maria] Innoprot SL, Derio, Spain. [Riestra, Pia; Vidal-Vanaclocha, Fernando] CEU San Pablo Univ, Inst Appl Mol Med, Madrid 28668, Spain. [Vidal-Vanaclocha, Fernando] HM Hosp Sch Med, Madrid, Spain. [Lopez-Guerrero, Jose A.; Nagore, Eduardo] Valencia Oncol Inst, Valencia, Spain. [Mandruzzato, Susanna] Univ Padua, Oncol & Immunol Sect, Dept Surg Oncol & Gastroenterol, Padua, Italy. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. RP Vidal-Vanaclocha, F (reprint author), CEU San Pablo Univ, Inst Appl Mol Med, Urb Monteprincipe S-N, Madrid 28668, Spain. EM fernando.vidalvanaclocha@ceu.es OI MANDRUZZATO, SUSANNA/0000-0002-0707-995X; CRENDE ARRUABARRENA, OLATZ/0000-0002-3245-9575 FU Basque Country Government [IT-487-07]; Spanish Carlos HI Health Institute, Madrid, grant [ADE09/90041]; Burdinola Professorship on Molecular Medicine; Ministry of Education fellowship FX Supported in part by Basque Country Government grant IT-487-07, Spanish Carlos HI Health Institute, Madrid, grant ADE09/90041, the Burdinola Professorship on Molecular Medicine (F.V.-V.), and a Ministry of Education fellowship (O.C., M.V., and T.C.). NR 55 TC 10 Z9 11 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUL PY 2013 VL 183 IS 1 BP 69 EP 82 DI 10.1016/j.ajpath.2013.03.026 PG 14 WC Pathology SC Pathology GA 177VN UT WOS:000321403600009 PM 23707237 ER PT J AU Li, Y Cui, XZ Solomon, SB Remy, K Fitz, Y Eichacker, PQ AF Li, Yan Cui, Xizhong Solomon, Steven B. Remy, Kenneth Fitz, Yvonne Eichacker, Peter Q. TI B. anthracis edema toxin increases cAMP levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE anthrax; edema toxin; lethal toxin; arterial contraction; aortic ring model ID NITRIC-OXIDE RELEASE; LETHAL TOXIN; BACILLUS-ANTHRACIS; INHALATIONAL ANTHRAX; ENDOTHELIAL BARRIER; HYPERTENSIVE-RATS; DRUG-USERS; SHOCK; INFECTION; DYSFUNCTION AB B. anthracis edema toxin (ET) and lethal toxin (LT) are each composed of protective antigen (PA), necessary for toxin uptake by host cells, and their respective toxic moieties, edema factor (EF) and lethal factor (LF). Although both toxins likely contribute to shock during infection, their mechanisms are unclear. To test whether ET and LT produce arterial relaxation, their effects on phenylephrine (PE)-stimulated contraction in a Sprague-Dawley rat aortic ring model were measured. Rings were prepared and connected to pressure transducers. Their viability was confirmed, and peak contraction with 60 mM KCl was determined. Compared with PA pretreatment (control, 60 min), ET pretreatment at concentrations similar to those noted in vivo decreased the mean (+/- SE) maximum contractile force (MCF; percent peak contraction) in rings generated during stimulation with increasing PE concentrations (96.2 +/- 7.0 vs. 57.3 +/- 9.1) and increased the estimated PE concentration producing half the MCF (EC50; 10(-7) M, 1.1 +/- 0.3 vs. 3.7 +/- 0.8, P < 0.002). ET inhibition with PA-directed monoclonal antibodies, selective EF inhibition with adefovir, or removal of the ring endothelium inhibited the effects of ET on MCF and EC50 (P > 0.02). Consistent with its adenyl cyclase activity, ET increased tissue cAMP in endothelium-intact but not endothelium-denuded rings (P < 0.0001 and 0.25, respectively). LT pretreatment, even in high concentrations, did not significantly decrease MCF or increase EC50 (all P > 0.05). In rings precontracted with PE compared with posttreatment with PA (90 min), ET posttreatment produced progressive reductions in contractile force and increases in relaxation in endothelium-intact rings (P < 0.0001) but not endothelium-denuded rings (P = 0.51). Thus, ET may contribute to shock by producing arterial relaxation. C1 [Li, Yan; Cui, Xizhong; Solomon, Steven B.; Remy, Kenneth; Fitz, Yvonne; Eichacker, Peter Q.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Bldg 10,Rm 2C145,9000 Rockville Pike, Bethesda, MD 20892 USA. EM peichacker@mail.cc.nih.gov OI Remy, Kenneth/0000-0001-5222-9884 FU Intramural Program of the National Institutes of Health, Clinical Center, Critical Care Medicine Department FX This work was supported by the Intramural Program of the National Institutes of Health, Clinical Center, Critical Care Medicine Department. NR 45 TC 9 Z9 9 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUL PY 2013 VL 305 IS 2 BP H238 EP H250 DI 10.1152/ajpheart.00185.2013 PG 13 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 184PD UT WOS:000321903500011 PM 23585140 ER PT J AU Wu, QJ Xie, L Zheng, W Vogtmann, E Li, HL Yang, G Ji, BT Gao, YT Shu, XO Xiang, YB AF Wu, Q. J. Xie, L. Zheng, W. Vogtmann, E. Li, H. L. Yang, G. Ji, B. T. Gao, Y. T. Shu, X. O. Xiang, Y. B. TI Cruciferous vegetables consumption and the risk of female lung cancer: a prospective study and a meta-analysis SO ANNALS OF ONCOLOGY LA English DT Article DE cruciferous vegetable; lung cancer; meta-analysis; prospective study; women ID CIGARETTE-SMOKING; ISOTHIOCYANATES; FRUIT; SMOKERS; WOMEN; POLYMORPHISMS; INDOLE-3-CARBINOL; INHIBITION; METABOLISM; HEALTH AB Background: Epidemiological studies evaluating the association between cruciferous vegetables (CVs) intake and female lung cancer risk have produced inconsistent results. Patients and methods: This study followed 74 914 Chinese women aged 40-70 years who participated in the Shanghai Women's Health Study. CV intake was assessed through a validated food-frequency questionnaire (FFQ) at baseline and reassessed during follow-up. Hazard ratios (HRs) and 95% confidence interval (as) were estimated by using Cox proportional hazards models. Furthermore, we carried out a meta-analysis of all observational studies until December 2011. Results: After excluding the first 2 years of follow-up, 417 women developed lung. cancer over a mean of 11.1 years of follow-up. An inverse association of borderline statistical significance was observed between CV consumption and female lung cancer risk, with HR for the highest compared with the lowest quartiles of 0.73 (95% CI 0.54-1.00, P trend = 0.1607). The association was strengthened in analyses restricting to never smokers, with the corresponding HR of 0.59 (95% CI 0.40-0.87, P trend = 0.0510). The finding of an inverse association between CV intake and lung cancer risk in women was supported by our meta-analysis of 10 included studies. Conclusions: Our study suggests that CV consumption may reduce the risk of lung cancer in women, particularly among never smokers. C1 [Wu, Q. J.] Fudan Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai 200433, Peoples R China. [Wu, Q. J.; Xie, L.; Li, H. L.; Xiang, Y. B.] Shanghai Canc Inst, State Key Lab Oncogene & Related Genes, Shanghai, Peoples R China. [Wu, Q. J.; Xie, L.; Li, H. L.; Gao, Y. T.; Xiang, Y. B.] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Shanghai Canc Inst,Dept Epidemiol, Shanghai 200032, Peoples R China. [Zheng, W.; Yang, G.; Shu, X. O.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Vogtmann, E.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Ji, B. T.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Xiang, YB (reprint author), Shanghai Jiao Tong Univ, Sch Med, State Key Lab Oncogene & Related Genes, 25,Lane 2200,Xie Tu Rd, Shanghai 200032, Peoples R China. EM ybxiang@shsci.org FU State Key Project Specialized for Infectious Diseases of China [2008ZX10002-015, 2012ZX10002008-002]; United States National Institutes of Health [R37 CA070867, R01 CA82729, R01 HL095931]; Fogarty International Clinical Research Scholars and Fellows Support Center at the Vanderbilt Institute for Global Health; Fogarty International Center, NIH [R24TW007988-5]; Cancer Prevention and Control Training Program at the University of Alabama at Birmingham; National Institutes of Health [5R25 CA047888] FX This work was supported by the funds of State Key Project Specialized for Infectious Diseases of China (No. 2008ZX10002-015 and 2012ZX10002008-002) and grants from the United States National Institutes of Health (R37 CA070867, R01 CA82729 and R01 HL095931). EV was also supported by the Fogarty International Clinical Research Scholars and Fellows Support Center at the Vanderbilt Institute for Global Health, funded by the Fogarty International Center, NIH, through an R24 Training Grant (Grant number: R24TW007988-5), and the Cancer Prevention and Control Training Program at the University of Alabama at Birmingham funded through the National Institutes of Health (5R25 CA047888). NR 36 TC 24 Z9 24 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD JUL PY 2013 VL 24 IS 7 BP 1918 EP 1924 DI 10.1093/annonc/mdt119 PG 7 WC Oncology SC Oncology GA 184HV UT WOS:000321881600031 PM 23553059 ER PT J AU Berger, VW AF Berger, V. W. TI Spin and bias: the tip of the iceberg SO ANNALS OF ONCOLOGY LA English DT Letter C1 [Berger, V. W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, V. W.] UMBC, Bethesda, MD USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 2 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD JUL PY 2013 VL 24 IS 7 BP 1949 EP 1949 DI 10.1093/annonc/mdt189 PG 1 WC Oncology SC Oncology GA 184HV UT WOS:000321881600037 PM 23704199 ER PT J AU Mohebati, A Milne, GL Zhou, XK Duffield-Lillico, AJ Boyle, JO Knutson, A Bosworth, BP Kingsley, PJ Marnett, LJ Brown, PH Akpa, EG Szabo, E Dannenberg, AJ AF Mohebati, Arash Milne, Ginger L. Zhou, Xi Kathy Duffield-Lillico, Anna J. Boyle, Jay O. Knutson, Allison Bosworth, Brian P. Kingsley, Philip J. Marnett, Lawrence J. Brown, Powel H. Akpa, Esther G. Szabo, Eva Dannenberg, Andrew J. TI Effect of Zileuton and Celecoxib on Urinary LTE4 and PGE-M Levels in Smokers SO CANCER PREVENTION RESEARCH LA English DT Article ID ARACHIDONIC-ACID; 5-LIPOXYGENASE PATHWAY; LUNG-CANCER; CYCLOOXYGENASE-2 INHIBITION; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; CLINICAL-TRIAL; LEUKOTRIENES; METABOLITE; RISK AB COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E-4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6 +/- 1 days on urinary PGE-M and LTE4 levels in smokers. Treatment with zileuton led to an 18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by 61% in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P = 0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4. (c) 2013 AACR. C1 [Mohebati, Arash; Duffield-Lillico, Anna J.; Boyle, Jay O.] Weill Cornell Med Coll, Dept Surg, Head & Neck Serv, Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Zhou, Xi Kathy] Weill Cornell Med Coll, Dept Publ Hlth, Div Biostat & Epidemiol, New York, NY 10065 USA. [Knutson, Allison; Bosworth, Brian P.; Dannenberg, Andrew J.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Milne, Ginger L.] Vanderbilt Univ, Dept Med, Div Clin Pharmacol, Vanderbilt Inst Chem Biol,Ctr Mol Toxicol, Nashville, TN USA. [Kingsley, Philip J.; Marnett, Lawrence J.] Vanderbilt Univ, AB Hancock Jr Mem Lab Canc Res, Dept Biochem Chem, Vanderbilt Inst Chem Biol,Ctr Mol Toxicol, Nashville, TN 37235 USA. [Kingsley, Philip J.; Marnett, Lawrence J.] Vanderbilt Univ, Dept Pharmacol, Ctr Mol Toxicol, Vanderbilt Inst Chem Biol, Nashville, TN USA. [Brown, Powel H.; Akpa, Esther G.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Clin Canc Prevent, Div OVP Canc Prevent & Populat Sci, Houston, TX 77030 USA. [Szabo, Eva] NCI, Lung & Upper Aerodigest Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Dannenberg, AJ (reprint author), Weill Cornell Med Coll, Dept Med, 525 East 68th St,Room F-206, New York, NY 10065 USA. EM ajdannen@med.cornell.edu RI Milne, Ginger/D-7648-2014; OI Milne, Ginger/0000-0003-3890-151X; Bosworth, Brian/0000-0002-9964-9859 FU NIH [UL1-RR024996, T32 CA09685, N01-CN-35159] FX This work was supported by NIH grants UL1-RR024996, T32 CA09685, and NIH contract N01-CN-35159. NR 50 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUL PY 2013 VL 6 IS 7 BP 646 EP 655 DI 10.1158/1940-6207.CAPR-13-0083 PG 10 WC Oncology SC Oncology GA 174YR UT WOS:000321195000005 PM 23682075 ER PT J AU Mikulec, CD Rundhaug, JE Simper, MS Lubet, RA Fischer, SM AF Mikulec, Carol D. Rundhaug, Joyce E. Simper, Melissa S. Lubet, Ronald A. Fischer, Susan M. TI The Chemopreventive Efficacies of Nonsteroidal Anti-inflammatory Drugs: The Relationship of Short-term Biomarkers to Long-term Skin Tumor Outcome SO CANCER PREVENTION RESEARCH LA English DT Article ID INDUCED INFLAMMATION; DOUBLE-BLIND; MURINE SKIN; CANCER; CARCINOGENESIS; CYCLOOXYGENASE-2; INHIBITION; EXPRESSION; SULINDAC; ASPIRIN AB The ultraviolet B (UVB) component of sunlight, which causes DNA damage and inflammation, is the major cause of nonmelanoma skin cancer (NMSC), the most prevalent of all cancers. Nonsteroidal anti-inflammatory drugs (NSAID) and coxibs have been shown to be effective chemoprevention agents in multiple preclinical trials, including NMSC, colon, and urinary bladder cancer. NSAIDs, however, cause gastrointestinal irritation, which led to the recent development of nitric oxide (NO) derivatives that may partially ameliorate this toxicity. This study compared the efficacy of several NSAIDs and NO-NSAIDs on UV-induced NMSC in SKH-1 hairless mice and determined whether various short-term biomarkers were predictive of long-term tumor outcome with these agents. Naproxen at 100 (P = 0.05) and 400 ppm (P < 0.01) in the diet reduced tumor multiplicity by 26% and 63%, respectively. The NO-naproxen at slightly lower molar doses shows similar activities. Aspirin at 60 or 750 ppm in the diet reduced tumor multiplicity by 19% and 50%, whereas the equivalent doses (108 and 1,350 ppm) were slightly less effective. Sulindac at 25 and 150 ppm in the diet, doses far below the human equivalent dose was the most potent NSAID with reductions of 50% and 94%, respectively. In testing short-term biomarkers, we found that agents that reduce UV-induced prostaglandin E-2 synthesis and/or inhibit UV-induced keratinocyte proliferation yielded long-term tumor efficacy. (c) 2013 AACR. C1 [Mikulec, Carol D.; Rundhaug, Joyce E.; Simper, Melissa S.; Fischer, Susan M.] Univ Texas MD Anderson Canc Ctr, Dept Mol Carcinogenesis, Smithville, TX 78957 USA. [Lubet, Ronald A.] NIH, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Fischer, SM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Mol Carcinogenesis, Sci Pk, Smithville, TX 78957 USA. EM smfischer@mdanderson.org FU National Cancer Institute [N01-CN-53300]; University of Texas MD Anderson Cancer Center [CA16672]; National Institute of Environmental Health Science Center [ES07784] FX This work was supported by funds (N01-CN-53300) from The National Cancer Institute, The University of Texas MD Anderson Cancer Center Support Grant CA16672, and the National Institute of Environmental Health Science Center Grant ES07784. NR 40 TC 14 Z9 14 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUL PY 2013 VL 6 IS 7 BP 675 EP 685 DI 10.1158/1940-6207.CAPR-13-0064 PG 11 WC Oncology SC Oncology GA 174YR UT WOS:000321195000008 PM 23682071 ER PT J AU Zheng, YL Ogundiran, TO Falusi, AG Nathanson, KL John, EM Hennis, AJM Ambs, S Domchek, SM Rebbeck, TR Simon, MS Nemesure, B Wu, SY Leske, MC Odetunde, A Niu, Q Zhang, J Afolabi, C Gamazon, ER Cox, NJ Olopade, CO Olopade, OI Huo, DZ AF Zheng, Yonglan Ogundiran, Temidayo O. Falusi, Adeyinka G. Nathanson, Katherine L. John, Esther M. Hennis, Anselm J. M. Ambs, Stefan Domchek, Susan M. Rebbeck, Timothy R. Simon, Michael S. Nemesure, Barbara Wu, Suh-Yuh Leske, Maria Cristina Odetunde, Abayomi Niu, Qun Zhang, Jing Afolabi, Chibuzor Gamazon, Eric R. Cox, Nancy J. Olopade, Christopher O. Olopade, Olufunmilayo I. Huo, Dezheng TI Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers SO CARCINOGENESIS LA English DT Article ID BRCA1 MUTATION CARRIERS; AMERICAN WOMEN; COMMON VARIANTS; CONFER SUSCEPTIBILITY; TERT-CLPTM1L LOCUS; RISK VARIANT; POPULATION; FGFR2; POLYMORPHISMS; REPLICATION AB Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] 1.40, 95% confidence interval [CI] 1.111.76; P 0.004), 5q11.2 (OR 1.22, 95% CI 1.091.36; P 0.00053) and 10p15.1 (OR 1.22, 95% CI 1.081.38; P 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13 and 16q12.1q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR 1.21, 95% CI 1.161.27; P 9.7 10(16)). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora. C1 [Zheng, Yonglan; Niu, Qun; Zhang, Jing; Olopade, Christopher O.; Olopade, Olufunmilayo I.] Univ Chicago, Dept Med, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA. [Ogundiran, Temidayo O.; Afolabi, Chibuzor] Univ Ibadan, Coll Med, Dept Surg, Ibadan 23402, Oyo, Nigeria. [Falusi, Adeyinka G.; Odetunde, Abayomi] Univ Ibadan, Coll Med, Inst Med Res & Training, Ibadan 23402, Oyo, Nigeria. [Nathanson, Katherine L.; Domchek, Susan M.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA 94538 USA. [John, Esther M.] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [John, Esther M.] Stanford Univ, Stanford Canc Inst, Div Epidemiol, Sch Med, Stanford, CA 94305 USA. [Hennis, Anselm J. M.] Univ W Indies, Res Inst Trop Med, Chron Dis Res Ctr, BB-11000 Bridgetown, Saint Michael, Barbados. [Hennis, Anselm J. M.; Nemesure, Barbara; Wu, Suh-Yuh; Leske, Maria Cristina] SUNY Stony Brook, Med Ctr, Dept Prevent Med, Stony Brook, NY 11794 USA. [Ambs, Stefan] NCI, Lab Human Carcinogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rebbeck, Timothy R.] Univ Penn, Dept Stat & Epidemiol, Philadelphia, PA 19104 USA. [Simon, Michael S.] Wayne State Univ, Karmanos Canc Inst, Dept Oncol, Detroit, MI 48201 USA. [Gamazon, Eric R.; Cox, Nancy J.] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA. [Huo, Dezheng] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. RP Huo, DZ (reprint author), Univ Chicago, Dept Med, Ctr Clin Canc Genet & Global Hlth, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM dhuo@uchicago.edu OI Nathanson, Katherine/0000-0002-6740-0901; Gamazon, Eric/0000-0003-4204-8734 FU National Cancer Institute [R01 CA89085, P50 ES012382, R01 CA141712, R01 CA142996, P01 CA82707, P50 CA125183]; Noreen Fraser Foundation; Breast Cancer Research Foundation; NCI [RFA CA-06-503]; Cancer Prevention Institute of California [U01 CA69417] FX National Cancer Institute (R01 CA89085, P50 ES012382, R01 CA141712, R01 CA142996, P01 CA82707 and P50 CA125183); Noreen Fraser Foundation; Breast Cancer Research Foundation. The Breast Cancer Family Registry (BCFR) was supported by the NCI under RFA CA-06-503 and through cooperative agreements with members of the BCFR and Principal Investigators, including the Cancer Prevention Institute of California (U01 CA69417). NR 51 TC 13 Z9 14 U1 0 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2013 VL 34 IS 7 BP 1520 EP 1528 DI 10.1093/carcin/bgt090 PG 9 WC Oncology SC Oncology GA 182OI UT WOS:000321753000013 PM 23475944 ER PT J AU Li, WQ Hu, N Hyland, PL Gao, Y Wang, ZM Yu, K Su, H Wang, CY Wang, LM Chanock, SJ Burdett, L Ding, T Qiao, YL Fan, JH Wang, Y Xu, Y Shi, JX Gu, FY Wheeler, W Xiong, XQ Giffen, C Tucker, MA Dawsey, SM Freedman, ND Abnet, CC Goldstein, AM Taylor, PR AF Li, Wen-Qing Hu, Nan Hyland, Paula L. Gao, Ying Wang, Zhao-Ming Yu, Kai Su, Hua Wang, Chao-Yu Wang, Le-Min Chanock, Stephen J. Burdett, Laurie Ding, Ti Qiao, You-Lin Fan, Jin-Hu Wang, Yuan Xu, Yi Shi, Jian-Xin Gu, Fangyi Wheeler, William Xiong, Xiao-Qin Giffen, Carol Tucker, Margaret A. Dawsey, Sanford M. Freedman, Neal D. Abnet, Christian C. Goldstein, Alisa M. Taylor, Philip R. TI Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; BASE EXCISION-REPAIR; BREAST-CANCER RISK; SUSCEPTIBILITY LOCI; DAMAGE RESPONSE; POLYMORPHISMS; IDENTIFICATION; METAANALYSIS; INDIVIDUALS; GLYCOSYLASE AB The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P 6.37 10(4)), but not with GC (P 0.20). The most significant gene in ESCC was CHEK2 (P 2.00 10(6)) and in GC was CLK2 (P 3.02 10(4)). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms. C1 [Li, Wen-Qing; Hu, Nan; Hyland, Paula L.; Gao, Ying; Wang, Zhao-Ming; Yu, Kai; Su, Hua; Wang, Chao-Yu; Wang, Le-Min; Shi, Jian-Xin; Gu, Fangyi; Tucker, Margaret A.; Dawsey, Sanford M.; Freedman, Neal D.; Abnet, Christian C.; Goldstein, Alisa M.; Taylor, Philip R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. [Wang, Zhao-Ming; Chanock, Stephen J.; Burdett, Laurie] SAIC Frederick Inc, NCI Frederick, Canc Genom Res Lab, Frederick, MD USA. [Ding, Ti; Wang, Yuan; Xu, Yi] Shanxi Canc Hosp, Taiyuan, Shanxi, Peoples R China. [Qiao, You-Lin; Fan, Jin-Hu] Chinese Acad Med Sci, Canc Inst Hosp, Dept Epidemiol, Beijing 100730, Peoples R China. [Wheeler, William; Xiong, Xiao-Qin; Giffen, Carol] Informat Management Serv Inc, Silver Spring, MD USA. RP Li, WQ (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20852 USA. EM liw9@mail.nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; Gu, Fangyi/I-5957-2014; Li, Wenqing/N-2293-2014; Qiao, You-Lin/B-4139-2012; Tucker, Margaret/B-4297-2015 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Li, Wenqing/0000-0002-1283-4091; Qiao, You-Lin/0000-0001-6380-0871; FU National Cancer Institute [NO2-SC-66211, NO1-SC-91030, HHSN261200477001C]; Shanxi Cancer Hospital and Institute; Cancer Institute of the Chinese Academy of Medical Sciences; National Institute of Health, National Cancer Institute; Division of Cancer Epidemiology and Genetics FX The Shanxi Upper Gastrointestinal Cancer Genetics Project was supported by the National Cancer Institute contract NO2-SC-66211 with the Shanxi Cancer Hospital and Institute. The Nutrition Intervention Trials were supported by National Cancer Institute contracts NO1-SC-91030 and HHSN261200477001C with the Cancer Institute of the Chinese Academy of Medical Sciences. The current analysis was supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute and the Division of Cancer Epidemiology and Genetics. NR 48 TC 29 Z9 29 U1 1 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2013 VL 34 IS 7 BP 1536 EP 1542 DI 10.1093/carcin/bgt094 PG 7 WC Oncology SC Oncology GA 182OI UT WOS:000321753000015 PM 23504502 ER PT J AU Kwon, SM Kim, DS Won, NH Park, SJ Chwae, YJ Kang, HC Lee, SH Baik, EJ Thorgeirsson, SS GooWoo, H AF Kwon, So Mee Kim, Dong-Sik Won, Nam Hee Park, Soo Jeong Chwae, Yong-Joon Kang, Ho Chul Lee, Soo Hwan Baik, Eun Joo Thorgeirsson, Snorri S. GooWoo, Hyun TI Genomic copy number alterations with transcriptional deregulation at 6p identify an aggressive HCC phenotype SO CARCINOGENESIS LA English DT Article ID EARLY-RESPONSE GENE; HUMAN HEPATOCELLULAR-CARCINOMA; STEM/PROGENITOR CELLS; PANCREATIC-CANCER; IDENTIFICATION; EXPRESSION; PROGRESSION; SURVIVAL; IEX-1; RADIATION AB Genomic analyses have revealed the enormous heterogeneity in essentially all cancer types. However, the identification of precise subtypes, which are biologically informative and clinically useful, remains a challenge. The application of integrative analysis of multilayered genomic profiles to define the chromosomal regions of genomic copy number alterations with concomitant transcriptional deregulation is posited to provide a promising strategy to identify driver targets. In this study, we performed an integrative analysis of the DNA copy numbers and gene expression profiles of hepatocellular carcinoma (HCC). By comparing DNA copy numbers between HCC subtypes based on gene expression pattern, we revealed the DNA copy number alteration with concordant gene expression changes at 6p21p24 particularly in the HCC subtype of aggressive phenotype without expressing stemness genes. Among the genes at 6p21p24, we identified IER3 as a potential driver. The clinical utility of IER3 copy numbers was demonstrated by validating its clinical correlation with independent cohorts. In addition, short hairpin RNAmediated knock-down experiment revealed the functional relevance of IER3 in liver cancer progression. In conclusion, our results suggest that genomic copy number alterations with transcriptional deregulation at 6p21p24 identify an aggressive HCC phenotype and a novel functional biomarker. C1 [Kwon, So Mee; Kang, Ho Chul; Lee, Soo Hwan; Baik, Eun Joo; GooWoo, Hyun] Ajou Univ, Sch Med, Dept Physiol, Suwon 443721, South Korea. [Kim, Dong-Sik] Korea Univ, Coll Med, Dept Surg, Seoul 136705, South Korea. [Won, Nam Hee] Korea Univ, Coll Med, Dept Pathol, Seoul 136705, South Korea. [Park, Soo Jeong; Chwae, Yong-Joon] Ajou Univ, Sch Med, Dept Microbiol, Suwon 443721, South Korea. [Thorgeirsson, Snorri S.] NCI, Lab Expt Carcinogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP GooWoo, H (reprint author), Ajou Univ, Sch Med, Dept Physiol, Suwon 443721, South Korea. EM snorri_thorgeirsson@nih.gov; hg@ajou.ac.kr.or FU Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea [A111574]; National Research Foundation of Korea (NRF); Korea government (MEST) [2012R1A1A2005674, 2012R1A5A2051423, 2012-0000995]; Korea University Research Fund [K0933161] FX Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A111574); National Research Foundation of Korea (NRF) funded by the Korea government (MEST) (2012R1A1A2005674, 2012R1A5A2051423, and 2012-0000995); Korea University Research Fund (K0933161). NR 31 TC 5 Z9 7 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2013 VL 34 IS 7 BP 1543 EP 1550 DI 10.1093/carcin/bgt095 PG 8 WC Oncology SC Oncology GA 182OI UT WOS:000321753000016 PM 23508637 ER PT J AU Glass, L Krueger, F Solomon, J Raymont, V Grafman, J AF Glass, Leila Krueger, Frank Solomon, Jeffrey Raymont, Vanessa Grafman, Jordan TI Mental Paper Folding Performance Following Penetrating Traumatic Brain Injury in Combat Veterans: A Lesion Mapping Study SO CEREBRAL CORTEX LA English DT Article DE inferior parietal; left hippocampal gyms; lesion analysis; mental paper folding; penetrating head injury ID POSTERIOR PARIETAL CORTEX; HEAD-INJURY; FUNCTIONAL ACTIVATION; PARKINSONS-DISEASE; COGNITIVE DECLINE; NEURAL MECHANISMS; SEX-DIFFERENCES; ROTATION TASK; MRI; RECOGNITION AB Mental paper folding is a complex measure of visuospatial ability involving a coordinated sequence of mental transformations and is often considered a measure of mental ability. The literature is inconclusive regarding the precise neural architecture that underlies performance. We combined the administration of the Armed Forces Qualification Test boxes subtest measuring mental paper folding ability, with a voxel-based lesion symptom mapping approach to identify brain regions associated with impaired mental paper folding ability. Using a large sample of subjects with penetrating traumatic brain injury and defined lesions studied over 2 time points, roughly 15 and 35 years post-injury, enabled us to answer the causal questions regarding mental paper folding impairment. Our results revealed that brain injury significantly exacerbates the decline of performance on mental paper folding tasks over time. Our study adds novel neuropsychological and neuroimaging support for parietal lobe involvement; specifically the right inferior parietal lobule (Broadmann's Area [BA] 40) and the left parahippocampal region (BAs 19, 36). Both areas were consistently associated with mental paper folding performance and demonstrate that the right parietal lobe and the left parahippocampal gyrus play an integral role in mental paper folding tasks. C1 [Glass, Leila; Krueger, Frank; Raymont, Vanessa; Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Glass, Leila] SDSU UCSD Joint Doctoral Program Clin Psychol, San Diego, CA USA. [Krueger, Frank] George Mason Univ, Dept Mol Neurosci, Fairfax, VA 22030 USA. [Krueger, Frank] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Solomon, Jeffrey] Expert Image Anal LLC, Potomac, MD USA. [Raymont, Vanessa] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Raymont, Vanessa] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. [Grafman, Jordan] Kessler Fdn Res Ctr, Traumat Brain Injury Res Lab, W Orange, NJ USA. RP Krueger, F (reprint author), George Mason Univ, Dept Mol Neurosci, 4400 Univ Dr,Mail Stop 2A1, Fair, VA 22030 USA. EM fkrueger@gmu.edu OI Grafman, Jordan H./0000-0001-8645-4457 FU US Army Medical Research and Material Command [DAMD17-01-1-0675]; National Navy Medical Center [B03-043] FX This study was conducted by the US National Institute of Neurological Disorders and Stroke Intramural Research Program and an individual project grant (DAMD17-01-1-0675) from the US Army Medical Research and Material Command administrated by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: A 30-year post-injury follow-up study). It took place at the National Navy Medical Center (project number B03-043). The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of Defence, nor the US Government. For further information about the Vietnam Head Injury Study, contact J. G. at jgrafman@kesslerfoundation.org. NR 67 TC 2 Z9 2 U1 1 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD JUL PY 2013 VL 23 IS 7 BP 1663 EP 1672 DI 10.1093/cercor/bhs153 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 174NW UT WOS:000321163700016 PM 22669970 ER PT J AU Scheidweiler, KB Schwope, DM Karschner, EL Desrosiers, NA Gorelick, DA Huestis, MA AF Scheidweiler, Karl B. Schwope, David M. Karschner, Erin L. Desrosiers, Nathalie A. Gorelick, David A. Huestis, Marilyn A. TI In Vitro Stability of Free and Glucuronidated Cannabinoids in Blood and Plasma Following Controlled Smoked Cannabis SO CLINICAL CHEMISTRY LA English DT Article ID TANDEM MASS-SPECTROMETRY; WHOLE-BLOOD; DELTA-9-TETRAHYDROCANNABINOL THC; DELTA(9)-TETRAHYDROCANNABINOL; MARIJUANA; URINE; TETRAHYDROCANNABINOL; PHARMACOKINETICS; THCCOOH; USERS AB BACKGROUND: Blood and plasma cannabinoid stability is important for test interpretation and is best studied in authentic rather than fortified samples. METHODS: Low and high blood and plasma pools were created for each of 10 participants after they smoked a cannabis cigarette. The stabilities of Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), cannabinol (CBN), THC-glucuronide, and THCCOOH-glucuronide were determined after 1 week at room temperature; 1, 2, 4, 12, and 26 (+/- 2) weeks at 4 degrees C; and 1, 2, 4, 12, 26 (+/- 2), and 52 (+/- 4) weeks at -20 degrees C. Stability was assessed by Friedman test. RESULTS: Numbers of THC-glucuronide and CBD-positive blood samples were insufficient to assess stability. In blood, 11-OH-THC and CBN were stable for 1 week at room temperature, whereas THC and THCCOOH-glucuronide decreased and THCCOOH increased. In blood, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, and CBN were stable for 12, 4, 4, 12, and 26 weeks, respectively, at 4 degrees C and 12, 12, 26, 26, and 52 weeks at -20 degrees C. In plasma, THC-glucuronide, THC, CBN, and CBD were stable for 1 week at room temperature, whereas THCCOOH-glucuronide and 11-OH-THC decreased and THCCOOH increased. In plasma, THC-glucuronide, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, CBN, and CBD were stable for 26, 26, 2, 2, 26, 12, and 26 weeks, respectively, at 4 degrees C and 52, 52, 26, 26, 52, 52, and 52 weeks, respectively, at -20 degrees C. CONCLUSIONS: Blood and plasma samples should be stored at -20 degrees C for no more than 3 and 6 months, respectively, to assure accurate cannabinoid quantitative results. (C) 2013 American Association for Clinical Chemistry C1 [Scheidweiler, Karl B.; Schwope, David M.; Karschner, Erin L.; Desrosiers, Nathalie A.; Gorelick, David A.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Schwope, David M.; Karschner, Erin L.] Aegis Sci Corp, Nashville, TN USA. RP Huestis, MA (reprint author), NIDA, IRP, Biomed Res Ctr, NIH, 251 Bayview Blvd,Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, NIH FX Research Funding: Intramural Research Program of the National Institute on Drug Abuse, NIH. NR 27 TC 16 Z9 16 U1 0 U2 6 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUL PY 2013 VL 59 IS 7 BP 1108 EP 1117 DI 10.1373/clinchem.2012.201467 PG 10 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 179VK UT WOS:000321549400017 PM 23519966 ER PT J AU Klabunde, CN Han, PKJ Earle, CC Smith, T Ayanian, JZ Lee, R Ambs, A Rowland, JH Potosky, AL AF Klabunde, Carrie N. Han, Paul K. J. Earle, Craig C. Smith, Tenbroeck Ayanian, John Z. Lee, Richard Ambs, Anita Rowland, Julia H. Potosky, Arnold L. TI Physician Roles in the Cancer-Related Follow-Up Care of Cancer Survivors SO FAMILY MEDICINE LA English DT Article ID BREAST-CANCER; COLORECTAL-CANCER; SURVEILLANCE MAMMOGRAPHY; PREVENTIVE CARE; ONCOLOGISTS; HEALTH; UPDATE AB BACKGROUND AND OBJECTIVES: Information about primary care physicians' (PCPs) and oncologists' involvement in cancer-related follow-up care, and care coordination practices, is lacking but essential to improving cancer survivors' care. This study assesses PCPs' and oncologists' self-reported roles in providing cancer-related follow-up care for survivors who are within 5 years of completing cancer treatment. METHODS: In 2009, the National Cancer Institute and the American Cancer Society conducted a nationally representative survey of PCPs (n=1,014) and medical oncologists (n=1,125) (response rate=57.6%, cooperation rate=65.1%). Mailed questionnaires obtained information on physicians' roles in providing cancer-related follow-up care to early-stage breast and colon cancer survivors, personal and practice characteristics, beliefs about and preferences for follow-up care, and care coordination practices. RESULTS: More than 50% of PCPs reported providing cancer-related follow-up care for survivors, mainly by co-managing with an oncologist. In contrast, more than 70% of oncologists reported fulfilling these roles by providing the care themselves. In adjusted analyses, PCP co-management was associated with specialty, training in late or long-term effects of cancer, higher cancer patient volume, favorable attitudes about PCP care involvement, preference for a shared model of survivorship care, and receipt of treatment summaries from oncologists. Among oncologists, only preference for a shared care model was associated with co-management with PCPs. CONCLUSIONS: PCPs and oncologists differ in their involvement in cancer-related follow-up care of survivors, with co-management more often reported by PCPs than by oncologists. Given anticipated national shortages of PCPs and oncologists, study results suggest that improved communication and coordination between these providers is needed to ensure optimal delivery of follow-up C1 [Klabunde, Carrie N.; Ambs, Anita; Rowland, Julia H.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Han, Paul K. J.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Portland, ME 04102 USA. [Earle, Craig C.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Smith, Tenbroeck] Amer Canc Soc, Intramural Res Dept, Atlanta, GA 30329 USA. [Ayanian, John Z.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Ayanian, John Z.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Cambridge, MA 02138 USA. [Lee, Richard] Informat Management Serv Inc, Silver Spring, MD USA. [Potosky, Arnold L.] Georgetown Univ, Med Ctr, Canc Control Program, Washington, DC 20057 USA. RP Klabunde, CN (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, EPN 4005,6130 Execut Blvd, Bethesda, MD 20892 USA. EM KlabundC@mail.nih.gov OI Han, Paul/0000-0003-0165-1940 FU National Cancer Institute [HSN261200700068C]; American Cancer Society through its intramural research funds FX Funding for the Survey of Physicians' Attitudes Regarding the Care of Cancer Survivors (SPARCCS) was provided by the National Cancer Institute (contract number HSN261200700068C) and the American Cancer Society through its intramural research funds. NR 35 TC 26 Z9 26 U1 0 U2 13 PU SOC TEACHERS FAMILY MEDICINE PI LEAWOOD PA 11400 TOMAHAWK CREEK PARKWAY, STE 540, LEAWOOD, KS 66207 USA SN 0742-3225 J9 FAM MED JI Fam. Med. PD JUL-AUG PY 2013 VL 45 IS 7 BP 463 EP 474 PG 12 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 183DZ UT WOS:000321795700002 PM 23846965 ER PT J AU Cho, H Kim, JSY Chung, H Perry, C Lee, H Kim, JN AF Cho, Hanbyoul Kim, Jane Seon-Young Chung, Hyunsoo Perry, Candice Lee, Heejeong Kim, Jae-Noon TI Loss of ARID1A/BAF250a expression is linked to tumor progression and adverse prognosis in cervical cancer SO HUMAN PATHOLOGY LA English DT Article DE ARID1A/BAF250a; Cervical cancer; Immunohistochemistry; Prognostic marker; Tissue microarray ID REMODELING GENE ARID1A; CLEAR-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS; PROTEIN EXPRESSION; SWI/SNF COMPLEX; SUPPRESSOR GENE; BREAST-CANCER; CHROMATIN; MUTATIONS AB The tumor suppressor gene ARID1A encodes BAF250a, a component of human SWI/SNF chromatin-remodeling complexes. Loss of BAF250a expression has recently been reported in several tumor types. To investigate the potential correlation between BAF250a and various clinicopathologic parameters, we assessed the expression of BAF250a in archival tumor tissue specimens from 147 patients with cervical cancer and 191 with cervical intraepithelial neoplasia as well as 376 matched nonadjacent normal tissues by immunohistochemical staining. Messenger RNA expression level for BAF250a was decreased in cervical cancer cell lines (P = .013) and tissues (P = .010), when compared with normal cervical epithelial tissue using SYBR Green real-time polymerase chain reaction. BAF250a was also detected in nuclear fractions of HeLa cells and in nuclei of cervical cancer tissue samples by Western blotting and immunohistochemistry, respectively. BAF250a expression gradually decreased in transitioning from normal to cervical carcinoma (P < .001), and this loss of expression was significantly associated with tumor stage (P = .005), tumor grade (P = .029), tumor size (P = .003), and lymph node metastasis (P = .020). In multivariate analysis, overall survival in cervical cancer was significantly reduced in cases with BAF250a loss (hazard ratio, 2.78 [1.01-7.63]; P = .047). Our findings suggest a potential role for BAF250a in providing valuable prognostic information to clinicians for risk assessment in cervical cancer. (C) 2013 Elsevier Inc. All rights reserved. C1 [Cho, Hanbyoul; Kim, Jane Seon-Young; Kim, Jae-Noon] Yonsei Univ, Coll Med, Dept Obstet & Gynecol, Gangnam Severance Hosp, Seoul 135720, South Korea. [Cho, Hanbyoul; Chung, Hyunsoo; Perry, Candice] NCI, Tissue Array Res Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cho, Hanbyoul; Chung, Hyunsoo; Perry, Candice] NCI, Appl Mol Pathol Lab, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Kim, Jane Seon-Young] Univ Calif San Diego, Sch Med, San Diego, CA 92093 USA. [Lee, Heejeong] Catholic Univ Korea, Bucheon St Marys Hosp, Dept Pathol, Puchon 420717, Gyeonggi Do, South Korea. RP Lee, H (reprint author), Catholic Univ Korea, Bucheon St Marys Hosp, Dept Pathol, Puchon 420717, Gyeonggi Do, South Korea. EM heejung@catholic.ac.kr; jaehoonkim@yuhs.ac FU Basic Science Research Program through the National Research Foundation of Korea; Ministry of Education, Science and Technology [2011-0005230, 2011-0010286, 2011-0007146]; Yonsei University College of Medicine [3-2010-0072, 6-2011-0073] FX This work was supported in part by grants from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2011-0005230, 2011-0010286, and 2011-0007146), faculty research grants from Yonsei University College of Medicine for 2010 and 2011 (3-2010-0072 and 6-2011-0073). NR 29 TC 24 Z9 25 U1 0 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 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD JUL PY 2013 VL 44 IS 7 BP 1365 EP 1374 DI 10.1016/j.humpath.2012.11.007 PG 10 WC Pathology SC Pathology GA 175IS UT WOS:000321225000019 PM 23427874 ER PT J AU Wang, L Jia, Y Rogers, H Suzuki, N Gassmann, M Wang, Q McPherron, AC Kopp, JB Yamamoto, M Noguchi, CT AF Wang, Li Jia, Yi Rogers, Heather Suzuki, Norio Gassmann, Max Wang, Qian McPherron, Alexandra C. Kopp, Jeffery B. Yamamoto, Masayuki Noguchi, Constance Tom TI Erythropoietin contributes to slow oxidative muscle fiber specification via PGC-1 alpha and AMPK activation SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE Erythropoietin; slow twitch fiber; AMPK; PGC-1 alpha; mitochondrial activity ID MICE OVEREXPRESSING ERYTHROPOIETIN; FATTY-ACID OXIDATION; SKELETAL-MUSCLE; INSULIN-RESISTANCE; COACTIVATOR PGC-1; MITOCHONDRIAL DYSFUNCTION; METABOLIC-CONTROL; RECEPTOR-ALPHA; EXPRESSION; DISEASE AB Erythropoietin activity, required for erythropoiesis, is not restricted to the erythroid lineage. In light of reports on the metabolic effects of erythropoietin, we examined the effect of erythropoietin signaling on skeletal muscle fiber type development. Skeletal muscles that are rich in slow twitch fibers are associated with increased mitochondrial oxidative activity and corresponding expression of related genes compared to muscle rich in fast twitch fibers. Although erythropoietin receptor is expressed on muscle progenitor/precursor cells and is down regulated in mature muscle fibers, we found that skeletal muscles from mice with high erythropoietin production in vivo exhibit an increase in the proportion of slow twitch myofibers and increased mitochondrial activity. In comparison, skeletal muscle from wild type mice and mice with erythropoietin activity restricted to erythroid tissue have fewer slow twitch myofibers and reduced mitochondrial activity. PGC-1 alpha activates mitochondrial oxidative metabolism and converts the fast myofibers to slow myofibers when overexpressed in skeletal muscle and PGC-1 alpha was elevated by 2-fold in mice with high erythropoietin. In vitro erythropoietin treatment of primary skeletal myoblasts increased mitochondrial biogenesis gene expression including PGC-1 alpha by 2.6-fold, CytC by 2-fold, oxygen consumption rate by 2-fold, and citrate synthase activity by 58%. Erythropoietin also increases AMPK, which induces PGC-1 alpha and stimulates slow oxidative fiber formation. These data suggest that erythropoietin contributes to skeletal muscle fiber programming and metabolism, and increases PGC-1 alpha and AMPK activity during muscle development directly to affect the proportion of slow/fast twitch myofibers in mature skeletal muscle Published by Elsevier Ltd. C1 [Wang, Li; Jia, Yi; Rogers, Heather; Noguchi, Constance Tom] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Suzuki, Norio; Yamamoto, Masayuki] Tohoku Univ, Grad Sch Med, Dept Med Biochem, Aoba Ku, Sendai, Miyagi 9808575, Japan. [Gassmann, Max] Univ Zurich, Inst Vet Physiol, Zurich, Switzerland. [Gassmann, Max] Univ Zurich, Zurich Ctr Integrat Human Physiol ZIHP, Zurich, Switzerland. [Wang, Qian; McPherron, Alexandra C.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Kopp, Jeffery B.] NIDDK, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. RP Noguchi, CT (reprint author), NIDDK, Mol Med Branch, NIH, Bldg 10,Rm 9N319,10 Ctr Dr,MSC 1822, Bethesda, MD 20892 USA. EM connien@niddk.nih.gov RI Yamamoto, Masayuki/A-4873-2010 FU National Institute of Diabetes and Digestive and Kidney Diseases FX Funding is provided by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 39 TC 9 Z9 9 U1 1 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD JUL PY 2013 VL 45 IS 7 BP 1155 EP 1164 DI 10.1016/j.biocel.2013.03.007 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 175KH UT WOS:000321229100001 PM 23523698 ER PT J AU Wittig, JH Boahen, K AF Wittig, John H., Jr. Boahen, Kwabena TI Potassium conductance dynamics confer robust spike-time precision in a neuromorphic model of the auditory brain stem SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE silicon neuron; phase locking; bushy cells; g(KL); heterogeneity ID VENTRAL COCHLEAR NUCLEUS; GLOBULAR BUSHY CELLS; TO-NOISE RATIO; NERVE FIBERS; GUINEA-PIG; NEURAL SYNCHRONIZATION; SYNAPTIC INPUTS; PHASE-LOCKING; FUNCTIONAL CONSEQUENCES; INFERIOR COLLICULUS AB A fundamental question in neuroscience is how neurons perform precise operations despite inherent variability. This question also applies to neuromorphic engineering, where low-power microchips emulate the brain using large populations of diverse silicon neurons. Biological neurons in the auditory pathway display precise spike timing, critical for sound localization and interpretation of complex waveforms such as speech, even though they are a heterogeneous population. Silicon neurons are also heterogeneous, due to a key design constraint in neuromorphic engineering: smaller transistors offer lower power consumption and more neurons per unit area of silicon, but also more variability between transistors and thus between silicon neurons. Utilizing this variability in a neuromorphic model of the auditory brain stem with 1,080 silicon neurons, we found that a low-voltage-activated potassium conductance (g(KL)) enables precise spike timing via two mechanisms: statically reducing the resting membrane time constant and dynamically suppressing late synaptic inputs. The relative contribution of these two mechanisms is unknown because blocking g(KL) in vitro eliminates dynamic adaptation but also lengthens the membrane time constant. We replaced g(KL) with a static leak in silico to recover the short membrane time constant and found that silicon neurons could mimic the spike-time precision of their biological counterparts, but only over a narrow range of stimulus intensities and biophysical parameters. The dynamics of g(KL) were required for precise spike timing robust to stimulus variation across a heterogeneous population of silicon neurons, thus explaining how neural and neuromorphic systems may perform precise operations despite inherent variability. C1 [Wittig, John H., Jr.] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. [Boahen, Kwabena] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. RP Wittig, JH (reprint author), NIMH, Neuropsychol Lab, 49 Convent Dr,Bldg 49,Rm 1B80, Bethesda, MD 20892 USA. EM john.wittig@nih.gov FU National Institute on Deafness and Other Communication Disorders Grant [T32 DC 005363]; MOSIS Educational Program; Packard Foundation Grant [99-1454] FX This work was supported by National Institute on Deafness and Other Communication Disorders Grant T32 DC 005363 (fellowship to J. H. Wittig, Jr.), the MOSIS Educational Program (chip fabrication), and Packard Foundation Grant 99-1454. NR 74 TC 0 Z9 0 U1 2 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 2013 VL 110 IS 2 BP 307 EP 321 DI 10.1152/jn.00433.2012 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 183UX UT WOS:000321843800004 PM 23554436 ER PT J AU Smallwood, RF Laird, AR Ramage, AE Parkinson, AL Lewis, J Clauw, DJ Williams, DA Schmidt-Wilcke, T Farrell, MJ Eickhoff, SB Robin, DA AF Smallwood, Rachel F. Laird, Angela R. Ramage, Amy E. Parkinson, Amy L. Lewis, Jeffrey Clauw, Daniel J. Williams, David A. Schmidt-Wilcke, Tobias Farrell, Michael J. Eickhoff, Simon B. Robin, Donald A. TI Structural Brain Anomalies and Chronic Pain: A Quantitative Meta-Analysis of Gray Matter Volume SO JOURNAL OF PAIN LA English DT Review DE Chronic pain; voxel-based morphometry; meta-analysis; gray matter volume ID SUPERIOR TEMPORAL GYRUS; VOXEL-BASED MORPHOMETRY; MIDDLE FRONTAL GYRUS; CHRONIC BACK-PAIN; AUDITORY-CORTEX; LIKELIHOOD ESTIMATION; PSYCHOLOGICAL DISTRESS; AFFECTIVE COMPONENTS; THERMAL-STIMULATION; ANTERIOR CINGULATE AB The diversity of chronic pain syndromes and the methods employed to study them make integrating experimental findings challenging. This study performed coordinate-based meta-analyses using voxel-based morphometry imaging results to examine gray matter volume (GMV) differences between chronic pain patients and healthy controls. There were 12 clusters where GMV was decreased in patients compared with controls, including many regions thought to be part of the "pain matrix" of regions involved in pain perception, but also including many other regions that are not commonly regarded as pain-processing areas. The right hippocampus and parahippocampal gyrus were the only regions noted to have increased GMV in patients. Functional characterizations were implemented using the BrainMap database to determine which behavioral domains were significantly represented in these regions. The most common behavioral domains associated with these regions were cognitive, affective, and perceptual domains. Because many of these regions are not classically connected with pain and because there was such significance in functionality outside of perception, it is proposed that many of these regions are related to the constellation of comorbidities of chronic pain, such as fatigue and cognitive and emotional impairments. Further research into the mechanisms of GMV changes could provide a perspective on these findings. Perspective: Quantitative meta-analyses revealed structural differences between brains of individuals with chronic pain and healthy controls. These differences may be related to comorbidities of chronic pain. (C) 2013 by the American Pain Society C1 [Smallwood, Rachel F.] Univ Texas Hlth Sci Ctr San Antonio, Joint Program Biomed Engn, San Antonio, TX 78229 USA. [Smallwood, Rachel F.] Univ Texas San Antonio, San Antonio, TX USA. [Laird, Angela R.] Florida Int Univ, Dept Phys, Miami, FL 33199 USA. [Ramage, Amy E.; Parkinson, Amy L.; Robin, Donald A.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Ramage, Amy E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Parkinson, Amy L.; Robin, Donald A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Neurol, San Antonio, TX 78229 USA. [Lewis, Jeffrey] NINDS, Behav Neurol Unit, NIH, Bethesda, MD 20892 USA. [Clauw, Daniel J.; Williams, David A.] Univ Michigan, Chron Pain & Fatigue Res Ctr, Ann Arbor, MI 48109 USA. [Schmidt-Wilcke, Tobias] Ruhr Univ Bochum, Bergmannsheil, Dept Neurol, Bochum, Germany. [Farrell, Michael J.] Univ Melbourne, Florey Neurosci Inst, Melbourne, Vic 3010, Australia. [Eickhoff, Simon B.] Univ Dusseldorf, Inst Clin Neurosci & Med Psychol, D-40225 Dusseldorf, Germany. [Eickhoff, Simon B.] Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany. RP Robin, DA (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 7703 Floyd Curl Dr,MSC 6240, San Antonio, TX 78229 USA. EM robind@uthscsa.edu RI Eickhoff, Simon/K-2061-2013; OI Eickhoff, Simon/0000-0001-6363-2759; Farrell, Michael/0000-0003-4126-8911 FU United States Army Medical Research Acquisition Act (USAMRAA) Grant [W81XWH-11-2-0061]; National Institute of Mental Health [R01-MH074457] FX The study was funded by United States Army Medical Research Acquisition Act (USAMRAA) Grant W81XWH-11-2-0061 (D.A.R.) and National Institute of Mental Health grants R01-MH074457 (A.R.L.). NR 107 TC 57 Z9 58 U1 1 U2 17 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD JUL PY 2013 VL 14 IS 7 BP 663 EP 675 DI 10.1016/j.jpain.2013.03.001 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 183DW UT WOS:000321795400001 PM 23685185 ER PT J AU McDowell, MA Hubbard, VS AF McDowell, Margaret A. Hubbard, Van S. TI Adherence to National Diet and Physical Activity Objectives among Active Duty Military Personnel: What Are the Implications? SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Editorial Material DE Dietary Guidelines; Healthy People; Military personnel; Physical activity C1 [McDowell, Margaret A.; Hubbard, Van S.] NIH, US Dept Hlth & Human Serv, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. RP McDowell, MA (reprint author), 6707 Democracy Blvd,Suite 629, Bethesda, MD 20892 USA. EM Margaret.McDowell@nih.hhs.gov FU Intramural NIH HHS [Z99 DK999999] NR 10 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD JUL PY 2013 VL 113 IS 7 BP 903 EP 906 DI 10.1016/j.jand.2013.03.003 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 183FI UT WOS:000321799300005 PM 23647835 ER PT J AU Weber, G Gerdemann, U Caruana, I Savoldo, B Hensel, NF Rabin, KR Shpall, EJ Melenhorst, JJ Leen, AM Barrett, AJ Bollard, CM AF Weber, G. Gerdemann, U. Caruana, I. Savoldo, B. Hensel, N. F. Rabin, K. R. Shpall, E. J. Melenhorst, J. J. Leen, A. M. Barrett, A. J. Bollard, C. M. TI Generation of multi-leukemia antigen-specific T cells to enhance the graft-versus-leukemia effect after allogeneic stem cell transplant SO LEUKEMIA LA English DT Article DE immunotherapy; cytotoxic T cells; tumor-associated antigens; myeloid leukemia; stem cell transplantation; graft-versus-leukemia effect ID ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; WILMS-TUMOR-1 PROTEIN; PEPTIDE VACCINATION; ADOPTIVE TRANSFER; IMMUNE-RESPONSES; HEALTHY DONORS; LYMPHOCYTES; EXPANSION; EPITOPES AB Adoptive immunotherapy with ex vivo expanded T cells is a promising approach to prevent or treat leukemia. Myeloid leukemias express tumor-associated antigens (TAA) that induce antigen-specific cytotoxic T lymphocyte (CTL) responses in healthy individuals. We explored the feasibility of generating TAA-specific CTLs from stem cell donors of patients with myeloid leukemia to enhance the graft-versus-leukemia effect after stem cell transplantation. CTL lines were manufactured from peripheral blood of 10 healthy donors by stimulation with 15mer peptide libraries of five TAA (proteinase 3 (Pr3), preferentially expressed antigen in melanoma, Wilms tumor gene 1 (WT1), human neutrophil elastase (NE) and melanoma-associated antigen A3) known to be expressed in myeloid leukemias. All CTL lines responded to the mix of five TAA and were multi-specific as assessed by interferon-gamma enzyme-linked immunospot. Although donors showed individual patterns of antigen recognition, all responded comparably to the TAAmix. Immunogenic peptides of WT1, Pr3 or NE could be identified by epitope mapping in all donor CTL lines. In vitro experiments showed recognition of partially human leukocyte antigen (HLA)-matched myeloid leukemia blasts. These findings support the development of a single clinical grade multi-tumor antigen-specific T-cell product from the stem cell source, capable of broad reactivity against myeloid malignancies for use in donor-recipient pairs without limitation to a certain HLA-type. C1 [Weber, G.; Gerdemann, U.; Caruana, I.; Savoldo, B.; Leen, A. M.; Bollard, C. M.] Methodist Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX USA. [Weber, G.; Gerdemann, U.; Caruana, I.; Savoldo, B.; Leen, A. M.; Bollard, C. M.] Texas Childrens Hosp, Houston, TX 77030 USA. [Weber, G.; Gerdemann, U.; Caruana, I.; Savoldo, B.; Rabin, K. R.; Leen, A. M.; Bollard, C. M.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Weber, G.; Hensel, N. F.; Melenhorst, J. J.; Barrett, A. J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Shpall, E. J.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Bollard, C. M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Bollard, C. M.] Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. RP Bollard, CM (reprint author), Baylor Coll Med, Ctr Cell & Gene Therapy, 1102 Bates St,Suite 1770-01, Houston, TX 77030 USA. EM cmbollar@txch.org OI Caruana, Ignazio/0000-0002-9250-0605 FU NIH grant [1P01CA148600-01]; CPRIT Grant [RP100484]; career development award from the Leukemia Lymphoma Society; Gillson Longenbaugh Foundation FX This work was supported in parts by NIH grant 1P01CA148600-01 and CPRIT Grant RP100484. CMB was also supported by the career development award from the Leukemia Lymphoma Society and an award from the Gillson Longenbaugh Foundation. NR 46 TC 32 Z9 33 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUL PY 2013 VL 27 IS 7 BP 1538 EP 1547 DI 10.1038/leu.2013.66 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 180RU UT WOS:000321614000012 PM 23528871 ER PT J AU Yin, Z Sadok, A Sailem, H McCarthy, A Xia, XF Li, FH Garcia, MA Evans, L Barr, AR Perrimon, N Marshall, CJ Wong, STC Bakal, C AF Yin, Zheng Sadok, Amine Sailem, Heba McCarthy, Afshan Xia, Xiaofeng Li, Fuhai Garcia, Mar Arias Evans, Louise Barr, Alexis R. Perrimon, Norbert Marshall, Christopher J. Wong, Stephen T. C. Bakal, Chris TI A screen for morphological complexity identifies regulators of switch-like transitions between discrete cell shapes SO NATURE CELL BIOLOGY LA English DT Article ID AUTOMATIC SEGMENTATION; MOTILE CELLS; CLASSIFICATION; MELANOMA; ACTIVATION; FEATURES; IMAGES; PROTEOLYSIS; MECHANISM; MIGRATION AB The way in which cells adopt different morphologies is not fully understood. Cell shape could be a continuous variable or restricted to a set of discrete forms. We developed quantitative methods to describe cell shape and show that Drosophila haemocytes in culture are a heterogeneous mixture of five discrete morphologies. In an RNAi screen of genes affecting the morphological complexity of heterogeneous cell populations, we found that most genes regulate the transition between discrete shapes rather than generating new morphologies. In particular, we identified a subset of genes, including the tumour suppressor PTEN, that decrease the heterogeneity of the population, leading to populations enriched in rounded or elongated forms. We show that these genes have a highly conserved function as regulators of cell shape in both mouse and human metastatic melanoma cells. C1 [Yin, Zheng; Xia, Xiaofeng; Li, Fuhai; Wong, Stephen T. C.] Methodist Hosp, Res Inst, Weill Cornell Med Coll, NCI Ctr Modeling Canc Dev, Houston, TX 77030 USA. [Yin, Zheng; Xia, Xiaofeng; Li, Fuhai; Wong, Stephen T. C.] Methodist Hosp, Res Inst, Dept Syst Med & Bioengn, Weill Cornell Med Coll, Houston, TX 77030 USA. [Sadok, Amine; Sailem, Heba; McCarthy, Afshan; Garcia, Mar Arias; Evans, Louise; Barr, Alexis R.; Marshall, Christopher J.; Bakal, Chris] Inst Canc Res, Chester Beatty Labs, Div Canc Biol, London SW3 6JB, England. [Perrimon, Norbert] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA. [Perrimon, Norbert] Howard Hughes Med Inst, Boston, MA 02215 USA. [Wong, Stephen T. C.] Methodist Hosp, Weill Cornell Med Coll, Dept Radiol, Houston, TX 77030 USA. RP Wong, STC (reprint author), Methodist Hosp, Res Inst, Weill Cornell Med Coll, NCI Ctr Modeling Canc Dev, 6670 Bertner Ave,R6 South, Houston, TX 77030 USA. EM STWong@tmhs.org; cbakal@icr.ac.uk RI Yin, Zheng/J-9307-2015; OI Yin, Zheng/0000-0002-3547-0606; Barr, Alexis/0000-0002-6684-8114 FU NCI [R01CA121225, U54CA149196]; CRUK [13478, C107/A10433] FX We are indebted to the Drosophila RNAi Screening Center staff at Harvard Medical School for their invaluable assistance. We especially thank I. Flockhart for assistance with data management. We thank J. Wang, X. Zhou and P. Bradley for their initial involvement in this study. We are grateful to N. Dhomen and R. Marais for melanoma cell lines. Work was financially supported in part by NCI grants (Grants R01CA121225 and U54CA149196) to S.T.C.W. and CRUK grants to C.B. (Grant 13478) and C.J.M. (Grant C107/A10433). N.P. is an Investigator of the Howard Hughes Medical Institute. A.S. is a Marie Curie Intra-European Fellow. C.J.M. is a Gibb Life Fellow of CRUK. C.B. is a Research Career Development Fellow of the Wellcome Trust. NR 53 TC 63 Z9 65 U1 2 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUL PY 2013 VL 15 IS 7 BP 860 EP + DI 10.1038/ncb2764 PG 38 WC Cell Biology SC Cell Biology GA 174UQ UT WOS:000321181400019 PM 23748611 ER PT J AU Lane, RF Friedman, LG Keith, C Braithwaite, SP Frearson, JA Lowe, DA Longo, FM Refolo, LM Watterson, DM Tsaioun, K Shineman, DW Fillit, HM AF Lane, Rachel F. Friedman, Lauren G. Keith, Curtis Braithwaite, Steven P. Frearson, Julie A. Lowe, David A. Longo, Frank M. Refolo, Lorenzo M. Watterson, D. Martin Tsaioun, Katya Shineman, Diana W. Fillit, Howard M. TI Optimizing the use of CROs by academia and small companies SO NATURE REVIEWS DRUG DISCOVERY LA English DT Editorial Material AB Contract research organizations (CROs) have a key role in drug discovery and development, but processes for evaluating, engaging and managing CRO contracts may not be well established in academic institutions or small companies. Here, we recommend an approach to optimize the execution of drug discovery programmes in such environments. C1 [Lane, Rachel F.; Shineman, Diana W.; Fillit, Howard M.] Alzheimers Drug Discovery Fdn, New York, NY 10019 USA. [Friedman, Lauren G.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Keith, Curtis] Harvard Univ, Cambridge, MA 02138 USA. [Braithwaite, Steven P.] Circuit Therapeut, Menlo Pk, CA 94025 USA. [Frearson, Julie A.] BioFocus, Saffron Walden CB10 1XL, Essex, England. [Lowe, David A.] NeuroAssets, CH-1800 Vevey, Switzerland. [Longo, Frank M.] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Palo Alto, CA 94305 USA. [Refolo, Lorenzo M.] US Natl Inst Aging, Bethesda, MD 20892 USA. [Watterson, D. Martin] Northwestern Univ, Chicago, IL 60611 USA. [Tsaioun, Katya] Pharma Launcher, Belmont, MA 02478 USA. RP Lane, RF (reprint author), Alzheimers Drug Discovery Fdn, 57 W 57th St, New York, NY 10019 USA. OI Watterson, Daniel/0000-0001-7605-5866 NR 0 TC 2 Z9 2 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD JUL PY 2013 VL 12 IS 7 BP 487 EP 488 DI 10.1038/nrd4057 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 173VU UT WOS:000321110600001 PM 23812255 ER PT J AU Du, XJ Wojtowicz, D Bowers, AA Levens, D Benham, CJ Przytycka, TM AF Du, Xiangjun Wojtowicz, Damian Bowers, Albert A. Levens, David Benham, Craig J. Przytycka, Teresa M. TI The genome-wide distribution of non-B DNA motifs is shaped by operon structure and suggests the transcriptional importance of non-B DNA structures in Escherichia coli SO NUCLEIC ACIDS RESEARCH LA English DT Article ID C-MYC GENE; DUPLEX DESTABILIZATION SIDD; G-QUADRUPLEX; G4 DNA; FORMING SEQUENCES; IN-VIVO; SACCHAROMYCES-CEREVISIAE; REGULATORY ELEMENTS; BINDING PROTEINS; UPSTREAM DNA AB Although the right-handed double helical B-form DNA is most common under physiological conditions, DNA is dynamic and can adopt a number of alternative structures, such as the four-stranded G-quadruplex, left-handed Z-DNA, cruciform and others. Active transcription necessitates strand separation and can induce such non-canonical forms at susceptible genomic sequences. Therefore, it has been speculated that these non-B DNA motifs can play regulatory roles in gene transcription. Such conjecture has been supported in higher eukaryotes by direct studies of several individual genes, as well as a number of large-scale analyses. However, the role of non-B DNA structures in many lower organisms, in particular proteobacteria, remains poorly understood and incompletely documented. In this study, we performed the first comprehensive study of the occurrence of B DNA-non-B DNA transition-susceptible sites (non-B DNA motifs) within the context of the operon structure of the Escherichia coli genome. We compared the distributions of non-B DNA motifs in the regulatory regions of operons with those from internal regions. We found an enrichment of some non-B DNA motifs in regulatory regions, and we show that this enrichment cannot be simply explained by base composition bias in these regions. We also showed that the distribution of several non-B DNA motifs within intergenic regions separating divergently oriented operons differs from the distribution found between convergent ones. In particular, we found a strong enrichment of cruciforms in the termination region of operons; this enrichment was observed for operons with Rho-dependent, as well as Rho-independent terminators. Finally, a preference for some non-B DNA motifs was observed near transcription factor-binding sites. Overall, the conspicuous enrichment of transition-susceptible sites in these specific regulatory regions suggests that non-B DNA structures may have roles in the transcriptional regulation of specific operons within the E. coli genome. C1 [Du, Xiangjun; Wojtowicz, Damian; Przytycka, Teresa M.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Bowers, Albert A.] UNC Eshselman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Levens, David] NCI, Gene Regulat Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Benham, Craig J.] Univ Calif Davis, UC Davis Genome Ctr, Davis, CA 95616 USA. RP Przytycka, TM (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM przytyck@ncbi.nlm.nih.gov RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X FU Intramural Research Program of the US National Institute of Health; National Library of Medicine; National Cancer Institute; Center for Cancer Research FX Intramural Research Program of the US National Institute of Health; National Library of Medicine; National Cancer Institute; Center for Cancer Research. Funding for access charge: Intramural Research Program of the US National Institute of Health; National Library of Medicine. NR 82 TC 18 Z9 18 U1 4 U2 28 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 12 BP 5965 EP 5977 DI 10.1093/nar/gkt308 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 173DA UT WOS:000321057100010 PM 23620297 ER PT J AU Cagliero, C Grand, RS Jones, MB Jin, DJ O'Sullivan, JM AF Cagliero, Cedric Grand, Ralph S. Jones, M. Beatrix Jin, Ding J. O'Sullivan, Justin M. TI Genome conformation capture reveals that the Escherichia coli chromosome is organized by replication and transcription SO NUCLEIC ACIDS RESEARCH LA English DT Article ID NUCLEOID-ASSOCIATED PROTEINS; RIBOSOMAL-RNA OPERONS; MACRODOMAIN ORGANIZATION; ACTIVE TRANSCRIPTION; BACTERIAL CHROMATIN; STRINGENT RESPONSE; GENE LOOPS; H-NS; SEGREGATION; DNA AB To fit within the confines of the cell, bacterial chromosomes are highly condensed into a structure called the nucleoid. Despite the high degree of compaction in the nucleoid, the genome remains accessible to essential biological processes, such as replication and transcription. Here, we present the first high-resolution chromosome conformation capture-based molecular analysis of the spatial organization of the Escherichia coli nucleoid during rapid growth in rich medium and following an induced amino acid starvation that promotes the stringent response. Our analyses identify the presence of origin and terminus domains in exponentially growing cells. Moreover, we observe an increased number of interactions within the origin domain and significant clustering of SeqA-binding sequences, suggesting a role for SeqA in clustering of newly replicated chromosomes. By contrast, 'histone-like' protein (i.e. Fis, IHF and H-NS) -binding sites did not cluster, and their role in global nucleoid organization does not manifest through the mediation of chromosomal contacts. Finally, genes that were downregulated after induction of the stringent response were spatially clustered, indicating that transcription in E. coli occurs at transcription foci. C1 [Cagliero, Cedric; Jin, Ding J.] NCI, Gene Regulat & Chromosome Biol Lab, Frederick Natl Lab Canc Res, NIH, Frederick, MD 21702 USA. [Grand, Ralph S.; Jones, M. Beatrix] Massey Univ, Inst Nat & Math Sci, Auckland 0745, New Zealand. [Grand, Ralph S.; O'Sullivan, Justin M.] Univ Auckland, Liggins Inst, Auckland 1023, New Zealand. RP O'Sullivan, JM (reprint author), Univ Auckland, Liggins Inst, Auckland 1023, New Zealand. EM justin.osullivan@auckland.ac.nz FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Marsden Fund; Massey University research fund; Massey University scholarship; Liggins Institute Auckland University FX Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (to C.C. and J.D.); the Marsden Fund (to J.M.O.S.); Massey University research fund (to J.M.O.S and B.H.A.R.); Massey University scholarship (to R.S.G.). Funding for open access charge: The Liggins Institute Auckland University. NR 80 TC 40 Z9 40 U1 1 U2 31 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 12 BP 6058 EP 6071 DI 10.1093/nar/gkt325 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 173DA UT WOS:000321057100017 PM 23632166 ER PT J AU Mechold, U Potrykus, K Murphy, H Murakami, KS Cashel, M AF Mechold, Undine Potrykus, Katarzyna Murphy, Helen Murakami, Katsuhiko S. Cashel, Michael TI Differential regulation by ppGpp versus pppGpp in Escherichia coli SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RIBONUCLEIC-ACID SYNTHESIS; RIBOSOMAL-RNA SYNTHESIS; STRINGENT-RESPONSE; STREPTOCOCCUS-EQUISIMILIS; GUANOSINE TETRAPHOSPHATE; OMEGA SUBUNIT; GROWTH-RATE; X-RAY; TRANSCRIPTION INITIATION; THERMUS-THERMOPHILUS AB Both ppGpp and pppGpp are thought to function collectively as second messengers for many complex cellular responses to nutritional stress throughout biology. There are few indications that their regulatory effects might be different; however, this question has been largely unexplored for lack of an ability to experimentally manipulate the relative abundance of ppGpp and pppGpp. Here, we achieve preferential accumulation of either ppGpp or pppGpp with Escherichia coli strains through induction of different Streptococcal (p)ppGpp synthetase fragments. In addition, expression of E. coli GppA, a pppGpp 5'-gamma phosphate hydrolase that converts pppGpp to ppGpp, is manipulated to fine tune differential accumulation of ppGpp and pppGpp. In vivo and in vitro experiments show that pppGpp is less potent than ppGpp with respect to regulation of growth rate, RNA/DNA ratios, ribosomal RNA P1 promoter transcription inhibition, threonine operon promoter activation and RpoS induction. To provide further insights into regulation by (p)ppGpp, we have also determined crystal structures of E. coli RNA polymerase-Sigma(70) holoenzyme with ppGpp and pppGpp. We find that both nucleotides bind to a site at the interface between beta' and omega subunits. C1 [Mechold, Undine; Potrykus, Katarzyna; Murphy, Helen; Cashel, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Murakami, Katsuhiko S.] Penn State Univ, Ctr RNA Mol Biol, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. RP Murakami, KS (reprint author), Penn State Univ, Ctr RNA Mol Biol, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. EM kum14@psu.edu; cashelm@mail.nih.gov FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health; National Institutes of Health [GM087350-A1]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (USA) FX Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, and by National Institutes of Health grant [GM087350-A1 (to K. S. M.)]. Funding for open access charge: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892 (USA). Intramural Program. Contact M. Cashel. NR 68 TC 52 Z9 52 U1 1 U2 17 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 12 BP 6175 EP 6189 DI 10.1093/nar/gkt302 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 173DA UT WOS:000321057100026 PM 23620295 ER PT J AU Arab, L Su, J Steck, SE Ang, A Fontham, ETH Bensen, JT Mohler, JL AF Arab, Lenore Su, Joseph Steck, Susan E. Ang, Alfonso Fontham, Elizabeth T. H. Bensen, Jeannette T. Mohler, James L. TI Adherence to World Cancer Research Fund/American Institute for Cancer Research Lifestyle Recommendations Reduces Prostate Cancer Aggressiveness Among African and Caucasian Americans SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID GUIDELINES-FOR-AMERICANS; MAJOR CHRONIC DISEASE; DIETARY-GUIDELINES; PHYSICAL-ACTIVITY; EPIDEMIOLOGIC EVIDENCE; RADICAL PROSTATECTOMY; SUBSEQUENT RISK; PREVENTION; COHORT; MEN AB The effect of adherence to the World Cancer Research Fund (WCRF) lifestyle recommendations on cancer aggressiveness is unknown. We examined associations between adherence to recommendations and risk of highly aggressive prostate cancer in research subjects enrolled in the North Carolina-Louisiana Prostate Cancer Project (PCaP). We examined associations between adherence to WCRF recommendations and risk of highly aggressive prostate cancer among 2212 newly diagnosed African Americans (AA) or Caucasian Americans (CA) aged 40-70years in PCaP. Prostate cancer aggressiveness was based on Gleason scores, serum prostate-specific antigens, and TNM stage. Adherence to WCRF recommendations was based on point scores and odds ratios estimated. Results showed that adherence to recommendations was significantly and negatively associated with risk of a highly aggressive prostate cancer. Each additional point in the total adherence score corresponded to a 13% risk reduction. Total adherence score <4 predicted increased risk in both AA (OR = 1.36; 95% CI = 1.01-1.85) and CA (OR = 1.41; 95% CI = 1.01-1.98). Consumption of <500g red meat per week or 125 total kcal/100g solid food per day is a statistically significant protective factor in the overall cohort. Recommendations aimed at preventing all cancers also may reduce risk of highly aggressive prostate cancer. C1 [Arab, Lenore; Ang, Alfonso] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Su, Joseph] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Steck, Susan E.] Univ S Carolina, Dept Epidemiol & Biostat, Statewide Canc Prevent & Control Program, Columbia, SC 29208 USA. [Fontham, Elizabeth T. H.] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, New Orleans, LA USA. [Bensen, Jeannette T.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Sch Med, Chapel Hill, NC USA. [Bensen, Jeannette T.; Mohler, James L.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA. [Mohler, James L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Mohler, James L.] SUNY Buffalo, Sch Med & Biotechnol, Buffalo, NY 14260 USA. RP Arab, L (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, 12-262 Factor Bldg,Box 951736, Los Angeles, CA 90095 USA. EM Larab@ucla.edu FU Department of Defense [DAMD 17-03-2-0052] FX This work was supported by the Department of Defense (grant number DAMD 17-03-2-0052) through the Prostate Cancer Project, a collaborative study. The authors thank the North Carolina Central Cancer Registry, the Louisiana Tumor Registry, and the PCaP staff, advisory committees and participants for their important contributions. The authors also thank Martha Sensel, PhD and Jasmine Yaxun Chen for assistance in writing the article. NR 42 TC 14 Z9 14 U1 0 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0163-5581 J9 NUTR CANCER JI Nutr. Cancer PD JUL 1 PY 2013 VL 65 IS 5 BP 633 EP 643 DI 10.1080/01635581.2013.789540 PG 11 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 184KE UT WOS:000321887700002 PM 23859030 ER PT J AU Brooks, BP Thompson, AH Bishop, RJ Clayton, JA Chan, CC Tsilou, ET Zein, WM Tamura, D Khan, SG Ueda, T Boyle, J Oh, KS Imoto, K Inui, H Moriwaki, SI Emmert, S Iliff, NT Bradford, P DiGiovanna, JJ Kraemer, KH AF Brooks, Brian P. Thompson, Amy H. Bishop, Rachel J. Clayton, Janine A. Chan, Chi-Chao Tsilou, Ekaterini T. Zein, Wadih M. Tamura, Deborah Khan, Sikandar G. Ueda, Takahiro Boyle, Jennifer Oh, Kyu-Seon Imoto, Kyoko Inui, Hiroki Moriwaki, Shin-Ichi Emmert, Steffen Iliff, Nicholas T. Bradford, Porcia DiGiovanna, John J. Kraemer, Kenneth H. TI Ocular Manifestations of Xeroderma Pigmentosum SO OPHTHALMOLOGY LA English DT Article ID COCKAYNE-SYNDROME COMPLEX; COMPLEMENTATION GROUP-G; DEFECTIVE-DNA REPAIR; NEUROLOGICAL DISEASE; DRY EYE; ULTRAVIOLET-RADIATION; SKIN-CANCER; XPD GENE; TRICHOTHIODYSTROPHY; CORNEAL AB Objective: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in DNA repair genes. Clinical manifestations of XP include mild to extreme sensitivity to ultraviolet radiation resulting in inflammation and neoplasia in sun-exposed areas of the skin, mucous membranes, and ocular surfaces. This report describes the ocular manifestations of XP in patients systematically evaluated in the Clinical Center at the National Institutes of Health. Design: Retrospective observational case series. Participants: Eighty-seven participants, aged 1.3 to 63.4 years, referred to the National Eye Institute (NEI) for examination from 1964 to 2011. Eighty-three patients had XP, 3 patients had XP/Cockayne syndrome complex, and 1 patient had XP/trichothiodystrophy complex. Methods: Complete age-and developmental stage-appropriate ophthalmic examination. Main Outcome Measures: Visual acuity; eyelid, ocular surface, and lens pathology; tear film and tear production measures; and cytologic analysis of conjunctival surface swabs. Results: Of the 87 patients, 91% had at least 1 ocular abnormality. The most common abnormalities were conjunctivitis (51%), corneal neovascularization (44%), dry eye (38%), corneal scarring (26%), ectropion (25%), blepharitis (23%), conjunctival melanosis (20%), and cataracts (14%). Thirteen percent of patients had some degree of visual axis impingement, and 5% of patients had no light perception in 1 or both eyes. Ocular surface cancer or a history of ocular surface cancer was present in 10% of patients. Patients with an acute sunburning skin phenotype were less likely to develop conjunctival melanosis and ectropion but more likely to develop neoplastic ocular surface lesions than nonburning patients. Some patients also showed signs of limbal stem cell deficiency. Conclusions: Our longitudinal study reports the ocular status of the largest group of patients with XP systematically examined at 1 facility over an extended period of time. Structural eyelid abnormalities, neoplasms of the ocular surface and eyelids, tear film and tear production abnormalities, ocular surface disease and inflammation, and corneal abnormalities were present in this population. Burning and nonburning patients with XP exhibit different rates of important ophthalmologic findings, including neoplasia. In addition, ophthalmic characteristics can help refine diagnoses in the case of XP complex phenotypes. DNA repair plays a major role in protection of the eye from sunlight-induced damage. (C) 2013 by the American Academy of Ophthalmology. C1 [Brooks, Brian P.; Thompson, Amy H.; Bishop, Rachel J.; Clayton, Janine A.; Chan, Chi-Chao; Tsilou, Ekaterini T.; Zein, Wadih M.] NEI, NIH, Bethesda, MD 20892 USA. [Tamura, Deborah; Khan, Sikandar G.; Ueda, Takahiro; Boyle, Jennifer; Oh, Kyu-Seon; Imoto, Kyoko; Inui, Hiroki; Moriwaki, Shin-Ichi; Emmert, Steffen; DiGiovanna, John J.; Kraemer, Kenneth H.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Iliff, Nicholas T.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Bradford, Porcia] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Brooks, BP (reprint author), NEI, NIH, Bldg 10,Room 10B16, Bethesda, MD 20892 USA. EM brooksb@mail.nih.gov FU Center for Cancer Research, the National Cancer Institute; NEI, National Institutes of Health, Bethesda, MD FX Supported by the Intramural Research Program of the Center for Cancer Research, the National Cancer Institute, and the NEI, National Institutes of Health, Bethesda, MD. NR 58 TC 15 Z9 15 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 2013 VL 120 IS 7 BP 1324 EP 1336 DI 10.1016/j.ophtha.2012.12.044 PG 13 WC Ophthalmology SC Ophthalmology GA 173VC UT WOS:000321108500023 PM 23601806 ER PT J AU Moore, HM Kelly, A McShane, LM Vaught, J AF Moore, Helen M. Kelly, Andrea McShane, Lisa M. Vaught, Jim TI Biospecimen Reporting for Improved Study Quality (BRISQ) SO TRANSFUSION LA English DT Letter C1 [Moore, Helen M.; Vaught, Jim] NCI, Biorepositories & Biospecimen Res Branch, NIH, US Dept HHS, Rockville, MD USA. [Kelly, Andrea] Natl Inst Deafness & Other Commun Disorders, Sci Review Branch, NIH, US Dept HHS, Bethesda, MD USA. [McShane, Lisa M.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH,US Dept HHS, Rockville, MD USA. RP Moore, HM (reprint author), NCI, Biorepositories & Biospecimen Res Branch, NIH, US Dept HHS, Rockville, MD USA. EM kellya2@mail.nih.gov NR 4 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUL PY 2013 VL 53 IS 7 BP E1 EP E1 DI 10.1111/trf.12281 PG 1 WC Hematology SC Hematology GA 180RI UT WOS:000321612400001 PM 23844646 ER PT J AU Wess, J Nakajima, K Jain, S AF Wess, Juergen Nakajima, Kenichiro Jain, Shalini TI Novel designer receptors to probe GPCR signaling and physiology SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID MUSCARINIC ACETYLCHOLINE-RECEPTOR; PROTEIN-COUPLED RECEPTOR; BETA-CELL FUNCTION; SCANNING MUTAGENESIS; REMOTE-CONTROL; IN-VIVO; LIGAND; IDENTIFICATION; ACTIVATION; INHIBITION AB Muscarinic receptor-based designer receptors have emerged as powerful novel tools to study G-protein-coupled receptor (GPCR) signaling and physiology. These new designer GPCRs, which are most frequently referred to as DREADDs (designer receptors exclusively activated by designer drug), are unable to bind acetylcholine, the endogenous muscarinic receptor agonist, but can be activated by clozapine-N-oxide (CNO), an otherwise pharmacologically inert compound, with high potency and efficacy. The various DREADDs differ primarily in their G protein coupling preference. More recently, an arrestin-biased DREADD has also been developed. The expression of DREADDs in distinct tissues or cell types has enabled researchers to study the outcome of selective stimulation of distinct GPCR (or arrestin) signaling pathways in a temporally and spatially controlled fashion in vivo. In this review, we provide an up-to-date snapshot of where this field currently stands and which important novel insights have been gained using this new technology. C1 [Wess, Juergen; Nakajima, Kenichiro; Jain, Shalini] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bldg 8A,8 Ctr Dr MSC 0810, Bethesda, MD 20892 USA. EM jurgenw@helix.nih.gov FU NIH; NIDDK FX Our research covered in this review was supported by the Intramural Research Program of the NIH, NIDDK. We thank Drs Dahlia R. Weiss and Brian K. Shoichet (University of California, San Francisco) for preparing Figure 2B, Dr Daniel Appella (NIH, NIDDK) for his help in generating Figure 2A, and Mr Andrew Kruse (University of California, San Francisco) for helpful discussions. NR 48 TC 36 Z9 36 U1 4 U2 41 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD JUL PY 2013 VL 34 IS 7 BP 385 EP 392 DI 10.1016/j.tips.2013.04.006 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 190MP UT WOS:000322344500005 PM 23769625 ER PT J AU Grimes, CA Wright, JD Liu, K Nowson, CA Loria, CM AF Grimes, Carley A. Wright, Jacqueline D. Liu, Kiang Nowson, Caryl A. Loria, Catherine M. TI Dietary sodium intake is associated with total fluid and sugar-sweetened beverage consumption in US children and adolescents aged 2-18 y: NHANES 2005-2008 SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID SOFT DRINK CONSUMPTION; SALT INTAKE; OBESITY; THIRST; WATER; METAANALYSIS; EXCRETION; ENERGY; HEALTH; RATS AB Background: Increasing dietary sodium drives the thirst response. Because sugar-sweetened beverages (SSBs) are frequently consumed by children, sodium intake may drive greater consumption of SSBs and contribute to obesity risk. Objective: We examined the association between dietary sodium, total fluid, and SSB consumption in a nationally representative sample of US children and adolescents aged 2-18 y. Design: We analyzed cross-sectional data from NHANES 2005-2008. Dietary sodium, fluid, and SSB intakes were assessed with a 24-h dietary recall. Multiple regression analysis was used to assess associations between sodium, fluid, and SSBs adjusted for age, sex, race-ethnic group, body mass index (BMI), socioeconomic status (SES), and energy intake. Results: Of 6400 participants, 51.3% (n = 3230) were males, and the average (+/- SEM) age was 10.1 +/- 0.1 y. The average sodium intake was 3056 +/- 48 mg/d (equivalent to 7.8 +/- 0.1 g salt/d). Dietary sodium intake was positively associated with fluid consumption (r = 0.42, P < 0.001). After adjustment for age, sex, race-ethnic group, SES, and BMI, each additional 390 mg Na/d (1 g salt/d) was associated with a 74-g/d greater intake of fluid (P < 0.001). In consumers of SSBs (n = 4443; 64%), each additional 390 mg Na/d (1 g salt/d) was associated with a 32-g/d higher intake of SSBs (P < 0.001) adjusted for age, sex, race-ethnic group, SES, and energy intake. Conclusions: Dietary sodium is positively associated with fluid consumption and predicted SSB consumption in consumers of SSBs. The high dietary sodium intake of US children and adolescents may contribute to a greater consumption of SSBs, identifying a possible link between dietary sodium intake and excess energy intake. C1 [Grimes, Carley A.; Nowson, Caryl A.] Deakin Univ, Sch Exercise & Nutr Sci, Ctr Phys Act & Nutr Res, Melbourne, Vic, Australia. [Wright, Jacqueline D.; Loria, Catherine M.] NHLBI, Bethesda, MD 20892 USA. [Liu, Kiang] Northwestern Univ, Dept Preventat Med, Feinberg Sch Med, Chicago, IL 60611 USA. RP Loria, CM (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Suite 10018, Bethesda, MD 20892 USA. EM loriac@mail.nih.gov FU Helen MacPherson Smith Trust; National Heart Foundation (Australia) FX Supported by the Helen MacPherson Smith Trust and a postgraduate scholarship from the National Heart Foundation (Australia). NR 42 TC 22 Z9 23 U1 1 U2 12 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2013 VL 98 IS 1 BP 189 EP 196 DI 10.3945/ajcn.112.051508 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 171EZ UT WOS:000320909200023 PM 23676421 ER PT J AU Ahmed, HM Blaha, MJ Nasir, K Jones, SR Rivera, JJ Agatston, A Blankstein, R Wong, ND Lakoski, S Budoff, MJ Burke, GL Sibley, CT Ouyang, P Blumenthal, RS AF Ahmed, Haitham M. Blaha, Michael J. Nasir, Khurram Jones, Steven R. Rivera, Juan J. Agatston, Arthur Blankstein, Ron Wong, Nathan D. Lakoski, Susan Budoff, Matthew J. Burke, Gregory L. Sibley, Christopher T. Ouyang, Pamela Blumenthal, Roger S. TI Low-Risk Lifestyle, Coronary Calcium, Cardiovascular Events, and Mortality: Results From MESA SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE coronary artery disease; CT and MRI; diet; epidemiology; exercise; primary prevention; risk factors; weight reduction ID ALL-CAUSE MORTALITY; BODY-MASS INDEX; PHYSICAL-ACTIVITY; ARTERY CALCIUM; SUBCLINICAL ATHEROSCLEROSIS; MEDITERRANEAN DIET; HEART-ASSOCIATION; ADULTS; WOMEN; HEALTH AB Unhealthy lifestyle habits are a major contributor to coronary artery disease. The purpose of the present study was to investigate the associations of smoking, weight maintenance, physical activity, and diet with coronary calcium, cardiovascular events, and mortality. US participants who were 44-84 years of age (n = 6,229) were followed in the Multi-Ethnic Study of Atherosclerosis from 2000 to 2010. A lifestyle score ranging from 0 to 4 was created using diet, exercise, body mass index, and smoking status. Coronary calcium was measured at baseline and a mean of 3.1 (standard deviation, 1.3) years later to assess calcium progression. Participants who experienced coronary events or died were followed for a median of 7.6 (standard deviation, 1.5) years. Participants with lifestyle scores of 1, 2, 3, and 4 were found to have mean adjusted annual calcium progressions that were 3.5 (95% confidence interval (CI): 0.0, 7.0), 4.2 (95% CI: 0.6, 7.9), 6.8 (95% CI: 2.0, 11.5), and 11.1 (95% CI: 2.2, 20.1) points per year slower, respectively, relative to the reference group (P = 0.003). Unadjusted hazard ratios for death by lifestyle score were as follows: for a score of 1, the hazard ratio was 0.79 (95% CI: 0.61, 1.03); for a score of 2, the hazard ratio was 0.61 (95% CI: 0.46, 0.81); for a score of 3, the hazard ratio was 0.49 (95% CI: 0.32, 0.75); and for a score of 4, the hazard ratio was 0.19 (95% CI: 0.05, 0.75) (P < 0.001 by log-rank test). In conclusion, a combination of regular exercise, healthy diet, smoking avoidance, and weight maintenance was associated with lower coronary calcium incidence, slower calcium progression, and lower all-cause mortality over 7.6 years. C1 [Ahmed, Haitham M.; Blaha, Michael J.; Nasir, Khurram; Jones, Steven R.; Rivera, Juan J.; Blumenthal, Roger S.] Johns Hopkins Univ, Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. [Nasir, Khurram; Agatston, Arthur] Baptist Hlth Med Grp, Ctr Prevent & Wellness Res, Miami Beach, FL USA. [Nasir, Khurram; Agatston, Arthur] Florida Int Univ, Dept Med, Herbert Wertheim Coll Med, Miami, FL 33199 USA. [Nasir, Khurram] Florida Int Univ, Dept Epidemiol, Robert Stempel Coll Publ Hlth, Miami, FL 33199 USA. [Rivera, Juan J.; Agatston, Arthur] South Beach Prevent Cardiol, Miami Beach, FL USA. [Blankstein, Ron] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wong, Nathan D.] Univ Calif Irvine, Coll Med, Irvine, CA 92717 USA. [Lakoski, Susan] Univ Vermont, Coll Med, Burlington, VT USA. [Budoff, Matthew J.] Univ Calif Los Angeles, Sch Med, Torrance, CA 90509 USA. [Burke, Gregory L.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Sibley, Christopher T.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Ouyang, Pamela] Johns Hopkins Univ, Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. RP Ahmed, HM (reprint author), Johns Hopkins Univ Hosp, Ciccarone Ctr Prevent Heart Dis, 600 N Wolfe St, Baltimore, MD 21287 USA. EM hahmed2@jhmi.edu FU National Heart, Lung, and Blood Institute at the National Institutes of Health [R01-HL071739, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95169] FX This work was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health (grant R01-HL071739 and contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169). NR 35 TC 36 Z9 38 U1 1 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2013 VL 178 IS 1 BP 12 EP 21 DI 10.1093/aje/kws453 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 178LL UT WOS:000321449400002 PM 23733562 ER PT J AU Saha-Chaudhuri, P Weinberg, CR AF Saha-Chaudhuri, Paramita Weinberg, Clarice R. TI Specimen Pooling for Efficient Use of Biospecimens in Studies of Time to a Common Event SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE discrete event time outcome; pooling; pooling for biomarker; pooling for exposure; time to pregnancy ID POOLED EXPOSURE ASSESSMENT; ASSESSMENTS; ASSOCIATION; POPULATION; BIOMARKERS; SERUM AB For case-control studies that rely on expensive assays for biomarkers, specimen pooling offers a cost-effective and efficient way to estimate individual-level odds ratios. Pooling helps to conserve irreplaceable biospecimens for the future, mitigates limit-of-detection problems, and enables inclusion of individuals who have limited available volumes of biospecimen. Pooling can also allow the study of a panel of biomarkers under a fixed assay budget. Here, we extend this method for application to discrete-time survival studies. Assuming a proportional odds logistic model for risk of a common outcome, we propose a design strategy that forms pooling sets within those experiencing the outcome at the same event time. We show that the proposed design enables a cost-effective analysis to assess the association of a biomarker with the outcome. Because the standard likelihood is slightly misspecified for the proposed pooling strategy under a nonnull biomarker effect, the proposed approach produces slightly biased estimates of exposure odds ratios. We explore the extent of this bias via simulations and illustrate the method by revisiting a data set relating polychlorinated biphenyls and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene to time to pregnancy. C1 [Saha-Chaudhuri, Paramita] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Weinberg, Clarice R.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. RP Saha-Chaudhuri, P (reprint author), Duke Univ, Sch Med, Dept Biostat & Bioinformat, Hock Plaza,2424 Erwin Rd,Suite 1104,Room 11109,Bo, Durham, NC 27710 USA. EM paramita.sahachaudhuri@duke.edu OI Saha Chaudhuri, Paramita/0000-0003-1987-320X FU National Institute of Environmental Health Sciences, National Institutes of Health [ES040006-14] FX This research was supported, in part, by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (project ES040006-14). NR 18 TC 5 Z9 5 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2013 VL 178 IS 1 BP 126 EP 135 DI 10.1093/aje/kws442 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 178LL UT WOS:000321449400012 PM 23821316 ER PT J AU Pavkov, ME Knowler, WC Hanson, RL Williams, DE Lemley, KV Myers, BD Nelson, RG AF Pavkov, Meda E. Knowler, William C. Hanson, Robert L. Williams, Desmond E. Lemley, Kevin V. Myers, Bryan D. Nelson, Robert G. TI Comparison of Serum Cystatin C, Serum Creatinine, Measured GFR, and Estimated GFR to Assess the Risk of Kidney Failure in American Indians With Diabetic Nephropathy SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Glomerular filtration rate; serum cystatin C; end-stage renal disease; type 2 diabetes ID GLOMERULAR-FILTRATION-RATE; BODY-SURFACE AREA; TNF RECEPTORS 1; RENAL-FUNCTION; PREDICT ESRD; PIMA-INDIANS; ALL-CAUSE; DISEASE; MARKERS; METAANALYSIS AB Background: We compared values of baseline serum cystatin C (SCysC), serum creatinine (SCr), and measured glomerular filtration rate (mGFR) for predicting end-stage renal disease (ESRD) in patients with type 2 diabetes and elevated albuminuria. Study Design: Observational longitudinal study. Setting & Participants: Pima Indians with type 2 diabetes and elevated albumin-creatinine ratio (ACR >= 30 mg/g). Predictors: Baseline SCysC, SCr, and mGFR. Outcomes & Measurements: Individuals were followed up from their first examination with diabetes and ACR >= 30 mg/g until December 2010, onset of ESRD, or death, whichever came first. Incidence rates adjusted for age and sex were computed by Mantel-Haenszel stratification. The abilities of SCysC, SCr, and mGFR values to predict ESRD were compared with receiver operating characteristic curves. Results: Of 234 Pima Indians with a mean age of 42.8 years who were followed up for a median of 10.7 (range, 0.6-21.3) years, 68 (29%) developed ESRD. The incidence of ESRD was significantly higher in patients in the lowest versus highest tertile of 1/SCysC (incidence rate ratio, 2.43; 95% CI, 1.31-4.50). By contrast, mGFR and 1/SCr had J-shaped associations with ESRD. In unadjusted analyses, 1/SCysC had the highest area under the receiver operating characteristic curve (AUROC; 0.719 +/- 0.035) and mGFR had the lowest (0.585 +/- 0.042; P < 0.001); the AUROC for 1/SCr was intermediate (0.672 +/- 0.040; P = 0.1 and P = 0.03 vs 1/SCysC and mGFR, respectively). In analyses adjusted for age, sex, diabetes duration, height, weight, hemoglobin A(1c) level, and ACR, 1/SCysC had the highest AUROC (0.845 +/- 0.026). Models with mGFR or 1/SCr alone had similar AUROCs (P = 0.9) and both were lower than the model with 1/SCysC alone (P = 0.02 and P = 0.03, respectively). Limitations: The predictive values of the filtration markers are limited to the extent that their precision is based on a single measurement. Conclusions: SCysC level was a better predictor of ESRD than mGFR or SCr level in Pima Indians with type 2 diabetes and elevated albuminuria. Am J Kidney Dis. 62(1):33-41. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [Pavkov, Meda E.; Williams, Desmond E.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Knowler, William C.; Hanson, Robert L.; Nelson, Robert G.] NIDDK, NIH, Phoenix, AZ USA. [Lemley, Kevin V.] Childrens Hosp Los Angeles, Div Nephrol, Los Angeles, CA 90027 USA. [Myers, Bryan D.] Stanford Univ, Sch Med, Div Nephrol, Stanford, CA 94305 USA. RP Nelson, RG (reprint author), NIH, 1550 East Indian Sch Rd, Phoenix, AZ 85014 USA. EM rnelson@nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU Centers for Disease Control and Prevention (CDC) [09-FED-907651]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [09-FED-907651]; NIDDK FX This work was supported by an Interagency Agreement between the Centers for Disease Control and Prevention (CDC) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; 09-FED-907651) and by the Intramural Research Program of the NIDDK. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC. NR 44 TC 17 Z9 22 U1 0 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2013 VL 62 IS 1 BP 33 EP 41 DI 10.1053/j.ajkd.2012.11.044 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 167RZ UT WOS:000320653000011 PM 23347458 ER PT J AU Scheidweiler, KB Himes, SK Chen, XH Liu, HF Huestis, MA AF Scheidweiler, Karl B. Himes, Sarah K. Chen, Xiaohong Liu, Hua-Fen Huestis, Marilyn A. TI 11-Nor-9-carboxy-Delta 9-tetrahydrocannabinol quantification in human oral fluid by liquid chromatography-tandem mass spectrometry SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Cannabinoids; Carboxy THC; Oral fluid; Metabolites; Analytical method; LCMSMS ID CONTROLLED SMOKED CANNABIS; 11-NOR-DELTA(9)-TETRAHYDROCANNABINOL-9-CARBOXYLIC ACID; HEPATIC MICROSOMES; DELTA(9)-TETRAHYDROCANNABINOL; 11-NOR-9-CARBOXY-DELTA(9)-TETRAHYDROCANNABINOL; DISPOSITION; METABOLITES; EXPOSURE; PLASMA; DRUGS AB Currently, Delta 9-tetrahydrocannabinol (THC) is the analyte quantified for oral fluid cannabinoid monitoring. The potential for false-positive oral fluid cannabinoid results from passive exposure to THC-laden cannabis smoke raises concerns for this promising new monitoring technology. Oral fluid 11-nor-9-carboxy-Delta 9-tetrahydrocannabinol (THCCOOH) is proposed as a marker of cannabis intake since it is not present in cannabis smoke and was not measureable in oral fluid collected from subjects passively exposed to cannabis. THCCOOH concentrations are in the picogram per milliliter range in oral fluid and pose considerable analytical challenges. A liquid chromatography-tandem mass spectrometry (LCMSMS) method was developed and validated for quantifying THCCOOH in 1 mL Quantisal-collected oral fluid. After solid phase extraction, chromatography was performed on a Kinetex C18 column with a gradient of 0.01 % acetic acid in water and 0.01 % acetic acid in methanol with a 0.5-mL/min flow rate. THCCOOH was monitored in negative mode electrospray ionization and multiple reaction monitoring mass spectrometry. The THCCOOH linear range was 12-1,020 pg/mL (R (2) > 0.995). Mean extraction efficiencies and matrix effects evaluated at low and high quality control (QC) concentrations were 40.8-65.1 and -2.4-11.5 %, respectively (n = 10). Analytical recoveries (bias) and total imprecision at low, mid, and high QCs were 85.0-113.3 and 6.6-8.4 % coefficient of variation, respectively (n = 20). This is the first oral fluid THCCOOH LCMSMS triple quadrupole method not requiring derivatization to achieve a < 15 pg/mL limit of quantification. The assay is applicable for the workplace, driving under the influence of drugs, drug treatment, and pain management testing. C1 [Scheidweiler, Karl B.; Himes, Sarah K.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Chen, Xiaohong; Liu, Hua-Fen] ABSciex, Foster City, CA 94404 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, Biomed Res Ctr, 251 Bayview Blvd Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 28 TC 9 Z9 9 U1 3 U2 16 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD JUL PY 2013 VL 405 IS 18 BP 6019 EP 6027 DI 10.1007/s00216-013-7027-6 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 173GH UT WOS:000321065900016 PM 23681203 ER PT J AU Imayama, I Alfano, CM Neuhouser, ML George, SM Smith, AW Baumgartner, RN Baumgartner, KB Bernstein, L Wang, CY Duggan, C Ballard-Barbash, R McTiernan, A AF Imayama, Ikuyo Alfano, Catherine M. Neuhouser, Marian L. George, Stephanie M. Smith, Ashley Wilder Baumgartner, Richard N. Baumgartner, Kathy B. Bernstein, Leslie Wang, Ching-Yun Duggan, Catherine Ballard-Barbash, Rachel McTiernan, Anne TI Weight, inflammation, cancer-related symptoms and health-related quality of life among breast cancer survivors SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer survivors; Body weight; Inflammation; Cancer-related symptoms; Quality of life ID C-REACTIVE PROTEIN; BODY-MASS INDEX; PHYSICAL-ACTIVITY; PSYCHOMETRIC PROPERTIES; BEHAVIORAL SYMPTOMS; ALZHEIMER-DISEASE; MIDLIFE WOMEN; FOLLOW-UP; FATIGUE; DEPRESSION AB Maintaining weight is important for better prognosis of breast cancer survivors. The associations between weight and cancer-related symptoms are not known. We examined associations among weight, weight change, inflammation, cancer-related symptoms, and health-related quality of life (HRQOL) in a cohort of stage 0-IIIA breast cancer survivors. Participants were recruited on average 6 months (2-12 months) after diagnosis. Height, weight, and C-reactive protein (CRP) were assessed at approximately 30 months post-diagnosis; cancer-related symptoms (chest wall and arm symptoms, vasomotor symptoms, urinary incontinence, vaginal symptoms, cognition/mood problems, sleep, sexual interest/function), and HRQOL (SF-36) were assessed at approximately 40 months post-diagnosis. Weight was measured at baseline in a subset. Data on 661 participants were evaluable for body mass index (BMI); 483 were evaluable for weight change. We assessed associations between BMI (< 25.0, 25.0-29.9, a parts per thousand yen30.0 kg/m(2)), post-diagnosis weight change (lost a parts per thousand yen5 %, weight change < 5 %, gained a parts per thousand yen5 %), and CRP (tertile) with cancer-related symptoms and HRQOL using analysis of covariance. Higher symptoms scores indicate more frequent or severe symptoms. Higher HRQOL scores indicate better HRQOL. Compared with those with BMI < 25 kg/m(2), women with BMI a parts per thousand yen30 kg/m(2) had the following scores: increased for arm symptoms (+25.0 %), urinary incontinence (+40.0 %), tendency to nap (+18.9 %), and poorer physical functioning (-15.6 %, all p < 0.05). Obese women had lower scores in trouble falling asleep (-9.9 %; p < 0.05). Compared with weight change < 5 %, participants with a parts per thousand yen5 % weight gain had lower scores in physical functioning (-7.2 %), role-physical (-15.5 %) and vitality (-11.2 %), and those with weight loss a parts per thousand yen5 % had lower chest wall (-33.0 %) and arm symptom scores (-35.5 %, all p < 0.05). Increasing CRP tertile was associated with worse scores for chest wall symptoms, urinary incontinence, physical functioning, role-physical, vitality and physical component summary scores (all P (trend) < 0.05). Future studies should examine whether interventions to maintain a healthy weight and reduce inflammation could alleviate cancer-related symptoms and improve HRQOL. C1 [Imayama, Ikuyo; Neuhouser, Marian L.; Wang, Ching-Yun; Duggan, Catherine; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, NIH, Bethesda, MD 20892 USA. [Neuhouser, Marian L.; McTiernan, Anne] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [George, Stephanie M.; Ballard-Barbash, Rachel] NCI, Appl Res Program, NIH, Bethesda, MD 20892 USA. [Smith, Ashley Wilder] NCI, Outcomes Res Branch, NIH, Bethesda, MD 20892 USA. [Baumgartner, Richard N.; Baumgartner, Kathy B.] Univ Louisville, Dept Epidemiol & Populat Hlth, Sch Publ Hlth & Informat Sci, Louisville, KY 40292 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Div Canc Etiol, Dept Populat Sci, Beckman Res Inst, Duarte, CA USA. [Wang, Ching-Yun] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [McTiernan, Anne] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP McTiernan, A (reprint author), Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. EM amctiern@fhcrc.org RI Duggan, Catherine/F-9414-2015 OI Duggan, Catherine/0000-0001-7369-4021 FU National Cancer Institute [N01-CN-75036-20, N01-CN-05228, N01-PC-67010]; National Institutes of Health [M01-RR-00037]; University of New Mexico [NCRR M01-RR-0997] FX The HEAL study was supported by National Cancer Institute Grants: N01-CN-75036-20, N01-CN-05228, and N01-PC-67010. Portions of this work were conducted through the Clinical Research Laboratory at University of Washington, supported by the National Institutes of Health Grant M01-RR-00037, or through the University of New Mexico Grant NCRR M01-RR-0997. NR 72 TC 14 Z9 15 U1 1 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2013 VL 140 IS 1 BP 159 EP 176 DI 10.1007/s10549-013-2594-y PG 18 WC Oncology SC Oncology GA 180JB UT WOS:000321588900016 PM 23797178 ER PT J AU Faulkner, WB Memarzadeh, F Riskowski, G Hamilton, K Chang, CZ Chang, JR AF Faulkner, W. Brock Memarzadeh, Farhad Riskowski, Gerald Hamilton, Keith Chang, Ching-Zu Chang, Jieh-Ren TI Particulate concentrations within a reduced-scale room operated at various air exchange rates SO BUILDING AND ENVIRONMENT LA English DT Article DE Particulate concentrations; Variable air exchange rate; ACH; Ventilation system; Scaled chamber; No obstructions AB Precise prediction of particulate movement is needed to provide a better understanding of how airborne disease organisms move within ventilated facilities. Bacteria often adhere to larger airborne particulates, which will modify their movement behavior in ventilated rooms and may provide an environment to allow them to remain virulent longer. An empty chamber (206 H x 203 W x 386 cm L) with a circular air inlet and outlet on opposite ends was ventilated with air that had a known particulate density. The inlet and outlet openings were sized to maintain inlet and exit velocities at around 5.1 m/s at 5 different air exchange rates (around 2, 4, 5, 9, and 14 air changes per hour - ACH). Particulate concentrations were measured at the air outlet and at 12 locations within the chamber. In this study, the particulate concentration in the inlet air remained constant, so the amount of particulates injected into the chamber increased as the ACH increased. The measured particulate levels at the outlet also increased essentially linearly with an increase in ACH. However, the particulate concentrations in the occupied zone of the chamber did not increase linearly with an increase in actual ACH. Rather, it increased essentially linearly at the lower ACH levels (from around 2 to 5 ACH), but then leveled out at the higher ACH values. The advantages of increasing ACH in terms of providing better environments in the occupied zone of rooms may have limits, which warrant further investigation. (c) 2013 Elsevier Ltd. All rights reserved. C1 [Faulkner, W. Brock; Riskowski, Gerald; Hamilton, Keith] Texas A&M Univ, Biol & Agr Engn Dept, College Stn, TX 77843 USA. [Memarzadeh, Farhad] NIH, Div Tech Resources, Bethesda, MD 20892 USA. [Chang, Ching-Zu; Chang, Jieh-Ren] Natl Ilan Univ, Dept Food Sci, Ilan, Taiwan. RP Riskowski, G (reprint author), Texas A&M Univ, Biol & Agr Engn Dept, 2117 TAMU, College Stn, TX 77843 USA. EM Riskowski@tamu.edu NR 14 TC 3 Z9 3 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0360-1323 J9 BUILD ENVIRON JI Build. Environ. PD JUL PY 2013 VL 65 BP 71 EP 80 DI 10.1016/j.buildenv.2013.03.023 PG 10 WC Construction & Building Technology; Engineering, Environmental; Engineering, Civil SC Construction & Building Technology; Engineering GA 163PL UT WOS:000320349300007 ER PT J AU Iglesias-Bartolome, R Martin, D Gutkind, JS AF Iglesias-Bartolome, Ramiro Martin, Daniel Gutkind, J. Silvio TI Exploiting the Head and Neck Cancer Oncogenome: Widespread PI3K-mTOR Pathway Alterations and Novel Molecular Targets SO CANCER DISCOVERY LA English DT Editorial Material ID SQUAMOUS-CELL CARCINOMA; RAPAMYCIN AB Two studies published in this issue of Cancer Discovery describe the emerging mutational landscape of head and neck squamous cell carcinomas (HNSCC) and their genomic and epigenetic alterations, thus identifying novel actionable cancer drivers and predictive biomarkers for targeted therapies. Most genomic alterations in HNSCC converge in a handful of molecular pathways, resulting in cell-cycle deregulation, genomic instability, cell differentiation defects, and persistent mitogenic signaling, the latter involving aberrant phosphoinositide 3-kinase (PI3K)/mTOR pathway activation, thereby rendering HNSCC responsive to PI3K/mTOR inhibitors. (C) 2013 AACR. C1 [Iglesias-Bartolome, Ramiro; Martin, Daniel; Gutkind, J. Silvio] NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 320, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Iglesias-Bartolome, Ramiro/H-4460-2014 OI Iglesias-Bartolome, Ramiro/0000-0002-0792-1254 FU Intramural NIH HHS [Z01 DE000551-17, Z01 DE000558-16] NR 12 TC 27 Z9 27 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD JUL PY 2013 VL 3 IS 7 BP 722 EP 725 DI 10.1158/2159-8290.CD-13-0239 PG 4 WC Oncology SC Oncology GA 180SE UT WOS:000321615600018 PM 23847349 ER PT J AU Machiela, MJ Chanock, SJ AF Machiela, Mitchell J. Chanock, Stephen J. TI Scanning for Clues to Better Use Selective Estrogen Receptor Modulators SO CANCER DISCOVERY LA English DT Editorial Material ID AROMATASE INHIBITORS; BREAST-CANCER; ASSOCIATIONS; PREVENTION AB Ingle and colleagues present timely findings identifying genetic variants associated with response to selective estrogen receptor modulator therapy that when substantiated in follow-up may represent an important step toward understanding estrogen-dependent induction of BRCA1 expression and advancing individualized preventive medicine in women at high risk for developing breast cancer. (C) 2013 AACR. C1 [Machiela, Mitchell J.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD 20877 USA. RP Chanock, SJ (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. EM chanocks@mail.nih.gov OI Machiela, Mitchell/0000-0001-6538-9705 FU Intramural NIH HHS [Z99 CA999999] NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD JUL PY 2013 VL 3 IS 7 BP 728 EP 729 DI 10.1158/2159-8290.CD-13-0251 PG 2 WC Oncology SC Oncology GA 180SE UT WOS:000321615600020 PM 23847351 ER PT J AU Shi, JJ Sung, H Zhang, B Lu, W Choi, JY Xiang, YB Kim, MK Iwasaki, M Long, JR Ji, BT Park, SK Zheng, Y Tsugane, S Yoo, KY Wang, WJ Noh, DY Han, W Kim, SW Lee, MH Lee, JW Lee, JY Shen, CY Matsuo, K Ahn, SH Gao, YT Shu, XO Cai, QY Kang, D Zheng, W AF Shi, Jiajun Sung, Hyuna Zhang, Ben Lu, Wei Choi, Ji-Yeob Xiang, Yong-Bing Kim, Mi Kyung Iwasaki, Motoki Long, Jirong Ji, Bu-Tian Park, Sue K. Zheng, Ying Tsugane, Shoichiro Yoo, Keun-Young Wang, Wenjing Noh, Dong-Young Han, Wonshik Kim, Sung-Won Lee, Min Hyuk Lee, Jong Won Lee, Jong-Young Shen, Chen-Yang Matsuo, Keitaro Ahn, Sei-Hyun Gao, Yu-Tang Shu, Xiao Ou Cai, Qiuyin Kang, Daehee Zheng, Wei TI New Breast Cancer Risk Variant Discovered at 10q25 in East Asian Women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CONFER SUSCEPTIBILITY; GENETIC-VARIANTS; COMMON VARIANTS; REPLICATION; POPULATION; ANCESTRY; ALLELES; CHINESE AB Background: Recently, 41 new genetic susceptibility loci for breast cancer risk were identified in a genome-wide association study (GWAS) conducted in European descendants. Most of these risk variants have not been directly replicated in Asian populations. Methods: We evaluated nine of those nonreplication loci in East Asians to identify new risk variants for breast cancer in these regions. First, we analyzed single-nucleotide polymorphisms (SNP) in these regions using data from two GWAS conducted among Chinese and Korean women, including 5,083 cases and 4,376 controls (stage 1). In each region, we selected an SNP showing the strongest association with breast cancer risk for replication in an independent set of 7,294 cases and 9,404 controls of East Asian descents (stage 2). Logistic regression models were used to calculate adjusted ORs and 95% confidence intervals (CI) as a measure of the association of breast cancer risk and genetic variants. Results: Two SNPs were replicated in stage 2 at P < 0.05: rs1419026 at 6q14 [per allele OR, 1.07; 95% confidence interval (CI), 1.03-1.12; P = 3.0 x 10(-4)] and rs941827 at 10q25 (OR, 0.92, 95% CI, 0.89-0.96; P = 5.3 x 10(-5)). The association with rs941827 remained highly statistically significant after adjusting for the risk variant identified initially in women of European ancestry (OR, 0.88; 95% CI, 0.82-0.97; P = 5.3 x 10(-5)). Conclusion: We identified a new breast cancer risk variant at 10q25 in East Asian women. Impact: Results from this study improve the understanding of the genetic basis for breast cancer. (C) 2013 AACR. C1 [Shi, Jiajun; Zhang, Ben; Long, Jirong; Shu, Xiao Ou; Cai, Qiuyin; Zheng, Wei] Vanderbilt Univ, Sch Med,Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA. [Sung, Hyuna; Choi, Ji-Yeob; Park, Sue K.; Kang, Daehee] Seoul Natl Univ, Bundang Hosp, Coll Med, Dept Biomed Sci, Seoul 151, South Korea. [Park, Sue K.; Yoo, Keun-Young; Kang, Daehee] Seoul Natl Univ, Bundang Hosp, Coll Med, Dept Prevent Med, Seoul 151, South Korea. [Noh, Dong-Young; Han, Wonshik; Kim, Sung-Won] Seoul Natl Univ, Bundang Hosp, Coll Med, Dept Surg, Seoul 151, South Korea. [Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Han, Wonshik; Kang, Daehee] Seoul Natl Univ, Bundang Hosp, Coll Med, Ctr Canc Res, Seoul 151, South Korea. [Lee, Min Hyuk] Soonchunhynag Univ Hosp, Dept Surg, Asan, South Korea. [Kim, Mi Kyung; Lee, Jong Won; Ahn, Sei-Hyun] Univ Ulsan, Coll Med, Dept Surg, Seoul, South Korea. [Kim, Mi Kyung; Lee, Jong Won; Ahn, Sei-Hyun] Asan Med Ctr, Seoul, South Korea. [Lu, Wei; Zheng, Ying; Wang, Wenjing] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Kim, Mi Kyung; Ahn, Sei-Hyun] Natl Canc Ctr, Breast Canc Ctr, Canc Epidemiol Div, Goyang Si, Gyeonggi Do, South Korea. [Iwasaki, Motoki; Tsugane, Shoichiro] Natl Canc Ctr, Res Ctr Canc Prevent & Screening, Epidemiol & Prevent Div, Tokyo 104, Japan. [Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lee, Jong-Young] Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea. [Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Shen, Chen-Yang] China Med Univ, Coll Publ Hlth, Taichung, Taiwan. [Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan. RP Zheng, W (reprint author), Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Han, Wonshik/B-3699-2008; Noh, Dong-Young/G-5531-2011; Tsugane, Shocichiro/A-2424-2015; OI Matsuo, Keitaro/0000-0003-1761-6314 FU U.S. NIH [R01CA124558, R01CA148667, R01CA64277, R37CA070867, U19 CA148065, R01CA118229, R01CA092585, R01CA122756, R01 CA137013, R01CA63464, R01CA54281, CA132839]; Vanderbilt University; Vanderbilt-Ingram Cancer Center [P30 CA68485]; U.S. Department of Defense Breast Cancer Research Program [BC011118, BC050791]; National Research Foundation, Ministry of Education, Science and Technology, National Biobank of Korea; National R&D Program of the Republic of Korea [2011-0001564, 1020350, 0620410-1, 2012-0000347, KOBB-2011-03]; Japanese Ministry of Health, Labor and Welfare; Ministry of Education [17015049, 221S0001] FX The work for this project at Vanderbilt was supported primarily by U.S. NIH grants R01CA124558, R01CA148667, R01CA64277, R37CA070867, and U19 CA148065, as well as Ingram Professorship and Research Reward funds from Vanderbilt University. Sample preparation and genotyping assays at Vanderbilt were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource, which are supported in part by Vanderbilt-Ingram Cancer Center (P30 CA68485). Funding for the constituent studies was provided by U.S. NIH grants (R01CA124558, R01CA148667, R01CA64277, R37CA070867, R01CA118229, R01CA092585, R01CA122756, R01 CA137013, R01CA63464, R01CA54281, and CA132839); U.S. Department of Defense Breast Cancer Research Program (BC011118 and BC050791); National Research Foundation, Ministry of Education, Science and Technology, National Biobank of Korea; and National R&D Program of the Republic of Korea (2011-0001564, 1020350, 0620410-1, 2012-0000347, and KOBB-2011-03); and Japanese Ministry of Health, Labor and Welfare and Ministry of Education (17015049 and 221S0001). NR 40 TC 1 Z9 1 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2013 VL 22 IS 7 BP 1297 EP 1303 DI 10.1158/1055-9965.EPI-12-1393 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 176SC UT WOS:000321323600012 PM 23677579 ER PT J AU Luhn, P Dallal, CM Weiss, JM Black, A Huang, WY Lacey, JV Hayes, RB Stanczyk, FZ Wentzensen, N Brinton, LA AF Luhn, Patricia Dallal, Cher M. Weiss, Jocelyn M. Black, Amanda Huang, Wen-Yi Lacey, James V., Jr. Hayes, Richard B. Stanczyk, Frank Z. Wentzensen, Nicolas Brinton, Louise A. TI Circulating Adipokine Levels and Endometrial Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BODY-MASS-INDEX; HORMONE-REPLACEMENT THERAPY; INSULIN-RESISTANCE; LEPTIN LEVELS; POSTMENOPAUSAL WOMEN; ADIPONECTIN LEVELS; SERUM ADIPONECTIN; ADIPOSE-TISSUE; OBESITY; VISFATIN AB Background: Circulating adipokine levels may be associated with endometrial cancer risk, yet few studies have evaluated these markers prospectively. Methods: We conducted a nested case-control study of postmenopausal women in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n = 78,216), including 167 incident endometrial cancer cases and 327 controls that were matched on age, study center, race, study year of diagnosis, year of blood draw, time of day of blood draw, and menopausal hormone therapy (MHT) use. Adipokine and estradiol levels were categorized into tertiles (T). ORs and 95% confidence intervals (CIs) for the associations of adiponectin, leptin, and visfatin with endometrial cancer risk were estimated by conditional logistic regression, adjusting for known endometrial cancer risk factors, including body mass index (BMI) and circulating estradiol levels. Results: Adiponectin levels were inversely associated with risk of endometrial cancer [ORT3vsT1 = 0.48; 95% CI, 0.29-0.80); P-trend < 0.01], whereas elevated leptin levels showed a positive association [2.77 (1.60-4.79); P-trend < 0.01]. These results remained significant after adjustment for estradiol, but not after further adjustment for BMI. When analyses were restricted to non-MHT users, associations of adiponectin and leptin were stronger and remained significant after adjustment for estradiol and BMI [0.25 (0.08-0.75); P-trend = 0.01 and 4.72 (1.15-19.38); P-trend = 0.02, respectively]. Nonsignificant positive associations were observed for visfatin. Conclusion: Adipokines may influence endometrial cancer risk through pathways other than estrogen-mediated cell growth in postmenopausal women not currently on MHT. Impact: Understanding how adipokines influence endometrial cancer risk may help to elucidate biological mechanisms important for the observed obesity-endometrial cancer association. (C) 2013 AACR. C1 [Luhn, Patricia; Dallal, Cher M.; Black, Amanda; Huang, Wen-Yi; Wentzensen, Nicolas; Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Luhn, Patricia; Dallal, Cher M.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Rockville, MD 20892 USA. [Weiss, Jocelyn M.] Mt Sinai Adolescent Hlth Ctr, New York, NY USA. [Hayes, Richard B.] NYU, Langone Med Ctr, Dept Populat Hlth, New York, NY USA. [Lacey, James V., Jr.] Beckman Res Inst City Hope, Duarte, CA USA. [Stanczyk, Frank Z.] Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. RP Luhn, P (reprint author), NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, 6120 Execut Blvd,Suite 550, Rockville, MD 20892 USA. EM luhnpa@mail.nih.gov RI Brinton, Louise/G-7486-2015; OI Brinton, Louise/0000-0003-3853-8562; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS FX This work was supported by the Intramural Research Program of the National Cancer Institute.; This research was supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. The authors thank Drs. C. Berg and P. Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators, and staff of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mr. T. Riley and staff, Information Management Services, Inc., Ms. B. O'Brien and staff, Westat, Inc. Most importantly, the authors thank the study participants for their contributions to making this study possible. The authors also thank Dr. B. Trabert for her participation in scientific discussions. NR 37 TC 25 Z9 26 U1 1 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2013 VL 22 IS 7 BP 1304 EP 1312 DI 10.1158/1055-9965.EPI-13-0258 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 176SC UT WOS:000321323600013 PM 23696194 ER PT J AU Chen, Q Zheng, TZ Lan, Q Lerro, C Zhao, N Qin, Q Hu, XB Huang, H Liang, JX Holford, T Leaderer, B Boyle, P Chanock, SJ Rothman, N Zhang, YW AF Chen, Qiong Zheng, Tongzhang Lan, Qing Lerro, Catherine Zhao, Nan Qin, Qin Hu, Xiaobin Huang, Huang Liang, Jiaxin Holford, Theodore Leaderer, Brian Boyle, Peter Chanock, Stephen J. Rothman, Nathaniel Zhang, Yawei TI Single-Nucleotide Polymorphisms in Genes Encoding for CC Chemokines were Not Associated with the Risk of Non-Hodgkin Lymphoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article AB Background: Chemokines play a pivotal role in immune regulation and response, and previous studies suggest an association between immune deficiency and non-Hodgkin lymphoma (NHL). Methods: We evaluated the association between NHL and polymorphisms in 18 genes (CCL1, CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL18, CCL20, CCL24, CCL26, CCR1, CCR3, CCR4, CCR6, CCR7, CCR8, and CCR9) encoding for the CC chemokines using data from a population-based case-control study of NHL conducted in Connecticut women. Results: CCR8 was associated with diffuse large B-cell lymphoma (DLBCL; P = 0.012), and CCL13 was associated with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL; P = 0.003) at gene level. After adjustment for multiple comparisons, none of the genes or single-nucleotide polymorphisms (SNP) were associated with risk of overall NHL or NHL subtypes. Conclusions: Our results suggest that the genes encoding for CC chemokines are not significantly associated with the risk of NHL, and further studies are needed to verify these findings. Impact: Our data indicate that CC chemokine genes were not associated with NHL risk. (C) 2013 AACR. C1 [Chen, Qiong] Zhengzhou Univ, Affiliated Canc Hosp, Off Canc Control & Prevent, Henan Prov Canc Hosp, Zhengzhou 450052, Peoples R China. [Chen, Qiong; Zheng, Tongzhang; Lerro, Catherine; Zhao, Nan; Hu, Xiaobin; Huang, Huang; Liang, Jiaxin; Holford, Theodore; Leaderer, Brian; Zhang, Yawei] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Lan, Qing; Chanock, Stephen J.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD USA. [Qin, Qin] Univ So Maine, Wise Lab Environm & Genet Toxicol, Portland, ME 04103 USA. [Hu, Xiaobin] Lanzhou Univ, Sch Publ Hlth, Lanzhou 730000, Peoples R China. [Boyle, Peter] Int Prevent Res Inst, Lyon, France. [Chanock, Stephen J.] NCI, Core Genotyping Facil, Adv Technol Ctr, NIH,DHHS, Gaithersburg, MD USA. RP Zhang, YW (reprint author), Yale Univ, Sch Publ Hlth, Dept Environm Hlth Sci, 60 Coll St,LEPH 440, New Haven, CT 06520 USA. EM yawei.zhang@yale.edu RI Boyle, Peter/A-4380-2014 OI Boyle, Peter/0000-0001-6251-0610 FU NIH [CA62006, CA165923, 1D43TW008323, 1D43TW007864, HD70324]; Intramural Research Program of the National Cancer Institute FX This work was supported by the NIH grants CA62006, CA165923, 1D43TW008323, 1D43TW007864, and HD70324, and the Intramural Research Program of the National Cancer Institute. NR 11 TC 2 Z9 2 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2013 VL 22 IS 7 BP 1332 EP 1335 DI 10.1158/1055-9965.EPI-13-0328 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 176SC UT WOS:000321323600017 PM 23640258 ER PT J AU Jansen, RJ Robinson, DP Frank, RD Stolzenberg-Solomon, RZ Bamlet, WR Oberg, AL Rabe, KG Olson, JE Petersen, GM Sinha, R Anderson, KE AF Jansen, Rick J. Robinson, Dennis P. Frank, Ryan D. Stolzenberg-Solomon, Rachael Z. Bamlet, William R. Oberg, Ann L. Rabe, Kari G. Olson, Janet E. Petersen, Gloria M. Sinha, Rashmi Anderson, Kristin E. TI Meat-Related Mutagens and Pancreatic Cancer: Null Results from a Clinic-Based Case-Control Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ASSOCIATIONS; RISK; COHORT AB Background: Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case-control design. Methods: There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institute's CHARRED database (Bethesda, MD). Logistic regression was used to calculate ORs and 95% confidence intervals (CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus. Results: Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer. Conclusions: The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies. Impact: These data contribute to evidence about pancreatic cancer and potentially carcinogenic compounds in meat. (C) 2013 AACR. C1 [Jansen, Rick J.; Olson, Janet E.; Petersen, Gloria M.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN 55905 USA. [Robinson, Dennis P.; Frank, Ryan D.; Bamlet, William R.; Oberg, Ann L.; Rabe, Kari G.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Anderson, Kristin E.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Stolzenberg-Solomon, Rachael Z.] NIH, Dept Epidemiol, Bethesda, MD 20892 USA. [Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Jansen, RJ (reprint author), Mayo Clin, 200 1st St SW, Rochester, MN 55905 USA. EM jansen.rick@mayo.edu RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU Mayo Clinic SPORE in Pancreatic Cancer [P50 CA102701]; [R25TCA92049] FX This work was supported by partial funding by R25TCA92049 and Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701). NR 12 TC 4 Z9 5 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2013 VL 22 IS 7 BP 1336 EP 1339 DI 10.1158/1055-9965.EPI-13-0343 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 176SC UT WOS:000321323600018 PM 23632817 ER PT J AU Akagi, I Okayama, H Schetter, AJ Robles, AI Kohno, T Bowman, ED Kazandjian, D Welsh, JA Oue, N Saito, M Miyashita, M Uchida, E Takizawa, T Takenoshita, S Skaug, V Mollerup, S Haugen, A Yokota, J Harris, CC AF Akagi, Ichiro Okayama, Hirokazu Schetter, Aaron J. Robles, Ana I. Kohno, Takashi Bowman, Elise D. Kazandjian, Dickran Welsh, Judith A. Oue, Naohide Saito, Motonobu Miyashita, Masao Uchida, Eiji Takizawa, Toshihiro Takenoshita, Seiichi Skaug, Vidar Mollerup, Steen Haugen, Aage Yokota, Jun Harris, Curtis C. TI Combination of Protein Coding and Noncoding Gene Expression as a Robust Prognostic Classifier in Stage I Lung Adenocarcinoma SO CANCER RESEARCH LA English DT Article ID INDUCIBLE FACTOR 1-ALPHA; VINORELBINE PLUS CISPLATIN; B-CELL LYMPHOMA; TUMOR-SUPPRESSOR; NUCLEAR-EXPORT; CANCER GENE; SURVIVAL PREDICTION; SOLID TUMORS; DNA-DAMAGE; BRCA1 AB Prognostic tests for patients with early-stage lung cancer may provide needed guidance on postoperative surveillance and therapeutic decisions. We used a novel strategy to develop and validate a prognostic classifier for early-stage lung cancer. Specifically, we focused on 42 genes with roles in lung cancer or cancer prognosis. Expression of these biologically relevant genes and their association with relapse-free survival (RFS) were evaluated using microarray data from 148 patients with stage I lung adenocarcinoma. Seven genes associated with RFS were further examined by quantitative reverse transcription PCR in 291 lung adenocarcinoma tissues from Japan, the United States, and Norway. Only BRCA1, HIF1A, DLC1, and XPO1 were each significantly associated with prognosis in the Japan and US/Norway cohorts. A Cox regression-based classifier was developed using these four genes on the Japan cohort and validated in stage I lung adenocarcinoma from the US/Norway cohort and three publicly available lung adenocarcinoma expression profiling datasets. The results suggest that the classifier is robust across ethnically and geographically diverse populations regardless of the technology used to measure gene expression. We evaluated the combination of the four-gene classifier with miRNA miR-21 (MIR21) expression and found that the combination improved associations with prognosis, which were significant in stratified analyses on stage IA and stage IB patients. Thus, the four coding gene classifier, alone or with miR-21 expression, may provide a clinically useful tool to identify high-risk patients and guide recommendations regarding adjuvant therapy and postoperative surveillance of patients with stage I lung adenocarcinoma. (C) 2013 AACR. C1 [Akagi, Ichiro; Okayama, Hirokazu; Schetter, Aaron J.; Robles, Ana I.; Bowman, Elise D.; Kazandjian, Dickran; Welsh, Judith A.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Akagi, Ichiro; Miyashita, Masao; Uchida, Eiji] Nippon Med Sch, Grad Sch Med, Div Surg Organ Funct & Biol Regulat, Tokyo 113, Japan. [Takizawa, Toshihiro] Nippon Med Sch, Grad Sch Med, Div Mol Med & Anat, Tokyo 113, Japan. [Kohno, Takashi] Natl Canc Ctr, Res Inst, Div Genome Biol, Tokyo 104, Japan. [Yokota, Jun] Natl Canc Ctr, Res Inst, Div Multistep Carcinogenesis, Tokyo 104, Japan. [Okayama, Hirokazu; Saito, Motonobu; Takenoshita, Seiichi] Fukushima Med Univ, Sch Med, Dept Organ Regulatory Surg, Fukushima, Japan. [Oue, Naohide] Hiroshima Univ, Grad Sch Biomed Sci, Dept Mol Pathol, Hiroshima, Japan. [Skaug, Vidar; Mollerup, Steen; Haugen, Aage] Natl Inst Occupat Hlth, Dept Chem & Biol Working Environm, Sect Toxicol, Oslo, Norway. RP Harris, CC (reprint author), NCI, 37 Convent Dr,MSC 4258,Bldg 37,Room 3068A, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov RI Mendez, Pedro /J-8955-2016 OI Mendez, Pedro /0000-0001-6713-7907 FU National Cancer Institute, NIH, Department of Defense Congressionally Directed Medical Research Program [PR093793]; Norwegian Cancer Society; Ministry of Health, Labor and Welfare for the Third-term Comprehensive 10-year Strategy for Cancer Control, Japan; Ministry of Education, Culture, Sports, Science and Technology of Japan for Scientific Research on Innovative Areas [22131006] FX This research was supported by the Intramural Research Program of the National Cancer Institute, NIH, Department of Defense Congressionally Directed Medical Research Program Grant PR093793, the Norwegian Cancer Society, a Grant-in-Aid from the Ministry of Health, Labor and Welfare for the Third-term Comprehensive 10-year Strategy for Cancer Control, Japan, and a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan for Scientific Research on Innovative Areas (22131006). NR 54 TC 21 Z9 21 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2013 VL 73 IS 13 BP 3821 EP 3832 DI 10.1158/0008-5472.CAN-13-0031 PG 12 WC Oncology SC Oncology GA 173WM UT WOS:000321112700003 PM 23639940 ER PT J AU Bae, K Park, B Sun, HL Wang, JH Tao, C Chapman, AB Torres, VE Grantham, JJ Mrug, M Bennett, WM Flessner, MF Landsittel, DP Bae, KT AF Bae, Kyungsoo Park, Bumwoo Sun, Hongliang Wang, Jinhong Tao, Cheng Chapman, Arlene B. Torres, Vicente E. Grantham, Jared J. Mrug, Michal Bennett, William M. Flessner, Michael F. Landsittel, Doug P. Bae, Kyongtae T. CA Consortium Radiologic Imaging Stud TI Segmentation of Individual Renal Cysts from MR Images in Patients with Autosomal Dominant Polycystic Kidney Disease SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CONSORTIUM; COHORT; VOLUME; ADPKD AB Objective To evaluate the performance of a semi-automated method for the segmentation of individual renal cysts from magnetic resonance (MR) images in patients with autosomal dominant polycystic kidney disease (ADPKD). Design, setting, participants, & measurements This semi-automated method was based on a morphologic watershed technique with shape-detection level set for segmentation of renal cysts from MR images. T2-weighted MR image sets of 40 kidneys were selected from 20 patients with mild to moderate renal cyst burden (kidney volume < 1500 ml) in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP). The performance of the semi-automated method was assessed in terms of two reference metrics in each kidney: the total number of cysts measured by manual counting and the total volume of cysts measured with a region-based thresholding method. The proposed and reference measurements were compared using intraclass correlation coefficient (ICC) and Bland-Altman analysis. Results Individual renal cysts were successfully segmented with the semi-automated method in all 20 cases. The total number of cysts in each kidney measured with the two methods correlated well (ICC, 0.99), with a very small relative bias (0.3% increase with the semi-automated method; limits of agreement, 15.2% reduction to 17.2% increase). The total volume of cysts measured using both methods also correlated well (ICC, 1.00), with a small relative bias of <10%(9.0% decrease in the semi-automated method; limits of agreement, 17.1% increase to 43.3% decrease). Conclusion This semi-automated method to segment individual renal cysts in ADPKD kidneys provides a quantitative indicator of severity in early and moderate stages of the disease. C1 [Bae, Kyungsoo; Park, Bumwoo; Sun, Hongliang; Wang, Jinhong; Tao, Cheng; Bae, Kyongtae T.] Univ Pittsburgh, Sch Med, Dept Radiol, Pittsburgh, PA 15213 USA. [Landsittel, Doug P.] Univ Pittsburgh, Sch Med, Dept Internal Med, Pittsburgh, PA 15213 USA. [Chapman, Arlene B.] Emory Univ, Sch Med, Dept Internal Med, Atlanta, GA USA. [Torres, Vicente E.] Mayo Coll Med, Dept Internal Med, Rochester, MN USA. [Grantham, Jared J.] Univ Kansas, Med Ctr, Dept Internal Med, Kansas City, KS 66103 USA. [Mrug, Michal] Univ Alabama Birmingham, Div Nephrol, Birmingham, AL USA. [Bennett, William M.] Legacy Good Samaritan Hosp, Portland, OR USA. [Flessner, Michael F.] NIDDK, NIH, Bethesda, MD USA. RP Bae, KT (reprint author), Univ Pittsburgh, Sch Med, Dept Radiol, Presbyterian South Tower,Room 3950,200 Lothrop St, Pittsburgh, PA 15213 USA. EM baek@upmc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [DK056943, DK056956, DK056957, DK056961]; National Center for Research Resources General Clinical Research Centers [RR000039, RR00585, RR23940, RR000032]; National Center for Research Resources Clinical and Translational Science Awards [RR025008, RR024150, RR033179, RR025777, UL1TR000165, RR024153, UL1TR000005]; Otsuka Corp. FX CRISP is supported by cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (DK056943, DK056956, DK056957, DK056961), the National Center for Research Resources General Clinical Research Centers at each institution (RR000039, Emory University; RR00585, Mayo College of Medicine; RR23940, Kansas University Medical Center; RR000032, University of Alabama at Birmingham), and the National Center for Research Resources Clinical and Translational Science Awards at each institution (RR025008, Emory; RR024150, Mayo College of Medicine; RR033179, Kansas University Medical Center; RR025777 and UL1TR000165, University of Alabama at Birmingham; RR024153 and UL1TR000005, University of Pittsburgh School of Medicine).; A.B.C. and J.J.G. are consultants to Otsuka Corp, and V.E.T. received research support from Otsuka Corp. M.M. is a consultant to Otsuka Corp and Alexion Pharmaceuticals. NR 19 TC 11 Z9 11 U1 0 U2 6 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JUL PY 2013 VL 8 IS 7 BP 1089 EP 1097 DI 10.2215/CJN.10561012 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 178DA UT WOS:000321423100007 PM 23520042 ER PT J AU Thomas, A Xi, LQ Carter, CA Rajan, A Khozin, S Szabo, E Dennis, PA Giaccone, G Raffeld, M AF Thomas, Anish Xi, Liqiang Carter, Corey A. Rajan, Arun Khozin, Sean Szabo, Eva Dennis, Phillip A. Giaccone, Giuseppe Raffeld, Mark TI Concurrent Molecular Alterations in Tumors With Germ Line Epidermal Growth Factor Receptor T790M Mutations SO CLINICAL LUNG CANCER LA English DT Article DE Concurrent mutations; Familial lung cancer; Germline EGFR mutations; KRAS mutation; Lung cancer prevention ID CELL LUNG-CANCER; EGFR; RESISTANCE; SUSCEPTIBILITY; MUTANTS C1 [Thomas, Anish; Rajan, Arun; Khozin, Sean; Dennis, Phillip A.; Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Xi, Liqiang; Raffeld, Mark] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Carter, Corey A.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Szabo, Eva] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Raffeld, M (reprint author), NCI, Bldg 10,Room 2N110,10 Ctr Dr, Bethesda, MD 20892 USA. EM mraff@box-m.nih.gov RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Thomas, Anish/0000-0003-3293-3115 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). NR 15 TC 3 Z9 3 U1 0 U2 4 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1525-7304 J9 CLIN LUNG CANCER JI Clin. Lung Cancer PD JUL PY 2013 VL 14 IS 4 BP 452 EP 456 DI 10.1016/j.cllc.2013.01.005 PG 5 WC Oncology SC Oncology GA 165QV UT WOS:000320499300019 PM 23540867 ER PT J AU Morris, CP Evans, H Larsen, SE Mitre, E AF Morris, C. Paul Evans, Holly Larsen, Sasha E. Mitre, Edward TI A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis SO CLINICAL MICROBIOLOGY REVIEWS LA English DT Review ID JIRDS MERIONES-UNGUICULATUS; BRUGIA-MALAYI INFECTION; MUSTELA-PUTORIUS-FURO; ONCHOCERCA-LIENALIS-MICROFILARIAE; DIROFILARIA-IMMITIS INFECTION; 3RD STAGE LARVAE; CHEMICALLY-ABBREVIATED INFECTIONS; NEMATODE LITOMOSOIDES SIGMODONTIS; DIPETALONEMA-VITEAE INFECTION; MANDRILLS MANDRILLUS-SPHINX AB Filarial worms cause highly morbid diseases such as elephantiasis and river blindness. Since the 1940s, researchers have conducted vaccine trials in 27 different animal models of filariasis. Although no vaccine trial in a permissive model of filariasis has provided sterilizing immunity, great strides have been made toward developing vaccines that could block transmission, decrease pathological sequelae, or decrease susceptibility to infection. In this review, we have organized, to the best of our ability, all published filaria vaccine trials and reviewed them in the context of the animal models used. Additionally, we provide information on the life cycle, disease phenotype, concomitant immunity, and natural immunity during primary and secondary infections for 24 different filaria models. C1 [Morris, C. Paul; Evans, Holly; Larsen, Sasha E.; Mitre, Edward] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Morris, C. Paul] NIAID, NIH, Bethesda, MD 20892 USA. RP Mitre, E (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. EM edward.mitre@usuhs.edu OI Morris, Christopher/0000-0002-5989-3638 NR 280 TC 13 Z9 13 U1 1 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0893-8512 J9 CLIN MICROBIOL REV JI Clin. Microbiol. Rev. PD JUL PY 2013 VL 26 IS 3 BP 381 EP 421 DI 10.1128/CMR.00002-13 PG 41 WC Microbiology SC Microbiology GA 175SF UT WOS:000321252100002 PM 23824365 ER PT J AU Ward, MM AF Ward, Michael M. TI Parental Educational Attainment and Sense of Control in Mid- and Late-Adulthood SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article DE sense of control; mastery; parental education; childhood socioeconomic position ID PERCEIVED CONTROL; CUMULATIVE ADVANTAGE; CHILDRENS EDUCATION; ECONOMIC HARDSHIP; PERSONAL CONTROL; SOCIAL-CLASS; SELF-ESTEEM; HEALTH; LIFE; MASTERY AB Sense of control is greater among children who grow up in households of higher socioeconomic status. It is unclear if this childhood advantage persists throughout life or if schooling and adulthood experiences override any early childhood advantage. Using data from 2 nationally representative samples of primarily middle-aged (National Survey of Midlife Development in the United States, or MIDUS), and older adults (Health and Retirement Study, or FIRS), I tested if personal mastery and perceived constraints in adulthood were associated with the educational attainment of the participant's father or mother, adjusting for participant's education level, income, and other demographic characteristics. In both samples, personal mastery was not associated with either parent's education level, but perceived constraints had a graded inverse association with mother's education level. These results indicate that childhood experiences continue to be associated with perceived constraints, even in later life, and may not be completely overridden by adult experiences. C1 [Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, Intramural Res Program, NIH, Bldg 10 CRC,Room 4-1339, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS [ZIA AR041153-07]; NIA NIH HHS [P01 AG020166] NR 29 TC 2 Z9 2 U1 0 U2 12 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD JUL PY 2013 VL 49 IS 7 BP 1407 EP 1412 DI 10.1037/a0029557 PG 6 WC Psychology, Developmental SC Psychology GA 172TH UT WOS:000321027300019 PM 22889396 ER PT J AU Knowler, WC Ackermann, RT AF Knowler, William C. Ackermann, Ronald T. TI Preventing Diabetes in American Indian Communities SO DIABETES CARE LA English DT Editorial Material ID IMPAIRED GLUCOSE-TOLERANCE; LIFE-STYLE INTERVENTION; RANDOMIZED-CONTROLLED-TRIAL; WEIGHT-LOSS; FASTING GLUCOSE; PROGRAM; MELLITUS; REDUCTION; METFORMIN; OUTCOMES C1 [Knowler, William C.] NIDDK, NIH, Phoenix, AZ USA. [Ackermann, Ronald T.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Knowler, WC (reprint author), NIDDK, NIH, Phoenix, AZ USA. EM knowler@nih.gov FU Intramural NIH HHS; NCATS NIH HHS [UL1 TR000150, UL1TR000150]; NCCDPHP CDC HHS [U58DP002718, U58 DP002718]; NIDDK NIH HHS [R18DK079855, R18 DK079855] NR 21 TC 2 Z9 2 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2013 VL 36 IS 7 BP 1820 EP 1822 DI 10.2337/dc12-2635 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 178UK UT WOS:000321472700006 PM 23801794 ER PT J AU Bao, W Bowers, K Tobias, DK Hu, FB Zhang, CL AF Bao, Wei Bowers, Katherine Tobias, Deirdre K. Hu, Frank B. Zhang, Cuilin TI Prepregnancy Dietary Protein Intake, Major Dietary Protein Sources, and the Risk of Gestational Diabetes Mellitus A prospective cohort study SO DIABETES CARE LA English DT Article ID CORONARY-HEART-DISEASE; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; MEAT CONSUMPTION; LIFE-STYLE; FAT INTAKE; WOMEN; QUESTIONNAIRE; PREGNANCY; MEN AB OBJECTIVE-Dietary protein is an important modulator of glucose metabolism. However, studies regarding the association between dietary protein intake and gestational diabetes mellitus (GDM) risk are sparse. This study was to examine the association. RESEARCH DESIGN AND METHODS-Our study included 21,457 singleton pregnancies reported among 15,294 participants of the Nurses' Health Study II cohort between 1991 and 2001. Included pregnancies were free of chronic diseases before pregnancy or previous GDM. Generalized estimating equations were used to estimate the relative risks (RRs) and 95% CIs. RESULTS-After adjustment for age, parity, nondietary and dietary factors, and BMI, multivariable RRs (95% CIs) comparing the highest with lowest quintiles were 1.49 (1.03-2.17) for animal protein intake and 0.69 (0.50-0.97) for vegetable protein intake. The substitution of 5% energy from vegetable protein for animal protein was associated with a 51% lower risk of GDM (RR [95% CI], 0.49 [0.29-0.84]). For major dietary protein sources, multivariable RRs (95% CIs) comparing the highest with the lowest quintiles were 2.05 (1.55-2.73) for total red meat and 0.73 (0.56-0.95) for nuts, respectively. The substitution of red meat with poultry, fish, nuts, or legumes showed a significantly lower risk of GDM. CONCLUSIONS-Higher intake of animal protein, in particular red meat, was significantly associated with a greater risk of GDM. By contrast, higher intake of vegetable protein, specifically nuts, was associated with a significantly lower risk. Substitution of vegetable protein for animal protein, as well as substitution of some healthy protein sources for red meat, was associated with a lower risk of GDM. C1 [Bao, Wei; Bowers, Katherine; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Tobias, Deirdre K.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Tobias, Deirdre K.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. EM zhangcu@mail.nih.gov RI Bowers, Katherine/N-5226-2015; OI Bao, Wei/0000-0002-7301-5786 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN275201000020C]; National Institutes of Health [DK58845, CA50385, P30 DK46200] FX This study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract no. HHSN275201000020C). The Nurses' Health Study II was funded by research grants DK58845, CA50385, and P30 DK46200 from the National Institutes of Health. NR 41 TC 18 Z9 20 U1 2 U2 12 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2013 VL 36 IS 7 BP 2001 EP 2008 DI 10.2337/dc12-2018 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 178UK UT WOS:000321472700033 PM 23378620 ER PT J AU Ferrarelli, LK Popuri, V Ghosh, AK Tadokoro, T Canugovi, C Hsu, JK Croteau, DL Bohr, VA AF Ferrarelli, Leslie K. Popuri, Venkateswarlu Ghosh, Avik K. Tadokoro, Takashi Canugovi, Chandrika Hsu, Joseph K. Croteau, Deborah L. Bohr, Vilhelm A. TI The RECQL4 protein, deficient in Rothmund-Thomson syndrome is active on telomeric D-loops containing DNA metabolism blocking lesions SO DNA REPAIR LA English DT Article DE RECQL4; WRN; Thymine glycol; Telomeres ID BASE EXCISION-REPAIR; THYMINE GLYCOL LESIONS; WERNER-SYNDROME HELICASE; RNA-POLYMERASE-II; OXIDATIVE DAMAGE; LIFE-SPAN; EXONUCLEASE ACTIVITY; SHORTENS TELOMERES; NUCLEAR EXTRACTS; WRN PROTEIN AB Telomeres are critical for cell survival and functional integrity. Oxidative DNA damage induces telomeric instability and cellular senescence that are associated with normal aging and segmental premature aging disorders such as Werner Syndrome and Rothmund-Thomson Syndrome, caused by mutations in WRN and RECQL4 helicases respectively. Characterizing the metabolic roles of RECQL4 and WRN in telomere maintenance is crucial in understanding the pathogenesis of their associated disorders. We have previously shown that WRN and RECQL4 display a preference in vitro to unwind telomeric DNA substrates containing the oxidative lesion 8-oxoguanine. Here, we show that RECQL4 helicase has a preferential activity in vitro on telomeric substrates containing thymine glycol, a critical lesion that blocks DNA metabolism, and can be modestly stimulated further on a D-loop structure by TRF2, a telomeric shelterin protein. Unlike that reported for telomeric D-loops containing 8-oxoguanine, RECQL4 does not cooperate with WRN to unwind telomeric D-loops with thymine glycol, suggesting RECQL4 helicase is selective for the type of oxidative lesion. RECQL4's function at the telomere is not yet understood, and our findings suggest a novel role for RECQL4 in the repair of thymine glycol lesions to promote efficient telomeric maintenance. Published by Elsevier B.V. C1 [Ferrarelli, Leslie K.; Popuri, Venkateswarlu; Ghosh, Avik K.; Tadokoro, Takashi; Canugovi, Chandrika; Hsu, Joseph K.; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM lesliekhoh@yahoo.com; popuriv@mail.nih.gov; ghoshak24@gmail.com; takashi.tadokoro@mail.nih.gov; canugovic@mail.nih.gov; joseph.hsu@nih.gov; croteau@mail.nih.gov; bohrv@grc.nia.nih.gov RI Hsu, Joseph Kuang-Wu/N-2847-2013 FU Intramural Research Program of the NIH, National Institute on Aging FX We thank Huiming Lu and Christopher Dunn, NIA, for critically reading the manuscript. We also thank Marie Rossi and Lale Dawut, NIA, for biochemical methods instruction and technical help, Christopher Dunn and Tomasz Kulikowicz, NIA, for purification of the RecQ helicase proteins, and Patricia Opresko, University of Pittsburgh, for purified shelterin proteins. This work was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 67 TC 9 Z9 9 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD JUL PY 2013 VL 12 IS 7 BP 518 EP 528 DI 10.1016/j.dnarep.2013.04.005 PG 11 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 178AU UT WOS:000321417300008 PM 23683351 ER PT J AU George, DB Webb, CT Pepin, KM Savage, LT Antolin, MF AF George, Dylan B. Webb, Colleen T. Pepin, Kim M. Savage, Lisa T. Antolin, Michael F. TI Persistence of black-tailed prairie-dog populations affected by plague in northern Colorado, USA SO ECOLOGY LA English DT Article DE Cynomys ludovicianus; disease ecology; metapopulation; plague; prairie dog; stochastic patch occupancy model; Yersinia pestis ID PATCH OCCUPANCY MODELS; METAPOPULATION DYNAMICS; CYNOMYS-LUDOVICIANUS; YERSINIA-PESTIS; SYLVATIC PLAGUE; GENETIC-STRUCTURE; OROPSYLLA-HIRSUTA; DISEASE; LANDSCAPE; CLIMATE AB The spatial distribution of prairie dog (Cynomys ludovicianus) colonies in North America has changed from large, contiguous populations to small, isolated colonies in metapopulations. One factor responsible for this drastic change in prairie-dog population structure is plague (caused by the bacterium Yersinia pestis). We fit stochastic patch occupancy models to 20 years of prairie-dog colony occupancy data from two discrete metapopulations (west and east) in the Pawnee National Grassland in Colorado, USA, that differ in connectivity among suitable habitat patches. We conducted model selection between two hypothesized modes of plague movement: independent of prairie-dog dispersal (colony-area) vs. plague movement consistent with prairie-dog dispersal (connectivity to extinct colonies). The best model, which fit the data well (area under the curve [AUC]: 0.94 west area; 0.79 east area), revealed that over time the proportion of extant colonies was better explained by colony size than by connectivity to extinct (plagued) colonies. The idea that prairie dogs are not likely to be the main vector that spreads Y. pestis across the landscape is supported by the observation that colony extinctions are primarily caused by plague, prairie-dog dispersal is short range, and connectivity to extinct colonies was not selected as a factor in the models. We also conducted simulations with the best model to examine long-term patterns of colony occupancy and persistence of prairie-dog metapopulations. In the case where the metapopulations persist, our model predicted that the western metapopulation would have a colony occupancy rate approximately 2.5 times higher than that of the eastern metapopulation (approximate to 50% occupied colonies vs. 20%) in 50 years, but that the western metapopulation has approximate to 80% chance of extinction in 100 years while the eastern metapopulation has a less than 25% chance. Extinction probability of individual colonies depended on the frequency with which colonies of the same size class occurred in the metapopulation. Thus, the long-term persistence of prairie-dog metapopulations depended on specific details of the metapopulation. C1 [George, Dylan B.; Webb, Colleen T.; Pepin, Kim M.; Savage, Lisa T.; Antolin, Michael F.] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [George, Dylan B.; Pepin, Kim M.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Webb, CT (reprint author), Colorado State Univ, Dept Biol, Campus Delivery 1878, Ft Collins, CO 80523 USA. EM ctwebb@lamar.colostate.edu FU NSF Ecology of Infectious Disease Grant [EF-0327052]; NSF Short Grass Steppe Long Term Ecological Research Grant [DEB-0217631, 0823405]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NSF-IGERT fellowship [DGE-0221595]; Department of Defense, Science, Mathematics And Research for Transformation (SMART) fellowship FX We thank Dan Tripp and Dan Salkeld for insightful comments and criticisms. We acknowledge funding from the following sources: NSF Ecology of Infectious Disease Grant (EF-0327052); NSF Short Grass Steppe Long Term Ecological Research Grant (DEB-0217631, 0823405); and the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. D. B. George received additional support from a NSF-IGERT fellowship (DGE-0221595) and Department of Defense, Science, Mathematics And Research for Transformation (SMART) fellowship. NR 58 TC 11 Z9 11 U1 8 U2 86 PU ECOLOGICAL SOC AMER PI WASHINGTON PA 1990 M STREET NW, STE 700, WASHINGTON, DC 20036 USA SN 0012-9658 J9 ECOLOGY JI Ecology PD JUL PY 2013 VL 94 IS 7 BP 1572 EP 1583 DI 10.1890/12-0719.1 PG 12 WC Ecology SC Environmental Sciences & Ecology GA 180SY UT WOS:000321618400015 PM 23951717 ER PT J AU Warburton, D Gilliland, F Dashdendev, B AF Warburton, David Gilliland, Frank Dashdendev, Baigalmaa TI Environmental pollution in Mongolia: Effects across the lifespan SO ENVIRONMENTAL RESEARCH LA English DT Editorial Material ID EXHALED NITRIC-OXIDE; AMBIENT AIR-POLLUTION; CHILDRENS HEALTH; ASTHMA; SUSCEPTIBILITY; EXPOSURE; COHORT; ONSET; HOME C1 [Warburton, David] Univ So Calif, Keck Sch Med,Childrens Hosp Los Angeles, Fogarty NIEHS Lifespan Environm Pollut Global Imp, Dev Biol Regenerat Med & Stem Cell Program,Saban, Los Angeles, CA 90033 USA. [Warburton, David] Univ So Calif, Ostrow Sch Dent, Los Angeles, CA 90089 USA. [Gilliland, Frank] Univ So Calif, Keck Sch Med, Div Environm & Occupat Hlth, Los Angeles, CA 90033 USA. [Dashdendev, Baigalmaa] Hlth Sci Univ Mongolia, Natl Ctr Maternal & Child Hlth, Ulaanbaatar, Mongol Peo Rep. RP Warburton, D (reprint author), Childrens Hosp Los Angeles, 4650 Sunset Blvd M535, Los Angeles, CA 90027 USA. EM dwarburton@chla.usc.edu FU NIEHS NIH HHS [1D43ES022862-01A1, P30 ES007048, D43 ES022862] NR 15 TC 3 Z9 3 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 J9 ENVIRON RES JI Environ. Res. PD JUL PY 2013 VL 124 BP 65 EP 66 DI 10.1016/j.envres.2013.04.002 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 162VM UT WOS:000320294100009 PM 23673312 ER PT J AU Kawasoe, M Yamamoto, Y Okawa, K Funato, T Takeda, M Hara, T Tsurumi, H Moriwaki, H Arioka, Y Takemura, M Matsunami, H Markey, SP Saito, K AF Kawasoe, Misaki Yamamoto, Yasuko Okawa, Katsuya Funato, Tadao Takeda, Mayu Hara, Takeshi Tsurumi, Hisashi Moriwaki, Hisataka Arioka, Yuko Takemura, Masao Matsunami, Hidetoshi Markey, Sanford P. Saito, Kuniaki TI Acquired resistance of leukemic cells to AraC is associated with the upregulation of aldehyde dehydrogenase 1 family member A2 SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; TRANS-RETINOIC ACID; CYTOSINE-ARABINOSIDE; CYTIDINE DEAMINASE; PROLIFERATION; INTERVENTION; MECHANISMS; EXPRESSION; APOPTOSIS; KINASE AB The elucidation of drug resistance mechanisms is important in the development of clinical therapies for the treatment of leukemia. To study the drug resistance mechanisms, protein expression profiles of 1-beta-D-arabinofuranosylcytosine (AraC)-sensitive K562 (K562S) cells and AraC-resistant K562 (K562AC) cells were compared using two-dimensional fluorescence difference gel electrophoresis. In a comparison of protein expression profiles, 2073 protein spots were found to be altered, and 15 proteins of them were remarkably altered. These proteins were identified by mass spectrometry. The most differently expressed proteins were aldehyde dehydrogenase 1 family member A2 (ALDH1A2) and vimentin. Both proteins were verified using reverse transcriptase polymerase chain reaction and Western blot analysis. ALDH1A2 protein was found to be effective in AraC resistance. ALDH1A2 knock-down induced sensitivity to AraC treatment in K562AC cells, and ALDH1A2 overexpressed K562S cells acquired the AraC resistance. Furthermore, the findings also suggest that ALDH1A2 expression is increased after the appearance of AraC resistance in clinical cases. These results will be helpful in understanding the mechanism of AraC resistance. (C) 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. C1 [Kawasoe, Misaki; Yamamoto, Yasuko; Arioka, Yuko; Takemura, Masao; Saito, Kuniaki] Kyoto Univ, Grad Sch Med, Kyoto 6068507, Japan. [Kawasoe, Misaki; Yamamoto, Yasuko; Arioka, Yuko; Takemura, Masao; Saito, Kuniaki] Kyoto Univ, Fac Med, Kyoto 6068507, Japan. [Okawa, Katsuya] Kyowa Hakko Kirin, Drug Discovery Res Labs, Shizuoka, Japan. [Funato, Tadao; Takeda, Mayu] Tohoku Fukushi Univ, Dept Healthcare Econ & Qual Management, Sendai, Miyagi, Japan. [Hara, Takeshi; Tsurumi, Hisashi; Moriwaki, Hisataka] Gifu Univ, Grad Sch Med, Dept Internal Med 1, Gifu, Japan. [Matsunami, Hidetoshi] Matsunami Gen Hosp, Gifu, Japan. [Markey, Sanford P.] NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. RP Yamamoto, Y (reprint author), Kyoto Univ, Grad Sch Med, Kyoto 6068507, Japan. EM yamamoto-y@hs.med.kyoto-u.ac.jp FU Ministry of Education, Science and Culture of Japan [23390149, 23790621]; Smoking Research Foundation FX The authors thank Dr. Y. Ohta for scientific discussing and proofreading the manuscript. This study was supported in part by a Grant-in-Aid from the Ministry of Education, Science and Culture of Japan (23390149 to K.S. and 23790621 Y.Y.) and a grant from the Smoking Research Foundation. NR 25 TC 4 Z9 4 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2013 VL 41 IS 7 BP 597 EP 603 DI 10.1016/j.exphem.2013.03.004 PG 7 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 181RE UT WOS:000321685400003 PM 23507523 ER PT J AU Ding, KY de Andrade, M Manolio, TA Crawford, DC Rasmussen-Torvik, LJ Ritchie, MD Denny, JC Masys, DR Jouni, H Pachecho, JA Kho, AN Roden, DM Chisholm, R Kullo, IJ AF Ding, Keyue de Andrade, Mariza Manolio, Teri A. Crawford, Dana C. Rasmussen-Torvik, Laura J. Ritchie, Marylyn D. Denny, Joshua C. Masys, Daniel R. Jouni, Hayan Pachecho, Jennifer A. Kho, Abel N. Roden, Dan M. Chisholm, Rex Kullo, Iftikhar J. TI Genetic Variants That Confer Resistance to Malaria Are Associated with Red Blood Cell Traits in African-Americans: An Electronic Medical Record-based Genome-Wide Association Study SO G3-GENES GENOMES GENETICS LA English DT Article DE red blood cell (RBC) traits; genome-wide association study; African-Americans; natural selection; informatics; electronic medical record ID EMERGE NETWORK; POPULATION; CONSORTIUM; LINKAGE; WHITES; DEFICIENCY; VISCOSITY; PRESSURE; BLACKS; VOLUME AB To identify novel genetic loci influencing interindividual variation in red blood cell (RBC) traits in African-Americans, we conducted a genome-wide association study (GWAS) in 2315 individuals, divided into discovery (n = 1904) and replication (n = 411) cohorts. The traits included hemoglobin concentration (HGB), hematocrit (HCT), RBC count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Patients were participants in the electronic MEdical Records and GEnomics (eMERGE) network and underwent genotyping of similar to 1.2 million single-nucleotide polymorphisms on the Illumina Human1M-Duo array. Association analyses were performed adjusting for age, sex, site, and population stratification. Three loci previously associated with resistance to malaria-HBB (11p15.4), HBA1/HBA2 (16p13.3), and G6PD (Xq28)-were associated (P <= 1 x 10(-6)) with RBC traits in the discovery cohort. The loci replicated in the replication cohort (P <= 0.02), and were significant at a genome-wide significance level (P < 5 x 10(-8)) in the combined cohort. The proportions of variance in RBC traits explained by significant variants at these loci were as follows: rs7120391 (near HBB) 1.3% of MCHC, rs9924561 (near HBA1/A2) 5.5% of MCV, 6.9% of MCH and 2.9% of MCHC, and rs1050828 (in G6PD) 2.4% of RBC count, 2.9% of MCV, and 1.4% of MCH, respectively. We were not able to replicate loci identified by a previous GWAS of RBC traits in a European ancestry cohort of similar sample size, suggesting that the genetic architecture of RBC traits differs by race. In conclusion, genetic variants that confer resistance to malaria are associated with RBC traits in African-Americans. C1 [Ding, Keyue; Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. [Jouni, Hayan] Mayo Clin, Dept Internal Med, Rochester, MN 55905 USA. [de Andrade, Mariza] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Manolio, Teri A.] NHGRI, Off Populat Genom, Bethesda, MD 20892 USA. [Denny, Joshua C.; Roden, Dan M.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37232 USA. [Denny, Joshua C.; Roden, Dan M.] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA. [Denny, Joshua C.; Roden, Dan M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. [Crawford, Dana C.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37232 USA. [Ritchie, Marylyn D.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Masys, Daniel R.] Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA. [Chisholm, Rex] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA. [Rasmussen-Torvik, Laura J.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Pachecho, Jennifer A.; Kho, Abel N.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Pachecho, Jennifer A.; Kho, Abel N.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. RP Kullo, IJ (reprint author), Mayo Clin, 200 1st St SW, Rochester, MN 55905 USA. EM Kullo.iftikhar@mayo.edu FU National Human Genome Research Institute; National Institute of General Medical Sciences; [U01-HG-04599]; [U01-HG-06379]; [U01HG004609]; [U01-HG-04603] FX The eMERGE Network was initiated and funded by the National Human Genome Research Institute, with additional funding from National Institute of General Medical Sciences. The present study was supported through the following grants: U01-HG-04599 and U01-HG-06379 (Mayo Clinic); U01HG004609 (Northwestern University); and U01-HG-04603 (Vanderbilt University, also serving as the Administrative Coordinating Center). There are no relevant conflicts of interest to declare. NR 37 TC 14 Z9 14 U1 1 U2 13 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD JUL 1 PY 2013 VL 3 IS 7 BP 1061 EP 1068 DI 10.1534/g3.113.006452 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 181UV UT WOS:000321695600001 PM 23696099 ER PT J AU Zhu, B Ashley-Koch, AE Dunson, DB AF Zhu, Bin Ashley-Koch, Allison E. Dunson, David B. TI Generalized Admixture Mapping for Complex Traits SO G3-GENES GENOMES GENETICS LA English DT Article DE generalized linear model; local ancestry; mapping by admixture linkage disequilibrium; quadratic normal moment prior; quantitative traits ID GENOME-WIDE ASSOCIATION; AFRICAN-AMERICANS; ADMIXED POPULATIONS; VARIABLE SELECTION; CANDIDATE LOCUS; DISEASE; LINKAGE; MAP; REGULARIZATION; REGRESSION AB Admixture mapping is a popular tool to identify regions of the genome associated with traits in a recently admixed population. Existing methods have been developed primarily for identification of a single locus influencing a dichotomous trait within a case-control study design. We propose a generalized admixture mapping (GLEAM) approach, a flexible and powerful regression method for both quantitative and qualitative traits, which is able to test for association between the trait and local ancestries in multiple loci simultaneously and adjust for covariates. The new method is based on the generalized linear model and uses a quadratic normal moment prior to incorporate admixture prior information. Through simulation, we demonstrate that GLEAM achieves lower type I error rate and higher power than ANCESTRYMAP both for qualitative traits and more significantly for quantitative traits. We applied GLEAM to genome-wide SNP data from the Illumina African American panel derived from a cohort of black women participating in the Healthy Pregnancy, Healthy Baby study and identified a locus on chromosome 2 associated with the averaged maternal mean arterial pressure during 24 to 28 weeks of pregnancy. C1 [Zhu, Bin] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Ashley-Koch, Allison E.] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA. [Dunson, David B.] Duke Univ, Dept Stat Sci, Durham, NC 27708 USA. RP Zhu, B (reprint author), 9609 Med Ctr Dr,Suite 7E618, Rockville, MD 20850 USA. EM bin.zhu@nih.gov OI Ashley-Koch, Allison/0000-0001-5409-9155 FU National Institute of Environmental Health Sciences [R01ES017436]; National Institutes of Health [5P2O-RR020782-O3]; U.S. Environmental Protection Agency [RD-83329301-0]; Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, Maryland FX This work was supported by Award Number R01ES017436 from the National Institute of Environmental Health Sciences, by funding from the National Institutes of Health (5P2O-RR020782-O3), and the U.S. Environmental Protection Agency (RD-83329301-0) and by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences, the National Institutes of Health, or the U.S. Environmental Protection Agency. NR 36 TC 2 Z9 2 U1 0 U2 6 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD JUL 1 PY 2013 VL 3 IS 7 BP 1165 EP 1175 DI 10.1534/g3.113.006478 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 181UV UT WOS:000321695600010 PM 23665878 ER PT J AU Chambers, DA Mullican, CA Stirratt, M AF Chambers, David A. Mullican, Charlotte A. Stirratt, Michael TI Health information technology and mental health services research: a path forward SO GENERAL HOSPITAL PSYCHIATRY LA English DT Editorial Material C1 [Chambers, David A.] NIMH, Div Serv & Intervent Res, NIH, Bethesda, MD 20892 USA. [Mullican, Charlotte A.] Agcy Healthcare Res & Qual, Ctr Primary Care Prevent & Clin Partnerships, Rockville, MD USA. [Stirratt, Michael] NIMH, Div AIDS Res, NIH, Bethesda, MD 20892 USA. RP Chambers, DA (reprint author), NIMH, Div Serv & Intervent Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD JUL-AUG PY 2013 VL 35 IS 4 BP 329 EP 331 DI 10.1016/j.genhosppsych.2013.03.006 PG 3 WC Psychiatry SC Psychiatry GA 173UU UT WOS:000321107600001 PM 23582190 ER PT J AU Green, RC Berg, JS Grody, WW Kalia, SS Korf, BR Martin, CL McGuire, AL Nussbaum, RL O'Daniel, JM Ormond, KE Rehm, HL Watson, MS Williams, MS Biesecker, LG AF Green, Robert C. Berg, Jonathan S. Grody, Wayne W. Kalia, Sarah S. Korf, Bruce R. Martin, Christa L. McGuire, Amy L. Nussbaum, Robert L. O'Daniel, Julianne M. Ormond, Kelly E. Rehm, Heidi L. Watson, Michael S. Williams, Marc S. Biesecker, Leslie G. TI ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing SO GENETICS IN MEDICINE LA English DT Article DE genome; genomic medicine; incidental findings; personalized medicine; secondary findings; sequencing; whole exome; whole genome ID MEDICINE; RETURN; PERSPECTIVES; GENETICS; CHILDREN; FUTURE; POLICY AB In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including an open forum at the 2012 Annual Meeting and review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. The ACMG recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the "normal" of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples. We recognize that there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected. C1 [Green, Robert C.; Kalia, Sarah S.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Green, Robert C.; Kalia, Sarah S.; Rehm, Heidi L.] Harvard Univ, Sch Med, Boston, MA USA. [Green, Robert C.; Rehm, Heidi L.] Partners Healthcare Ctr Personalized Genet Med, Boston, MA USA. [Berg, Jonathan S.; O'Daniel, Julianne M.] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC USA. [Grody, Wayne W.] Univ Calif Los Angeles, Sch Med, Div Med Genet, Dept Human Genet, Los Angeles, CA USA. [Grody, Wayne W.] Univ Calif Los Angeles, Sch Med, Dept Pathol & Lab Med, Div Mol Pathol, Los Angeles, CA 90024 USA. [Grody, Wayne W.] Univ Calif Los Angeles, Sch Med, Dept Pediat, Div Pediat Genet, Los Angeles, CA 90024 USA. [Korf, Bruce R.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Martin, Christa L.] Geisinger Hlth Syst, Autism & Dev Med Inst, Danville, PA USA. [McGuire, Amy L.] Baylor Coll Med, Ctr Med Eth & Hlth Policy, Houston, TX 77030 USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med, Div Genom Med, San Francisco, CA USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Ormond, Kelly E.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Rehm, Heidi L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Watson, Michael S.] Amer Coll Med Genet & Genom, Bethesda, MD USA. [Williams, Marc S.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA. [Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Green, RC (reprint author), Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. EM rcgreen@genetics.med.harvard.edu; leslieb@helix.nih.gov OI Williams, Marc/0000-0001-6165-8701 FU Michael J. Fox Foundation; National Parkinson Disease Foundation; DOD [W81XWH-12-1-0569]; University of North Carolina Cancer Research Fund; UNC Bryson Philanthropic Fund; UNC Center for Genomics and Society; National Human Genome Research Institute; [HG006500]; [HG005092]; [HG003178]; [HG00603]; [HG006615]; [HG003170]; [GM007748]; [AG027841]; [CA154517]; [HG003389]; [HG006382]; [HG006485]; [HG006612]; [ES017793]; [DK087728]; [HG004488]; [RR025747]; [RR025746]; [RR025745]; [HG006487] FX Members of the ACMG Working Group on Secondary Findings in Exome and Genome Sequencing were all reviewed for conflicts of interest by the Board of the ACMG. Research funding from the following sources supported efforts by members of this Working Group: HG006500 (R. C. G., H. L. R., A. M.); HG005092, HG003178, HG00603, HG006615, HG003170, GM007748, AG027841, and CA154517 (R. C. G.); HG003389 (K.E.O.); HG006382 (M.S.W.); HG006500, HG006485, and HG006612 (A. M.); ES017793, DK087728, Michael J. Fox Foundation, National Parkinson Disease Foundation, and DOD W81XWH-12-1-0569 (R.L.N.); HG004488, RR025747, RR025746, RR025745, HG006487, University of North Carolina Cancer Research Fund, UNC Bryson Philanthropic Fund, and the UNC Center for Genomics and Society (J.S.B.). L. G. B. is supported by the Intramural Research Program of the National Human Genome Research Institute. We thank the following individuals for their review and comments on drafts of this article, many of which were adopted by the Working Group; Margaret Adam, Jeffrey Botkin, Wendy Chung, David Dimmock, Christine Eng, Madhuri Hegde, Gail Jarvik, Stephen Kingsmore, Michael Murray, Katherine Nathanson, Sharon Plon, Reed Pyeritz, Cheryl Reid, V. Reid Sutton, and Benjamin Wilfond. The final version of this article and its recommendations do not necessarily reflect the views of these individuals. NR 36 TC 686 Z9 692 U1 15 U2 91 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JUL PY 2013 VL 15 IS 7 BP 565 EP 574 DI 10.1038/gim.2013.73 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 176TS UT WOS:000321328500012 PM 23788249 ER PT J AU Biesecker, LG AF Biesecker, Leslie G. TI Hypothesis-generating research and predictive medicine SO GENOME RESEARCH LA English DT Article ID GENOME; INDIVIDUALS; VARIANTS AB Genomics has profoundly changed biology by scaling data acquisition, which has provided researchers with the opportunity to interrogate biology in novel and creative ways. No longer constrained by low-throughput assays, researchers have developed hypothesis-generating approaches to understand the molecular basis of nature-both normal and pathological. The paradigm of hypothesis-generating research does not replace or undermine hypothesis-testing modes of research; instead, it complements them and has facilitated discoveries that may not have been possible with hypothesis-testing research. The hypothesis-generating mode of research has been primarily practiced in basic science but has recently been extended to clinical-translational work as well. Just as in basic science, this approach to research can facilitate insights into human health and disease mechanisms and provide the crucially needed data set of the full spectrum of genotype-phenotype correlations. Finally, the paradigm of hypothesis-generating research is conceptually similar to the underpinning of predictive genomic medicine, which has the potential to shift medicine from a primarily population- or cohort-based activity to one that instead uses individual susceptibility, prognostic, and pharmacogenetic profiles to maximize the efficacy and minimize the iatrogenic effects of medical interventions. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov NR 10 TC 18 Z9 19 U1 0 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUL PY 2013 VL 23 IS 7 BP 1051 EP 1053 DI 10.1101/gr.157826.113 PG 3 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 173YO UT WOS:000321119900001 PM 23817045 ER PT J AU Snitkin, ES Zelazny, AM Gupta, J Palmore, TN Murray, PR Segre, JA AF Snitkin, Evan S. Zelazny, Adrian M. Gupta, Jyoti Palmore, Tara N. Murray, Patrick R. Segre, Julia A. CA NISC Comparative Sequencing Progra TI Genomic insights into the fate of colistin resistance and Acinetobacter baumannii during patient treatment SO GENOME RESEARCH LA English DT Article ID ANTIBIOTIC-RESISTANCE; MYCOBACTERIUM-TUBERCULOSIS; STAPHYLOCOCCUS-AUREUS; MULTIDRUG-RESISTANCE; IMPAIRED VIRULENCE; COST; MECHANISMS; EVOLUTION; MUTATIONS; EPIDEMIC AB Bacterial whole-genome sequencing (WGS) of human pathogens has provided unprecedented insights into the evolution of antibiotic resistance. Most studies have focused on identification of resistance mutations, leaving one to speculate on the fate of these mutants once the antibiotic selective pressure is removed. We performed WGS on longitudinal isolates of Acinetobacter baumannii from patients undergoing colistin treatment, and upon subsequent drug withdrawal. In each of the four patients, colistin resistance evolved via mutations at the pmr locus. Upon colistin withdrawal, an ancestral susceptible strain outcompeted resistant isolates in three of the four cases. In the final case, resistance was also lost, but by a compensatory inactivating mutation in the transcriptional regulator of the pmr locus. Notably, this inactivating mutation reduced the probability of reacquiring colistin resistance when subsequently challenged in vitro. On face value, these results supported an in vivo fitness cost preventing the evolution of stable colistin resistance. However, more careful analysis of WGS data identified genomic evidence for stable colistin resistance undetected by clinical microbiological assays. Transcriptional studies validated this genomic hypothesis, showing increased pmr expression of the initial isolate. Moreover, altering the environmental growth conditions of the clinical assay recapitulated the classification as colistin resistant. Additional targeted sequencing revealed that this isolate evolved undetected in a patient undergoing colistin treatment, and was then transmitted to other hospitalized patients, further demonstrating its stability in the absence of colistin. This study provides a unique window into mutational pathways taken in response to antibiotic pressure in vivo, and demonstrates the potential for genome sequence data to predict resistance phenotypes. C1 [Snitkin, Evan S.; Segre, Julia A.] NHGRI, Epithelial Biol Sect, GMBB, Bethesda, MD 20892 USA. [Zelazny, Adrian M.; Palmore, Tara N.; Murray, Patrick R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Gupta, Jyoti; NISC Comparative Sequencing Progra] NIH, Intramural Sequencing Ctr, Rockville, MD 20852 USA. RP Segre, JA (reprint author), NHGRI, Epithelial Biol Sect, GMBB, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov FU NHGRI Intramural Research Program; NIH CC Intramural Research Program; NIH; Pharmacology Research Associate Training Fellowship, NIGMS FX We thank David Lipman and Heidi Kong for their thoughtful discussions and advice. Research support came from NHGRI and NIH CC Intramural Research Programs and from an NIH Director's Challenge Award for genome sequencing. E.S.S. is supported by a Pharmacology Research Associate Training Fellowship, NIGMS. NR 45 TC 29 Z9 31 U1 1 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUL PY 2013 VL 23 IS 7 BP 1155 EP 1162 DI 10.1101/gr.154328.112 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 173YO UT WOS:000321119900012 PM 23564252 ER PT J AU Fusaro, A Monne, I Salomoni, A Angot, A Trolese, M Ferre, N Mutinelli, F Holmes, EC Capua, I Lemey, P Cattoli, G De Benedictis, P AF Fusaro, Alice Monne, Isabella Salomoni, Angela Angot, Angelique Trolese, Matteo Ferre, Nicola Mutinelli, Franco Holmes, Edward C. Capua, Ilaria Lemey, Philippe Cattoli, Giovanni De Benedictis, Paola TI The introduction of fox rabies into Italy (2008-2011) was due to two viral genetic groups with distinct phylogeographic patterns SO INFECTION GENETICS AND EVOLUTION LA English DT Article DE Fox rabies; Phylogeny; Phylogeography; Surveillance ID VIRUS-STRAINS; VACCINATION; EVOLUTION; PHYLOGENETICS; DIVERSITY; INFERENCE; ACCURATE; DYNAMICS; HISTORY; MODELS AB Fox rabies re-emerged in north-eastern Italy at the end of 2008 and circulated until early 2011. As with previous rabies epidemics, the Italian cases were linked to the epidemiological situation in adjacent regions. To obtain a comprehensive picture of the dynamics of the recent Italian epidemic, we performed a detailed evolutionary analysis of RABVs circulating in north-eastern Italy. Sequences were obtained for the hyper-variable region of the nucleoprotein gene, the complete glycoprotein gene, and the intergenic region G-L from 113 selected fox rabies cases. We identified two viral genetic groups, here referred to as Italy-1 and Italy-2. Phylogenetic and phylogeographic analyses revealed that both groups had been circulating in the Western Balkans and Slovenia in previous years and were only later introduced into Italy (into the Friuli Venezia Giulia region-FVG), occupying different areas of the Italian territories. Notably, viruses belonging to the Italy-1 group remained confined to the region of introduction and their spread was minimised by the implementation of oral fox vaccination campaigns. In contrast, Italy-2 viruses spread westward over a territory of 100 km from their first identification in FVG, likely crossing the northern territories where surveillance was inadequate. A genetic sub-group (Italy-2A), characterised by a unique amino acid mutation (D106A) in the N gene, was also observed to occupy a distinct geographic cluster. This molecular epidemiological analysis of the 2008-2011 fox rabies epidemic will contribute to future control programmes both at national and regional levels. In particular, our findings highlight the weaknesses of the national surveillance strategy in the period preceding rabies re-emergence, and of control plans implemented immediately after rabies notification, and underline the need of a coordinated approach at the regional level for both the surveillance and control of wildlife rabies. (C) 2013 Elsevier B.V. All rights reserved. C1 [Fusaro, Alice; Monne, Isabella; Salomoni, Angela; Angot, Angelique; Mutinelli, Franco; Capua, Ilaria; Cattoli, Giovanni; De Benedictis, Paola] Ist Zooprofilatt Sperimentale Venezie, FAO, I-35020 Legnaro, PD, Italy. [Fusaro, Alice; Monne, Isabella; Salomoni, Angela; Angot, Angelique; Mutinelli, Franco; Capua, Ilaria; Cattoli, Giovanni; De Benedictis, Paola] Ist Zooprofilatt Sperimentale Venezie, Natl Reference Ctr Rabies, I-35020 Legnaro, PD, Italy. [Fusaro, Alice; Monne, Isabella; Salomoni, Angela; Angot, Angelique; Mutinelli, Franco; Capua, Ilaria; Cattoli, Giovanni; De Benedictis, Paola] Ist Zooprofilatt Sperimentale Venezie, Div Biomed Sci, OIE Collaborating Ctr Dis Anim Human Interface, I-35020 Legnaro, PD, Italy. [Trolese, Matteo; Ferre, Nicola] Ist Zooprofilatt Sperimentale Venezie, GIS Off, Vet Epidemiol Unit, I-35020 Legnaro, PD, Italy. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lemey, Philippe] Katholieke Univ Leuven, Rega Inst, Dept Microbiol & Immunol, Louvain, Belgium. RP De Benedictis, P (reprint author), Ist Zooprofilatt Sperimentale Venezie, Div Biomed Sci, Viale Univ 10, I-35020 Legnaro, PD, Italy. EM pdebenedictis@izsvenezie.it OI Fusaro, Alice/0000-0002-8213-5472; Holmes, Edward/0000-0001-9596-3552 FU European Commission [278433]; Italian Ministry of Health [RC IZSVE 19/10] FX This study was funded in part by the European Commission through FP7, project PREDEMICS (Grant agreement no 278433), and by the Italian Ministry of Health through the RC IZSVE 19/10. Paolo Mulatti-IZSVe and Monica Lorenzetto-IZSVe, are gratefully acknowledged for their technical support. Authors wish to thank two anonymous reviewers for their constructive comments. This study was conducted in the framework of the Doctoral school in Veterinary Science at the University of Padua (Alice Fusaro). NR 28 TC 3 Z9 3 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-1348 J9 INFECT GENET EVOL JI Infect. Genet. Evol. PD JUL PY 2013 VL 17 BP 202 EP 209 DI 10.1016/j.meegid.2013.03.051 PG 8 WC Infectious Diseases SC Infectious Diseases GA 175MS UT WOS:000321235400026 PM 23603764 ER PT J AU Hales, D Stevens, J Murray, DM Taber, DR Roberts, A AF Hales, Derek Stevens, June Murray, David M. Taber, Dan R. Roberts, Amy TI Identifying state-level policy and provision domains for physical education and physical activity in high school SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Policy; Physical Activity; Physical Education; SHPPS ID HEALTH POLICIES; PROGRAMS; IMPACT AB Background: It is important to quickly and efficiently identify policies that are effective at changing behavior; therefore, we must be able to quantify and evaluate the effect of those policies and of changes to those policies. The purpose of this study was to develop state-level physical education (PE) and physical activity (PA) policy domain scores at the high-school level. Policy domain scores were developed with a focus on measuring policy change. Methods: Exploratory factor analysis was used to group items from the state-level School Health Policies and Programs Study (SHPPS) into policy domains. Items that related to PA or PE at the High School level were identified from the 7 SHPPS health program surveys. Data from 2000 and 2006 were used in the factor analysis. RESULTS: From the 98 items identified, 17 policy domains were extracted. Average policy domain change scores were positive for 12 policy domains, with the largest increases for "Discouraging PA as Punishment", "Collaboration", and "Staff Development Opportunities". On average, states increased scores in 4.94 +/- 2.76 policy domains, decreased in 3.53 +/- 2.03, and had no change in 7.69 +/- 2.09 policy domains. Significant correlations were found between several policy domain scores. Conclusions: Quantifying policy change and its impact is integral to the policy making and revision process. Our results build on previous research offering a way to examine changes in state-level policies related to PE and PA of high-school students and the faculty and staff who serve them. This work provides methods for combining state-level policies relevant to PE or PA in youth for studies of their impact. C1 [Hales, Derek] Univ N Carolina, Ctr Hlth Promot & Dis Prevent, Chapel Hill, NC 27599 USA. [Stevens, June; Roberts, Amy] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Murray, David M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. [Taber, Dan R.] Univ Illinois Chicago MC 275, Inst Hlth Res & Policy, Chicago, IL 60608 USA. RP Stevens, J (reprint author), Univ N Carolina, Dept Nutr, 245 Rosenau Hall CB 7461, Chapel Hill, NC 27599 USA. EM June_stevens@unc.edu NR 16 TC 1 Z9 1 U1 4 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD JUL 1 PY 2013 VL 10 AR 86 DI 10.1186/1479-5868-10-86 PG 10 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 182TR UT WOS:000321767900001 PM 23815860 ER PT J AU Liu, JF Subramanian, KR Yoo, TS AF Liu, Jianfei Subramanian, Kalpathi R. Yoo, Terry S. TI A robust method to track colonoscopy videos with non-informative images SO INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY LA English DT Article DE Colonoscopy; Tracking; Region flow; Temporal volume flow; Egomotion ID CT COLONOGRAPHY; OPTICAL-FLOW; REGISTRATION; BRONCHOSCOPY; MOTION; SIMULATION; EFFICIENT; DISTANCE; SYSTEM; SCALE AB Continuously, optical and virtual image alignment can significantly supplement the clinical value of colonoscopy. However, the co-alignment process is frequently interrupted by non-informative images. A video tracking framework to continuously track optical colonoscopy images was developed and tested. A video tracking framework with immunity to non-informative images was developed with three essential components: temporal volume flow, region flow, and incremental egomotion estimation. Temporal volume flow selects two similar images interrupted by non-informative images; region flow measures large visual motion between selected images; and incremental egomotion processing estimates significant camera motion by decomposing each large visual motion vector into a sequence of small optical flow vectors. The framework was extensively evaluated via phantom and colonoscopy image sequences. We constructed two colon-like phantoms, a straight phantom and a curved phantom, to measure actual colonoscopy motion. In the straight phantom, after 48 frames were excluded, the tracking error was 3 mm of 16 mm traveled. In the curved phantom, the error was 4 mm of 23.88 mm traveled after 72 frames were excluded. Through evaluations with clinical sequences, the robustness of the tracking framework was demonstrated on 30 colonoscopy image sequences from 22 different patients. Four specific sequences among these were chosen to illustrate the algorithm's decreased sensitivity to (1) fluid immersion, (2) wall contact, (3) surgery-induced colon deformation, and (4) multiple non-informative image sequences. A robust tracking framework for real-time colonoscopy was developed that facilitates continuous alignment of optical and virtual images, immune to non-informative images that enter the video stream. The system was validated in phantom testing and achieved success with clinical image sequences. C1 [Liu, Jianfei] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. [Subramanian, Kalpathi R.] Univ N Carolina, Dept Comp Sci, Charlotte, NC 28223 USA. [Yoo, Terry S.] NIH, Off High Performance Comp & Commun, Natl Lib Med, Bethesda, MD 20894 USA. RP Liu, JF (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM jianfei.liu@nih.gov NR 49 TC 3 Z9 3 U1 1 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-6410 J9 INT J COMPUT ASS RAD JI Int. J. Comput. Assist. Radiol. Surg. PD JUL PY 2013 VL 8 IS 4 BP 575 EP 592 DI 10.1007/s11548-013-0814-x PG 18 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Engineering; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA 179KW UT WOS:000321520200006 PM 23377706 ER PT J AU Stoszek, SK Duarte, G Hance, LF Pinto, J Gouvea, MI Cohen, RA Santos, B Teles, E Succi, R Alarcon, JO Read, JS AF Stoszek, Sonia K. Duarte, Geraldo Hance, Laura Freimanis Pinto, Jorge Gouvea, Maria I. Cohen, Rachel A. Santos, Breno Teles, Elizabete Succi, Regina Alarcon, Jorge O. Read, Jennifer S. CA NISDI Perinatal LILAC Study Grp TI Trends in the management and outcome of HIV-1-infected women and their infants in the NISDI Perinatal and LILAC cohorts, 2002-2009 SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Antiretroviral; HIV-1; Latin America; Mother-to-child transmission; Prophylaxis; Treatment ID RANDOMIZED CLINICAL-TRIAL; LATIN-AMERICAN; TRANSMISSION; SITES; HIV-1 AB Objective: To describe temporal management and outcome trends among HIV-1-infected pregnant women and their infants enrolled in the NISDI Perinatal and LILAC cohorts. Methods: A prospective cohort of 1548 HIV-1-infected pregnant women and their 1481 singleton live-born infants was analyzed. Participants were enrolled at 24 Latin American and Caribbean sites and followed-up for at least 6 months postpartum. Variables were compared by 2-year enrollment periods from September 27, 2002, to June 30, 2009, using logistic and linear regression modeling. Results: Antiretroviral (ARV) use during pregnancy remained high (99.0%). ARVs became increasingly used for treatment (P < 0.001). Regimens containing 2 nucleoside reverse transcriptase inhibitors plus a protease inhibitor became more common in later years (P < 0.001). The proportion of women with viral loads below 1000 copies/mL at hospital discharge after delivery (HD) increased over time (P = 0.0031). Median CD4 lymphocyte counts also rose at HD, from 441 cell/mm(3) to 515 cells/mm(3) (P < 0.05). Elective cesarean deliveries increased from 30.5% to 42.0% (P = 0.018). Most infants received ARV prophylaxis (99.7%). Few infants were breastfed (0.5%) or became infected with HIV-1 (1.2%). Conclusion: The results indicate that national HIV-1 treatment and transmission prevention policies are effective among patients with healthcare access in the region. (c) 2013 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics. C1 [Stoszek, Sonia K.; Hance, Laura Freimanis; Cohen, Rachel A.] WESTAT Corp, Hlth Studies Sect, Rockville, MD 20850 USA. [Duarte, Geraldo] Univ Sao Paulo, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, Brazil. [Pinto, Jorge] Univ Fed Minas Gerais, Dept Pediat, Div Immunol, Belo Horizonte, MG, Brazil. [Gouvea, Maria I.] Hosp Servidores Estado Saude, Serv Doencas Infecciosas & Parasitarias, Rio De Janeiro, Brazil. [Santos, Breno] Hosp Nossa Senhora da Conceicao, Serv Infectol, Porto Alegre, RS, Brazil. [Teles, Elizabete] Hosp Femina, Serv Infectol, Porto Alegre, RS, Brazil. [Succi, Regina] Univ Fed Sao Paulo, Escola Paulista Med, Sao Paulo, Brazil. [Alarcon, Jorge O.] Univ Nacl Mayor San Marcos, Inst Med Trop Daniel Alcides Carrion, Lima 14, Peru. [Read, Jennifer S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, US Dept HHS, Bethesda, MD USA. [Read, Jennifer S.] US Dept HHS, Natl Vaccine Program Off, Off Assistant Secretary Hlth, Off Secretary, Washington, DC 20201 USA. RP Stoszek, SK (reprint author), WESTAT Corp, 1600 Res Blvd,WB 280, Rockville, MD 20850 USA. EM soniastoszek@westat.com RI Duarte, Geraldo/J-7906-2012; OI Alarcon, Jorge/0000-0002-0800-2380 FU NICHD NIH HHS [N01HD33345, HHSN267200800001C] NR 11 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD JUL PY 2013 VL 122 IS 1 BP 37 EP 43 DI 10.1016/j.ijgo.2012.12.021 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 172BH UT WOS:000320974400009 PM 23566742 ER PT J AU Nishikawa, T Omura, M Saito, J Matsuzawa, Y Kino, T AF Nishikawa, Tetsuo Omura, Masao Saito, Jun Matsuzawa, Yoko Kino, Tomoshige TI Editorial Comment from Dr Nishikawa et al. to Preoperative masked renal damage in Japanese patients with primary aldosteronism: Identification of predictors for chronic kidney disease manifested after adrenalectomy SO INTERNATIONAL JOURNAL OF UROLOGY LA English DT Editorial Material ID DIAGNOSIS C1 [Nishikawa, Tetsuo; Omura, Masao; Saito, Jun; Matsuzawa, Yoko] Yokohama City Rosai Hosp, Endocrinol & Diabet Ctr, Yokohama, Kanagawa, Japan. [Kino, Tomoshige] NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Nishikawa, T (reprint author), Yokohama City Rosai Hosp, Endocrinol & Diabet Ctr, Yokohama, Kanagawa, Japan. EM tetsuon@yokohamah.rofuku.go.jp FU Intramural NIH HHS [ZIA HD008732-13] NR 6 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0919-8172 J9 INT J UROL JI Int. J. Urol. PD JUL PY 2013 VL 20 IS 7 BP 693 EP 694 DI 10.1111/iju.12052 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 180TL UT WOS:000321619900011 PM 23231595 ER PT J AU Rosenquist, KJ Pedley, A Massaro, JM Therkelsen, KE Murabito, JM Hoffmann, U Fox, CS AF Rosenquist, Klara J. Pedley, Alison Massaro, Joseph M. Therkelsen, Kate E. Murabito, Joanne M. Hoffmann, Udo Fox, Caroline S. TI Visceral and Subcutaneous Fat Quality and Cardiometabolic Risk SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE computed tomography imaging; epidemiology; obesity; risk factors ID ADIPOSE-TISSUE; INSULIN-RESISTANCE; HUMAN OBESITY; CARDIOVASCULAR-DISEASE; ACID-METABOLISM; BODY-FAT; FRAMINGHAM; HEART; INFLAMMATION; SENSITIVITY AB OBJECTIVES The aim of this study was to evaluate whether computed tomography (CT) attenuation, as a measure of fat quality, is associated with cardiometabolic risk factors above and beyond fat quantity. BACKGROUND Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are pathogenic fat depots associated with cardiometabolic risk. Adipose tissue attenuation in CT images is variable, similar to adipose tissue volume. However, whether the quality of abdominal fat attenuation is associated with cardiometabolic risk independent of the quantity is uncertain. METHODS Participants were drawn from the Framingham Heart Study CT substudy. The VAT and SAT volumes were acquired by semiquantitative assessment. Fat quality was measured by CT attenuation and recorded as mean Hounsfield unit (HU) within each fat depot. Sex-specific linear and logistic multivariable regression models were used to assess the association between standard deviation (SD) decrease in HU and each risk factor. RESULTS Lower CT attenuation of VAT and SAT was correlated with higher body mass index levels in both sexes. Risk factors were generally more adverse with decreasing HU values. For example, in women, per 1 SD decrease in VAT HU, the odds ratio (OR) was increased for hypertension (OR: 1.80), impaired fasting glucose (OR: 2.10), metabolic syndrome (OR: 3.65), and insulin resistance (OR: 3.36; all p < 0.0001). In models that further adjusted for VAT volume, impaired fasting glucose, metabolic syndrome, and insulin resistance remained significant. Trends were similar but less pronounced for SAT and for men. There was evidence of an interaction between HU and fat volume among both women and men. CONCLUSIONS Lower CT attenuation of VAT and SAT is associated with adverse cardiometabolic risk above and beyond total adipose tissue volume. Qualitative indices of abdominal fat depots may provide insight regarding cardiometabolic risk independent of fat quantity. (C) 2013 by the American College of Cardiology Foundation C1 [Rosenquist, Klara J.; Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Rosenquist, Klara J.; Hoffmann, Udo; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Rosenquist, Klara J.; Pedley, Alison; Therkelsen, Kate E.; Murabito, Joanne M.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Rosenquist, Klara J.; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA 01702 USA. [Rosenquist, Klara J.; Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA 01702 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. NHLBI, Framingham Heart Study, NIH, Framingham, MA 01702 USA. Boston Univ, Sch Med, Boston, MA 02215 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Murabito, Joanne/0000-0002-0192-7516; Massaro, Joseph/0000-0002-2682-4812 FU NHLBI FHS [N01-HC-25195]; Whitaker Cardiovascular Institute [T32 HL007224] FX This research was conducted in part using data and resources from the Framingham Heart Study (FHS) of the NHLBI of the National Institutes of Health and Boston University School of Medicine. This work was partially supported by NHLBI FHS (N01-HC-25195). Dr. Rosenquist is supported through funding from the Whitaker Cardiovascular Institute (T32 HL007224). Dr. Pedley is an employee of Merck & Co., Inc. All other authors have reported they have no relationships relevant to the contents of this paper to disclose. NR 36 TC 42 Z9 43 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD JUL PY 2013 VL 6 IS 7 BP 762 EP 771 DI 10.1016/j.jcmg.2012.11.021 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 181OB UT WOS:000321677300003 PM 23664720 ER PT J AU Simonds, NI Khoury, MJ Schully, SD Armstrong, K Cohn, WF Fenstermacher, DA Ginsburg, GS Goddard, KAB Knaus, WA Lyman, GH Ramsey, SD Xu, JF Freedman, AN AF Simonds, Naoko I. Khoury, Muin J. Schully, Sheri D. Armstrong, Katrina Cohn, Wendy F. Fenstermacher, David A. Ginsburg, Geoffrey S. Goddard, Katrina A. B. Knaus, William A. Lyman, Gary H. Ramsey, Scott D. Xu, Jianfeng Freedman, Andrew N. TI Comparative Effectiveness Research in Cancer Genomics and Precision Medicine: Current Landscape and Future Prospects SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID PERSONALIZED MEDICINE; MYELODYSPLASTIC SYNDROMES; EXPERIENCE; REGISTRIES; COST; CARE AB A major promise of genomic research is information that can transform health care and public health through earlier diagnosis, more effective prevention and treatment of disease, and avoidance of drug side effects. Although there is interest in the early adoption of emerging genomic applications in cancer prevention and treatment, there are substantial evidence gaps that are further compounded by the difficulties of designing adequately powered studies to generate this evidence, thus limiting the uptake of these tools into clinical practice. Comparative effectiveness research (CER) is intended to generate evidence on the real-world effectiveness compared with existing standards of care so informed decisions can be made to improve health care. Capitalizing on funding opportunities from the American Recovery and Reinvestment Act of 2009, the National Cancer Institute funded seven research teams to conduct CER in genomic and precision medicine and sponsored a workshop on CER on May 30, 2012, in Bethesda, Maryland. This report highlights research findings from those research teams, challenges to conducting CER, the barriers to implementation in clinical practice, and research priorities and opportunities in CER in genomic and precision medicine. Workshop participants strongly emphasized the need for conducting CER for promising molecularly targeted therapies, developing and supporting an integrated clinical network for open-access resources, supporting bioinformatics and computer science research, providing training and education programs in CER, and conducting research in economic and decision modeling. C1 [Simonds, Naoko I.; Khoury, Muin J.; Schully, Sheri D.; Freedman, Andrew N.] NCI, Div Canc Control & Populat Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Armstrong, Katrina] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Knaus, William A.] Univ Virginia, Sch Med, Div Biomed Informat, Charlottesville, VA 22908 USA. [Fenstermacher, David A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Biomed Informat Dept, Tampa, FL 33612 USA. [Ginsburg, Geoffrey S.] Duke Univ, Med Ctr, Inst Genome Sci & Policy, Durham, NC USA. [Goddard, Katrina A. B.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. [Knaus, William A.] North Shore Univ Hlth Syst, Appl Genom Res Inst, Ctr Clin & Res Informat, Evanston, IL USA. [Lyman, Gary H.] Duke Univ, Sch Med, Dept Med, Div Med Oncol, Durham, NC 27706 USA. [Lyman, Gary H.] Duke Canc Inst, Durham, NC USA. [Ramsey, Scott D.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Xu, Jianfeng] Wake Forest Sch Med, Ctr Canc Genom, Winston Salem, NC USA. RP Simonds, NI (reprint author), DCCPS, Clin & Translat Epidemiol Branch, 9609 Med Ctr Dr,Rm 4E228, Bethesda, MD 20892 USA. EM naoko.simonds@nih.gov NR 39 TC 15 Z9 15 U1 1 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD JUL PY 2013 VL 105 IS 13 BP 929 EP 936 DI 10.1093/jnci/djt108 PG 8 WC Oncology SC Oncology GA 178PR UT WOS:000321460400006 PM 23661804 ER PT J AU Abrams, JS Mooney, MM Zwiebel, JA Korn, EL Friedman, SH Finnigan, SR Schettino, PR Denicoff, AM Kruhm, MG Montello, M Misra, RR Ansher, SS DiPiazza, KJ Souhan, EM Wickerham, DL Giantonio, BJ O'Donnell, RT Sullivan, DM Soto, NI Fleming, GF Prindiville, SA Petryshyn, RA Hautala, JA Grad, O Zuckerman, BL Meyer, RM Yao, JC Baker, LA Buckner, JC Hortobagyi, GN Doroshow, JH AF Abrams, Jeffrey S. Mooney, Margaret M. Zwiebel, James A. Korn, Edward L. Friedman, Steven H. Finnigan, Shanda R. Schettino, Patricia R. Denicoff, Andrea M. Kruhm, Martha G. Montello, Mike Misra, R. Rita Ansher, Sherry S. DiPiazza, Kate J. Souhan, Erin M. Wickerham, D. Lawrence Giantonio, Bruce J. O'Donnell, Robert T. Sullivan, Daniel M. Soto, Nancy I. Fleming, Gini F. Prindiville, Sheila A. Petryshyn, Ray A. Hautala, Judith A. Grad, Oren Zuckerman, Brian L. Meyer, Ralph M. Yao, James C. Baker, Laurence A. Buckner, Jan C. Hortobagyi, Gabriel N. Doroshow, James H. TI Implementation of Timeline Reforms Speeds Initiation of National Cancer Institute-Sponsored Trials SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article AB Background The National Cancer Institute (NCI) organized the Operational Efficiency Working Group in 2008 to develop recommendations for improving the speed with which NCI-sponsored clinical trials move from the idea stage to a protocol open to patient enrollment. Methods Given the many stakeholders involved, the Operational Efficiency Working Group advised a multifaceted approach to mobilize the entire research community to improve their business processes. New staff positions to monitor progress, protocol-tracking Web sites, and strategically planned conference calls were implemented. NCI staff and clinical teams at Cooperative Groups and Cancer Centers strived to achieve new target timelines but, most important, agreed to abide by absolute deadlines. For phase I-II studies and phase III studies, the target timelines are 7 months and 10 months, whereas the absolute deadlines were set at 18 and 24 months, respectively. Trials not activated by the absolute deadline are automatically disapproved. Results The initial experience is encouraging and indicates a reduction in development times for phase I-II studies from the historical median of 541 days to a median of 442 days, an 18.3% decrease. The experience with phase III studies to date, although more limited (n = 25), demonstrates a 45.7% decrease in median days. Conclusions Based upon this progress, the NCI and the investigator community have agreed to reduce the absolute deadlines to 15 and 18 months for phase I-II and III trials, respectively. Emphasis on initiating trials rapidly is likely to help reduce the time it takes for clinical trial results to reach patients in need of new treatments. C1 [Abrams, Jeffrey S.; Mooney, Margaret M.; Zwiebel, James A.; Korn, Edward L.; Friedman, Steven H.; Finnigan, Shanda R.; Schettino, Patricia R.; Denicoff, Andrea M.; Kruhm, Martha G.; Montello, Mike; Misra, R. Rita; Ansher, Sherry S.; Doroshow, James H.] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD 20852 USA. [Prindiville, Sheila A.; Petryshyn, Ray A.] NCI, Coordinating Ctr Clin Trials, Off Director, Rockville, MD 20852 USA. [DiPiazza, Kate J.; Souhan, Erin M.] EMMES Corp, Rockville, MD USA. Natl Surg Adjuvant Breast & Bowel Project Operat, Pittsburgh, PA USA. [Giantonio, Bruce J.] Abramson Canc Ctr, Dept Med, Philadelphia, PA USA. [O'Donnell, Robert T.] Univ Calif Davis, Dept Internal Med, Davis, CA 95616 USA. [Sullivan, Daniel M.] Univ S Florida, H Lee Moffitt Canc Ctr, Blood & Marrow Transplantat Dept, Tampa, FL 33682 USA. [Soto, Nancy I.] Radiat Therapy Oncol Grp, Philadelphia, PA USA. [Fleming, Gini F.] Univ Chicago, Chicago, IL 60637 USA. [Meyer, Ralph M.] Canc Res Inst, NCIC Clin Trials Grp, Kingston, ON, Canada. [Hautala, Judith A.; Grad, Oren; Zuckerman, Brian L.] IDA Sci & Technol Policy Inst, Washington, DC USA. [Yao, James C.] Univ Texas MD Anderson Canc Ctr, Gastrointestinal Med Oncol Dept, Houston, TX 77030 USA. [Hortobagyi, Gabriel N.] Univ Texas MD Anderson Canc Ctr, Breast Med Oncol Dept, Houston, TX 77030 USA. [Baker, Laurence A.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Baker, Laurence A.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Buckner, Jan C.] Mayo Clin, Dept Oncol, Rochester, MN USA. RP Abrams, JS (reprint author), NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, 6130 Execut Blvd,Rm 7018, Rockville, MD 20852 USA. EM abramsj@mail.nih.gov FU National Cancer Institute, National Institutes of Health [U10CA076001, U10CA031946, U10CA098543, U10CA021115, U10CA027469, U10CA025224, U10CA077202, U10CA012027, U10CA021661, U10CA080098, U10CA032102, U10CA070095, U01CA099168, U01CA132194, U01CA062502, U01CA069912]; NCI, NIH [HHSN261201100099C, U01CA07657, HHSN261201100070C, U01CA062490, U01CA062491, U01CA062487, U01CA062505, U01CA069852, HHSN261201100071C, U01CA69856, U01CA132123, U01CA062461, HHSN261201100039C, HHSN261201100010C, HHSN261201100032C, HHSN261201100038C, HHSN261201100100C] FX This effort was supported by grant and contract funds from the National Cancer Institute, National Institutes of Health (U10CA076001 and U10CA031946 to Brigham and Women's Hospital; U10CA098543 to Children's Hospital of Philadelphia; U10CA021115 to Frontier Science & Tech Research Foundation, Inc; U10CA027469 to Gynecology Oncology Group; U10CA025224 to Mayo Clinic College of Medicine, Rochester; U10CA077202 to Queen's University at Kingston; U10CA012027 to NSABP Foundation, Inc; U10CA021661 and U10CA080098 to American College of Radiology; U10CA032102 to University of Michigan at Ann Arbor OPS; U10CA070095 to Johns Hopkins University; U01CA099168 to University of Pittsburgh at Pittsburgh; U01CA132194 to University of Med/Dent NJ-R W Johnson Medical School; U01CA062502 to Case Western Reserve University; U01CA069912 and HHSN261201100099C to Mayo Clinic; U01CA07657 and HHSN261201100070C to Ohio State University; U01CA062490 to Dana-Farber Cancer Institute; U01CA062491 to University of Wisconsin-Madison; U01CA062487 to Wayne State University; U01CA062505 to City of Hope/Beckman Research Institute; U01CA069852 and HHSN261201100071C to University of Chicago; U01CA69856 to Sloan-Kettering Institute of Cancer Research; U01CA132123 to University Health Network; U01CA062461 and HHSN261201100039C to MD Anderson Cancer Center; HHSN261201100010C to Emmes Corporation; HHSN261201100032C to University Health Network, Princess Margaret Hospital; HHSN261201100038C to University of California at Davis; and HHSN261201100100C to H. Lee Moffitt Cancer Center and Research Institute). NR 9 TC 10 Z9 10 U1 0 U2 5 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 13 BP 954 EP 959 DI 10.1093/jnci/djt137 PG 6 WC Oncology SC Oncology GA 178PR UT WOS:000321460400009 PM 23776198 ER PT J AU Pogue-Geile, K Yothers, G Taniyama, Y Tanaka, N Gavin, P Colangelo, L Blackmon, N Lipchik, C Kim, SR Sharif, S Allegra, C Petrelli, N O'Connell, MJ Wolmark, N Paik, S AF Pogue-Geile, Kay Yothers, Greg Taniyama, Yusuke Tanaka, Noriko Gavin, Patrick Colangelo, Linda Blackmon, Nicole Lipchik, Corey Kim, Seong Rim Sharif, Saima Allegra, Carmen Petrelli, Nicholas O'Connell, Michael J. Wolmark, Norman Paik, Soonmyung TI Defective Mismatch Repair and Benefit from Bevacizumab for Colon Cancer: Findings from NSABP C-08 SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID METASTATIC COLORECTAL-CANCER; ENDOTHELIAL GROWTH-FACTOR; MICROSATELLITE INSTABILITY; FLUOROURACIL; LEUCOVORIN; MATURATION; TUMORS; CELLS AB National Surgical Adjuvant Breast and Bowel Project protocol C-08 tested the worth of adding 1 year of bevacizumab to oxaliplatin-based standard adjuvant chemotherapy regimen in the treatment of stage II/III colon cancer. Although the overall result was negative, the possibility that a molecularly defined subset could benefit from bevacizumab cannot be ruled out. We performed post hoc Cox regression analyses to test for marker-by-treatment interactions for standard pathological features and survival analyses using the KaplanMeier method. All statistical tests were two-sided and considered statistically significant at the .05 level. Patients diagnosed with mismatch repair defective (dMMR) tumors derived statistically significant survival benefit from the addition of bevacizumab (hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.29 to 0.94; P .02) in contrast with no benefit in patients diagnosed with mismatch repair proficient tumors (HR 1.03; 95% CI 0.84 to 1.27; p .78; P-interaction .04). Although a post hoc finding, this data suggests that a molecularly defined subset of colon cancer patients may derive clinical benefit from antiangiogenesis agents and underscores the need for independent validation in other clinical trials. C1 [Pogue-Geile, Kay; Yothers, Greg; Taniyama, Yusuke; Tanaka, Noriko; Gavin, Patrick; Colangelo, Linda; Blackmon, Nicole; Lipchik, Corey; Kim, Seong Rim; Sharif, Saima; Allegra, Carmen; Petrelli, Nicholas; O'Connell, Michael J.; Wolmark, Norman; Paik, Soonmyung] Natl Surg Adjuvant Breast & Bowel Project NSABP, Pittsburgh, PA USA. [Yothers, Greg; Colangelo, Linda] NSABP Biostat Ctr, Pittsburgh, PA USA. [Yothers, Greg; Colangelo, Linda] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Sharif, Saima; Wolmark, Norman] Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. [Allegra, Carmen] Univ Florida, Dept Med, Shands Canc Ctr, Gainesville, FL USA. [Petrelli, Nicholas] Helen F Graham Canc Ctr Christiana Care, Newark, DE USA. [Paik, Soonmyung] Yonsei Univ, Coll Med, Severance Biomed Res Inst, Seoul, South Korea. RP Paik, S (reprint author), NSABP, Div Pathol, 1307 Fed St,Ste 303, Pittsburgh, PA 15212 USA. EM soon.paik@nsabp.org OI Yothers, Greg/0000-0002-7965-7333 FU Public Health Service Grant from the National Cancer Institute, Department of Health and Human Services [U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, U24-CA-114732]; Genentech Inc; Sanofi-Synthelabo Inc; Pennsylvania Department of Health FX This work was supported in part by Public Health Service Grants U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651, and U24-CA-114732 from the National Cancer Institute, Department of Health and Human Services. It was also supported by Genentech Inc and Sanofi-Synthelabo Inc and funded in part under a grant from the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analysis, interpretations, or conclusions. NR 16 TC 16 Z9 17 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD JUL PY 2013 VL 105 IS 13 BP 989 EP 992 DI 10.1093/jnci/djt140 PG 4 WC Oncology SC Oncology GA 178PR UT WOS:000321460400013 PM 23821759 ER PT J AU Hunsberger, S Rubinstein, L Boerner, SA LoRusso, P AF Hunsberger, Saly Rubinstein, Lary Boerner, Scott A. LoRusso, Patricia TI RE: Meta-analysis of the Relationship Between Dose and Benefit in Phase I Targeted Agent Trials Response SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Hunsberger, Saly; Rubinstein, Lary] NCI, Biometr Res Branch, NIH, Rockville, MD USA. [Boerner, Scott A.; LoRusso, Patricia] Karmanos Canc Inst, Dept Oncol, Detroit, MI USA. RP LoRusso, P (reprint author), Karmanos Canc Inst, Eisenberg Ctr Translat Therapeut, 4100 John R St,Mailcode HW04HO, Detroit, MI 48201 USA. EM lorussop@karmanos.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD JUL PY 2013 VL 105 IS 13 BP 993 EP 994 DI 10.1093/jnci/djt126 PG 2 WC Oncology SC Oncology GA 178PR UT WOS:000321460400015 PM 23723418 ER PT J AU Simons-Morton, BG Bingham, CR Ouimet, MC Pradhan, AK Chen, R Barretto, A Shope, JT AF Simons-Morton, Bruce G. Bingham, C. Raymond Ouimet, Marie Claude Pradhan, Anuj K. Chen, Rusan Barretto, Andrea Shope, Jean T. TI The Effect on Teenage Risky Driving of Feedback From a Safety Monitoring System: A Randomized Controlled Trial SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Adolescents; Elevated gravitational-force events; Injury; Monitoring; Motor vehicle crash; Parenting; Risk taking ID TRIGGERED VIDEO INTERVENTION; SENSATION SEEKING; DRIVERS; PARENTS; INFORMATION; PASSENGERS; CRASHES; SPEED; AGE AB Purpose: Teenage risky driving may be due to teenagers not knowing what is risky, preferring risk, or the lack of consequences. Elevated gravitational-force (g-force) events, caused mainly by hard braking and sharp turns, provide a valid measure of risky driving and are the target of interventions using in-vehicle data recording and feedback devices. The effect of two forms of feedback about risky driving events to teenagers only or to teenagers and their parents was tested in a randomized controlled trial. Methods: Ninety parent-teen dyads were randomized to one of two groups: (1) immediate feedback to teens (Lights Only); or (2) immediate feedback to teens plus family access to event videos and ranking of the teen relative to other teenage drivers (Lights Plus). Participants' vehicles were instrumented with data recording devices and events exceeding .5 g were assessed for 2 weeks of baseline and 13 weeks of feedback. Results: Growth curve analysis with random slopes yielded a significant decrease in event rates for the Lights Plus group (slope = -.11, p < .01), but no change for the Lights Only group (slope = .05, p = .67) across the 15 weeks. A large effect size of 1.67 favored the Lights Plus group. Conclusions: Provision of feedback with possible consequences associated with parents being informed reduced risky driving, whereas immediate feedback only to teenagers did not. Published by Elsevier Inc. on behalf of Society for Adolescent Health and Medicine. C1 [Simons-Morton, Bruce G.; Ouimet, Marie Claude; Pradhan, Anuj K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. [Bingham, C. Raymond; Barretto, Andrea; Shope, Jean T.] Univ Michigan, Transportat Res Inst, Young Driver Behav & Injury Prevent Grp, Ann Arbor, MI 48109 USA. [Ouimet, Marie Claude] Univ Sherbrooke, Fac Med & Hlth Sci, Dept Community Hlth Sci, Longueuil, PQ, Canada. [Chen, Rusan] Georgetown Univ, Ctr New Designs Learning & Scholarship, Washington, DC USA. RP Simons-Morton, BG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd Room 7B13M, Bethesda, MD 20892 USA. EM Mortonb@mail.nih.gov RI Chen, Robert/B-3899-2009; OI Chen, Robert/0000-0002-8371-8629; Pradhan, Anuj/0000-0002-7612-4208; Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [ZIA HD001707-14] NR 27 TC 14 Z9 14 U1 2 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JUL PY 2013 VL 53 IS 1 BP 21 EP 26 DI 10.1016/j.jadohealth.2012.11.008 PG 6 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 169GP UT WOS:000320768200005 PM 23375825 ER PT J AU Zakrajsek, JS Shope, JT Greenspan, AI Wang, J Bingham, CR Simons-Morton, BG AF Zakrajsek, Jennifer S. Shope, Jean T. Greenspan, Arlene I. Wang, Jing Bingham, C. Raymond Simons-Morton, Bruce G. TI Effectiveness of a Brief Parent-Directed Teen Driver Safety Intervention (Checkpoints) Delivered by Driver Education Instructors SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Checkpoints; Driver education; Driving restrictions; Parent management practices; Teen driving risk; Brief group intervention ID RISK; CRASHES; PROGRAM; LIMITS AB Background: The Checkpoints program (Checkpoints) uses a Parent-Teen Driving Agreement (PTDA) to help parents monitor teens' driving, and has shown efficacy in increasing parental restrictions on teens' driving and decreasing teens' risky driving. In previous trials, research staff administered Checkpoints. This study examined the effectiveness of Checkpoints when delivered by driver educators. It was hypothesized that Checkpoints would result in more PTDA use, greater PTDA limits on higher risk driving situations, and less high-risk driving. Methods: Eight trained driving instructors were randomly assigned to intervention or control groups in a group randomized trial. Instructors enrolled 148 parent-teen dyads (intervention = 99, control = 49); 35% of those eligible. Intervention parents joined teens for a 30-minute Checkpoints session during driver education. The session included a video, persuasive messages, discussion, and PTDA initiation. Teens completed four surveys: baseline, licensure, and 3- and 6-months post-licensure. Results: Intervention teens were more likely to report that they used a PTDA (OR = 15.92, p = .004) and had restrictions on driving with teen passengers (OR = 8.52, p = .009), on weekend nights (OR = 8.71, p = .021), on high-speed roads (OR = 3.56, p = .02), and in bad weather (b = .51, p = .05) during the first six months of licensure. There were no differences in offenses or crashes at six months, but intervention teens reported less high-risk driving (p = .04). Conclusions: Although challenges remain to encourage greater parent participation, Checkpoints conducted by driver education instructors resulted in more use of PTDAs, greater restrictions on high-risk driving, and less high-risk driving. Including Checkpoints in driver education parent meetings/classes has potential to enhance teen driver safety. (C) 2013 Society for Adolescent Health and Medicine. All rights reserved. C1 [Zakrajsek, Jennifer S.; Shope, Jean T.; Bingham, C. Raymond] Univ Michigan, Transportat Res Inst, Ann Arbor, MI 48109 USA. [Greenspan, Arlene I.] Ctr Dis Control & Prevent, Natl Ctr Injury Prevent & Control, Atlanta, GA USA. [Wang, Jing; Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Zakrajsek, JS (reprint author), Univ Michigan, Transportat Res Inst, 2901 Baxter Rd, Ann Arbor, MI 48109 USA. EM jzak@umich.edu OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Centers for Disease Control and Prevention's National Center for Injury Prevention and Control; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Support for this research was received from the Centers for Disease Control and Prevention's National Center for Injury Prevention and Control. This research was also supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 21 TC 14 Z9 14 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JUL PY 2013 VL 53 IS 1 BP 27 EP 33 DI 10.1016/j.jadohealth.2012.12.010 PG 7 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 169GP UT WOS:000320768200006 PM 23481298 ER PT J AU Manian, N Schmidt, E Bornstein, MH Martinez, P AF Manian, Nanmathi Schmidt, Elizabeth Bornstein, Marc H. Martinez, Pedro TI Factor structure and clinical utility of BDI-II factor scores in postpartum women SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Depression; Beck Depression Inventory-II; Postpartum depression; Clinical diagnoses; Factor analysis; Structural equation modeling ID BECK DEPRESSION INVENTORY; PSYCHOMETRIC CHARACTERISTICS; COLLEGE-STUDENTS; CHRONIC PAIN; SAMPLE; VALIDITY; EDITION; INSTRUMENTS; OUTPATIENTS; SYMPTOMS AB Background: The purpose of the current study was to examine the factorial dimensions underlying Beck Depression Inventory-II (BDI-II) in a large ethnically and economically diverse sample of postpartum women and to assess their relative contribution in differentiating clinical diagnoses in a subsample of depressed women. Methods: We administered the BDI-II to 953 women between 4 and 20 weeks postpartum. Women who had low (1-7) and high (>12) BDI-II total scores were administered the Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID-I). Results: Exploratory (EFA) and confirmatory factor analysis (CFA) revealed three factors, Cognitive, Somatic, and Affective, that accounted for 49.09% of the overall variance of items. Logistic regression analyses showed that somatic and affective factors contributed to diagnosis of major depression, while the somatic factor alone contributed to the diagnosis of depression with comorbid anxiety. The cognitive factor differentiated women with major depression from women who were never depressed. Limitations: Our definition of clinical depression included episodes of depression during the child's lifetime, and depressive symptoms were not necessarily current at the time of the assessment, which may impact the relative contribution of BDI-II factors to clinical diagnosis. Conclusion: Conceptualizing the structure of the BDI-II using these three factors could contribute to refining the measurement and scoring of depressive symptomatology and severity in postpartum women. Although somatic symptoms of depression may be difficult to differentiate from the physiological changes of normative postpartum adjustment, our results support the inclusion of somatic symptoms of depression in the calculation of a BDI-II total score. (C) 2013 Elsevier B.V. All rights reserved. C1 [Manian, Nanmathi; Schmidt, Elizabeth; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Martinez, Pedro] NIMH, Bethesda, MD 20892 USA. RP Manian, N (reprint author), WESTAT Corp, 1650 Res Blvd, Rockville, MD 20850 USA. EM NanmathiManian@westat.com FU Intramural Research Program of the NICHD, NIH FX This research was supported by the Intramural Research Program of the NICHD, NIH. NR 41 TC 9 Z9 9 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JUL PY 2013 VL 149 IS 1-3 BP 259 EP 268 DI 10.1016/j.jad.2013.01.039 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 166XJ UT WOS:000320593000034 PM 23521870 ER PT J AU Franco-Chaves, JA Mateus, CF Luckenbaugh, DA Martinez, PE Mallinger, AG Zarate, CA AF Franco-Chaves, Jose A. Mateus, Camilo F. Luckenbaugh, David A. Martinez, Pedro E. Mallinger, Alan G. Zarate, Carlos A., Jr. TI Combining a dopamine agonist and selective serotonin reuptake inhibitor for the treatment of depression: A double-blind, randomized pilot study SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Depression; Escitalopram; Pramipexole; Combination treatment; Augmentation strategies ID TREATMENT-RESISTANT DEPRESSION; VENLAFAXINE EXTENDED-RELEASE; BIPOLAR-II DEPRESSION; PARKINSONS-DISEASE; MAJOR DEPRESSION; 2ND-GENERATION ANTIDEPRESSANTS; COMPARATIVE BENEFITS; RECEPTOR AGONISTS; PARALLEL-GROUP; PRAMIPEXOLE AB Background: Antidepressants that act on two or more amine neurotransmitters may confer higher remission rates when first-line agents affecting a single neurotransmitter have failed. Pramipexole, a dopamine agonist, has antidepressant effects in patients with major depressive disorder (MDD). This pilot study examined the efficacy and safety of combination therapy with pramipexole and the selective serotonin reuptake inhibitor (SSRI) escitalopram in MDD. Methods: In this double-blind, controlled, pilot study, 39 patients with DSM-IV MDD who had failed to respond to a standard antidepressant treatment trial were randomized to receive pramipexole (n=13), escitalopram (n=13), or their combination (n=13) for six weeks. Pramipexole was started at 0.375 mg/day and titrated weekly up to 2.25 mg/day; escitalopram dosage remained at 10 mg/day. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Results: Subjects receiving pramipexole monotherapy had significantly lower MADRS scores than the combination group (p=0.01); no other primary drug comparisons were significant. The combination group had a substantially higher dropout rate than the escitalopram and pramipexole groups (69%, 15%, 15%, respectively). Only 15% of patients in the combination group tolerated regularly scheduled increases of pramipexole throughout the study, compared with 46% of patients in the pramipexole group. Limitations: Group size was small and the treatment phase lasted for only six weeks. Conclusions: The combination of an SSRI and a dopamine agonist was not more effective than either agent alone, nor did it produce a more rapid onset of antidepressant action. Combination therapy with escitalopram and pramipexole may not be well-tolerated. Published by Elsevier B.V. C1 [Franco-Chaves, Jose A.; Mateus, Camilo F.; Luckenbaugh, David A.; Mallinger, Alan G.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Martinez, Pedro E.] NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Mallinger, Alan G.] Dept Vet Affairs, Off Inspector Gen, Washington, DC USA. RP Zarate, CA (reprint author), Expt Therapeut & Pathophysiol Branch, 10 Ctr Dr CRC,Unit 7 Southeast,Room 7-3445, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). The NIMH had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 44 TC 11 Z9 11 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JUL PY 2013 VL 149 IS 1-3 BP 319 EP 325 DI 10.1016/j.jad.2013.02.003 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 166XJ UT WOS:000320593000042 PM 23517885 ER PT J AU Swezey, R Shinn, W Green, C Drover, DR Hammer, GB Schulman, SR Zajicek, A Jett, DA Boss, GR AF Swezey, Robert Shinn, Walter Green, Carol Drover, David R. Hammer, Gregory B. Schulman, Scott R. Zajicek, Anne Jett, David A. Boss, Gerry R. TI Comparison of a New Cobinamide-Based Method to a Standard Laboratory Method for Measuring Cyanide in Human Blood SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID NITROPRUSSIDE AB Most hospital laboratories do not measure blood cyanide concentrations, and samples must be sent to reference laboratories. A simple method is needed for measuring cyanide in hospitals. The authors previously developed a method to quantify cyanide based on the high binding affinity of the vitamin B12 analog, cobinamide, for cyanide and a major spectral change observed for cyanide-bound cobinamide. This method is now validated in human blood, and the findings include a mean inter-assay accuracy of 99.1, precision of 8.75 and a lower limit of quantification of 3.27 M cyanide. The method was applied to blood samples from children treated with sodium nitroprusside and it yielded measurable results in 88 of 172 samples (51), whereas the reference laboratory yielded results in only 19 samples (11). In all 19 samples, the cobinamide-based method also yielded measurable results. The two methods showed reasonable agreement when analyzed by linear regression, but not when analyzed by a standard error of the estimate or paired t-test. Differences in results between the two methods may be because samples were assayed at different times on different sample types. The cobinamide-based method is applicable to human blood, and can be used in hospital laboratories and emergency rooms. C1 [Swezey, Robert; Shinn, Walter; Green, Carol] SRI Int Inc, Menlo Pk, CA USA. [Drover, David R.; Hammer, Gregory B.] Stanford Univ, Palo Alto, CA 94304 USA. [Schulman, Scott R.] Duke Univ, Durham, NC USA. [Zajicek, Anne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Jett, David A.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Boss, Gerry R.] Univ Calif San Diego, La Jolla, CA 92093 USA. RP Boss, GR (reprint author), Univ Calif San Diego, La Jolla, CA 92093 USA. EM gboss@ucsd.edu FU Office of the Director, National Institutes of Health (OD); National Institute of Neurological Disorders and Stroke (NINDS) [U01 NS058030]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) under the Best Pharmaceuticals for Children Act [NO1-HD-4-3385] FX This work was supported by the CounterACT Program, Office of the Director, National Institutes of Health (OD) and the National Institute of Neurological Disorders and Stroke (NINDS), Grant Number U01 NS058030. The clinical trial was supported by Contract NO1-HD-4-3385 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) under the Best Pharmaceuticals for Children Act. NR 14 TC 1 Z9 1 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD JUL-AUG PY 2013 VL 37 IS 6 BP 382 EP 385 DI 10.1093/jat/bkt037 PG 4 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 178OI UT WOS:000321456900010 PM 23653045 ER PT J AU Shen, Y Bax, A AF Shen, Yang Bax, Ad TI Protein backbone and sidechain torsion angles predicted from NMR chemical shifts using artificial neural networks SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Heteronuclear chemical shift; Secondary structure; Backbone and sidechain conformation; Dynamics; TALOS; Order parameter; Protein structure; SPARTA ID DEPENDENT ROTAMER LIBRARY; SECONDARY STRUCTURE; DIPOLAR COUPLINGS; SEQUENCE HOMOLOGY; NUCLEIC-ACIDS; CUPID METHOD; DATA-BANK; C-13 NMR; C-13(ALPHA); RESTRAINTS AB A new program, TALOS-N, is introduced for predicting protein backbone torsion angles from NMR chemical shifts. The program relies far more extensively on the use of trained artificial neural networks than its predecessor, TALOS+. Validation on an independent set of proteins indicates that backbone torsion angles can be predicted for a larger, a parts per thousand yen90 % fraction of the residues, with an error rate smaller than ca 3.5 %, using an acceptance criterion that is nearly two-fold tighter than that used previously, and a root mean square difference between predicted and crystallographically observed (I center dot, psi) torsion angles of ca 12A(0). TALOS-N also reports sidechain chi(1) rotameric states for about 50 % of the residues, and a consistency with reference structures of 89 %. The program includes a neural network trained to identify secondary structure from residue sequence and chemical shifts. C1 [Shen, Yang; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Room 126 NIH, Bethesda, MD 20892 USA. EM bax@nih.gov RI Shen, Yang/C-3064-2008 OI Shen, Yang/0000-0003-1408-8034 FU NIDDK, NIH FX We thank Frank Delaglio for assistance and useful discussions. This work was funded by the Intramural Research Program of the NIDDK, NIH. NR 54 TC 153 Z9 154 U1 10 U2 71 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD JUL PY 2013 VL 56 IS 3 BP 227 EP 241 DI 10.1007/s10858-013-9741-y PG 15 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 179TQ UT WOS:000321544600004 PM 23728592 ER PT J AU Chappie, JS Dyda, F AF Chappie, Joshua S. Dyda, Fred TI Building a fission machine - structural insights into dynamin assembly and activation SO JOURNAL OF CELL SCIENCE LA English DT Article DE Membrane fission; Dynamin; Structure; Endocytosis; GTPase; Hydrolysis ID DEPENDENT CONFORMATIONAL-CHANGES; CLATHRIN-MEDIATED ENDOCYTOSIS; PLECKSTRIN HOMOLOGY DOMAIN; GTP-BINDING PROTEINS; CRYSTAL-STRUCTURE; MEMBRANE FISSION; NUCLEOTIDE-FREE; STALK REGION; HYDROLYSIS; MECHANISM AB Dynamin is a large multidomain GTPase that assembles into helical arrays around the necks of deeply invaginated clathrin-coated pits and catalyzes membrane fission during the final stages of endocytosis. Although it is well established that the function of dynamin in vivo depends on its oligomerization and its capacity for efficient GTP hydrolysis, the molecular mechanisms governing these activities have remained poorly defined. In recent years, there has been an explosion of structural data that has provided new insights into the architecture, organization and nucleotide-dependent conformational changes of the dynamin fission machine. Here, we review the key findings of these efforts and discuss the implications of each with regard to GTP hydrolysis, dynamin assembly and membrane fission. C1 [Chappie, Joshua S.; Dyda, Fred] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Chappie, JS (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM chappiej@niddk.nih.gov; dyda@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX The work of our laboratory was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). J.S.C. is supported by a Nancy Nossal Fellowship award from NIDDK. Deposited in PMC for release after 12 months. NR 70 TC 26 Z9 26 U1 0 U2 15 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JUL 1 PY 2013 VL 126 IS 13 BP 2773 EP 2784 DI 10.1242/jcs.108845 PG 12 WC Cell Biology SC Cell Biology GA 173VH UT WOS:000321109200003 PM 23781021 ER PT J AU Rizzo, G Veronese, M Zanotti-Fregonara, P Bertoldo, A AF Rizzo, Gaia Veronese, Mattia Zanotti-Fregonara, Paolo Bertoldo, Alessandra TI Voxelwise quantification of [C-11](R)-rolipram PET data: a comparison between model-based and data-driven methods SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE parametric images; positron-emission tomography; spectral analysis; voxelwise quantification; [C-11](R)-rolipram ID POSITRON-EMISSION-TOMOGRAPHY; MAJOR DEPRESSIVE DISORDER; SPECTRAL-ANALYSIS; SUICIDE VICTIMS; INPUT FUNCTION; ANTIDEPRESSANT TREATMENT; GRAPHICAL ANALYSIS; TEMPORAL CORTEX; BRAIN IMAGES; OPTIMIZATION AB This study compared model-based and data-driven methods to assess the best methodology for generating precise and accurate parametric maps of the parameters of interest in [C-11](R)-rolipram brain positron-emission tomography studies. Parametric images were generated using (1) a two-tissue compartmental model (2TCM) solved with the hierarchical basis function method (H-BFM) linear estimator; (2) data-driven spectral-based methods: standard spectral analysis (std SA) and rank-shaping SA (RS); and (3) the Logan graphical plot. Nonphysiologic V-T estimates were eliminated and the remaining ones were compared with the reference values, i.e., those obtained with a voxelwise 2TCM solved with a nonlinear estimator. With regard to voxelwise V-T estimates, H-BFM showed the best agreement with weighted nonlinear least square (WNLLS) values and the lowest percentage of mean relative difference (1+/-1%). All methods showed comparable variability in the relative differences. H-BFM provided the best correlation with WNLLS (y=1.034x-0.013; R-2=0.973). Despite a slight bias, the other three methods also showed good agreement and high correlation (R-2>0.96). H-BFM yielded the most reliable voxelwise quantification of [C-11](R)-rolipram as well as the complete description of the tracer kinetic. The Logan plot represents a valid alternative if only V-T estimation is required. Its marginally higher bias was outweighed by a low computational time, ease of implementation, and robustness. C1 [Rizzo, Gaia; Veronese, Mattia; Bertoldo, Alessandra] Univ Padua, Dept Informat Engn, I-35131 Padua, Italy. [Zanotti-Fregonara, Paolo] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Bertoldo, A (reprint author), Univ Padua, Dept Informat Engn, Via G Gradenigo 6-B, I-35131 Padua, Italy. EM bertoldo@dei.unipd.it RI Rizzo, Gaia/A-8697-2013; Veronese, Mattia/A-6012-2013; OI Rizzo, Gaia/0000-0001-7272-8576; Veronese, Mattia/0000-0003-3562-0683; Bertoldo, Alessandra/0000-0002-6262-6354 FU Intramural Research Program, National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX This work was supported in part by the Intramural Research Program, National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). NR 32 TC 4 Z9 4 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUL PY 2013 VL 33 IS 7 BP 1032 EP 1040 DI 10.1038/jcbfm.2013.43 PG 9 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 174VW UT WOS:000321185800008 PM 23512132 ER PT J AU Barrington, DS James, SA AF Barrington, Debbie S. James, Sherman A. TI CHILDHOOD FAMILY STRUCTURE AND ADULT HYPERTENSION AMONG AFRICAN AMERICANS: THE PITT COUNTY STUDY SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Meeting Abstract DE African Americans; Hypertension; Family Characteristics; Social Conditions C1 [Barrington, Debbie S.] Natl Inst Minor Hlth & Hlth Dispar, Bethesda, MD USA. [James, Sherman A.] Duke Univ, Durham, 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 1524-6175 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD JUL PY 2013 VL 15 IS 7 BP 519 EP 520 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 174YP UT WOS:000321194700025 ER PT J AU Romero, R Chaiworapongsa, T AF Romero, Roberto Chaiworapongsa, Tinnakorn TI Preeclampsia: a link between trophoblast dysregulation and an antiangiogenic state SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID PREGNANCY-INDUCED HYPERTENSION; ELEVATED LIVER-ENZYMES; LOW PLATELET COUNT; HUMAN CYTOTROPHOBLASTS; ENDOVASCULAR INVASION; CLINICAL-SIGNIFICANCE; ANGIOGENIC FACTORS; NATURAL-HISTORY; RISK; DISEASE AB A 24-year-old nulliparous woman developed mildly elevated blood pressure (140-150/90-100 mmHg) without proteinuria (20 mg protein in a 24-hour urine collection) at 30(6/7) weeks of gestation. The fetus was small for gestational age (estimated fetal weight under the fifth percentile). At 32(5/7) weeks of gestation, the patient complained of epigastric pain, blood pressure was 180/110 mmHg, proteinuria was documented (780 mg protein in a 24-hour urine collection), schistocytes were detected in the peripheral smear, platelet count was 60,000 cells per mm(3), and serum glutamic oxaloacetic transaminase was 234 U/1. The patient was diagnosed with severe preeclampsia/HELLP syndrome. Antenatal steroids were administered to induce fetal lung maturity. She and her family want to know the causes of this condition, what treatment is available, and whether there are any longterm implications of this diagnosis. C1 [Romero, Roberto; Chaiworapongsa, Tinnakorn] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. [Chaiworapongsa, Tinnakorn] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Romero, R (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS, 3990 John R,4 Brush South, Detroit, MI 48201 USA. EM romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); federal funds from NICHD, NIH [HSN275201300006C] FX This work was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH) and, in part, with federal funds from NICHD, NIH, under contract no. HSN275201300006C. NR 47 TC 11 Z9 11 U1 1 U2 10 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2013 VL 123 IS 7 BP 2775 EP 2777 DI 10.1172/JCI70431 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 176PN UT WOS:000321316700005 PM 23934119 ER PT J AU Marquardt, JU Thorgeirsson, SS AF Marquardt, Jens U. Thorgeirsson, Snorri S. TI Linking MLL and the HGF-MET signaling pathway in liver cancer SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID HEPATOCELLULAR-CARCINOMA; GROWTH; REGENERATION; EXPRESSION; TIVANTINIB; MUTATIONS; LEUKEMIA; THERAPY; AGENTS; MICE AB Mixed-lineage leukemia (MLL; also known as myeloid/lymphoid), the human homolog of trithorax in Drosophila, is a transcriptional coactivator that plays an essential role during early development and hematopoiesis. Furthermore, MLL is critically involved in the epigenetic regulation of cell cycle, senescence, DNA damage, and stem cell self-renewal. Chromosomal aberrations of MLL in acute leukemias are well documented, but the role of this gene in solid malignancies remains unclear. In this issue of the JCI, Takeda et al. describe a novel epigenetic link between MLL and the HGF-MET signaling pathway conferring invasive and metastatic properties to hepatocellular carcinoma cells. C1 [Marquardt, Jens U.; Thorgeirsson, Snorri S.] NCI, LEC, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Marquardt, Jens U.] Johannes Gutenberg Univ Mainz, Dept Med 1, Mainz, Germany. RP Thorgeirsson, SS (reprint author), NCI, LEC, Ctr Canc Res, NIH, 37 Convent Dr,Room 4146, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov NR 26 TC 2 Z9 2 U1 0 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2013 VL 123 IS 7 BP 2780 EP 2783 DI 10.1172/JCI70235 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 176PN UT WOS:000321316700007 PM 23934122 ER PT J AU Boonnak, K Vogel, L Orandle, M Zimmerman, D Talor, E Subbarao, K AF Boonnak, Kobporn Vogel, Leatrice Orandle, Marlene Zimmerman, Daniel Talor, Eyal Subbarao, Kanta TI Antigen-activated dendritic cells ameliorate influenza A infections SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HERPES-SIMPLEX-VIRUS; MOUSE BONE-MARROW; IMMUNE-RESPONSES; LEAPS(TM) HETEROCONJUGATE; RESISTANT INFLUENZA; CYTOKINE STORM; TH1 RESPONSES; H5N1 VIRUS; IN-VITRO; VACCINES AB Influenza A viruses cause significant morbidity and mortality worldwide. There is a need for alternative or adjunct therapies, as resistance to currently used antiviral drugs is emerging rapidly. We tested ligand epitope antigen presentation system (LEAPS) technology as a new immune-based treatment for influenza virus infection in a mouse model. Lnfluenza-J-LEAPS peptides were synthesized by conjugating the binding ligand derived from the beta(2)-microglobulin chain of the human MHC class I molecule (J-LEAPS) with 15 to 30 amino acid-long peptides derived from influenza virus NP, M, or HA proteins. DCs were stimulated with influenza-J-LEAPS peptides (influenza-J-LEAPS) and injected intravenously into infected mice. Antigen-specific LEAPS-stimulated DCs were effective in reducing influenza virus replication in the lungs and enhancing survival of infected animals. Additionally, they augmented influenza-specific T cell responses in the lungs and reduced the severity of disease by limiting excessive cytokine responses, which are known to contribute to morbidity and mortality following influenza virus infection. Our data demonstrate that influenza-J-LEAPS-pulsed DCs reduce virus replication in the lungs, enhance survival, and modulate the protective immune responses that eliminate the virus while preventing excessive cytokines that could injure the host. This approach shows promise as an adjunct to antiviral treatment of influenza virus infections. C1 [Boonnak, Kobporn; Vogel, Leatrice; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Orandle, Marlene] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. [Zimmerman, Daniel; Talor, Eyal] CEL SCI Corp, Vienna, VA USA. RP Subbarao, K (reprint author), NIAID, Emerging Resp Viruses Sect, Infect Dis Lab, NIH, Bldg 33,Room 3E13C 1,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM KSUBBARAO@niaid.nih.gov FU NIAID, NIH FX This research was supported in part by the Intramural Research Program of the NIAID, NIH. All the peptides tested in this project were supplied by CEL-SCI Corp. We would like to thank Mat-thew Memoli and Jeffery Taubenberger for providing A/Bethesda/NIH107-D31/2009 (H1N1), the oseltamivir-resistant virus. NR 42 TC 6 Z9 6 U1 0 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2013 VL 123 IS 7 BP 2850 EP 2861 DI 10.1172/JCI67550 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 176PN UT WOS:000321316700015 PM 23934125 ER PT J AU Singh, A Happel, C Manna, SK Acquaah-Mensah, G Carrerero, J Kumar, S Nasipuri, P Krausz, KW Wakabayashi, N Dewi, R Boros, LG Gonzalez, FJ Gabrielson, E Wong, KK Girnun, G Biswal, S AF Singh, Anju Happel, Christine Manna, Soumen K. Acquaah-Mensah, George Carrerero, Julian Kumar, Sarvesh Nasipuri, Poonam Krausz, Kristopher W. Wakabayashi, Nobunao Dewi, Ruby Boros, Laszlo G. Gonzalez, Frank J. Gabrielson, Edward Wong, Kwok K. Girnun, Geoffrey Biswal, Shyam TI Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID LUNG-CANCER CELLS; PROSTATE-CANCER; NRF2-REGULATED GENES; MASS ISOTOPOMER; RECEPTOR-ALPHA; PENTOSE CYCLE; NUCLEIC-ACID; TUMOR-GROWTH; HUMAN BREAST; E3 LIGASE AB The mechanisms by which deregulated nuclear factor erythroid-2-related factor 2 (NRF2) and kelch-like ECH-associated protein 1 (KEAP1) signaling promote cellular proliferation and tumorigenesis are poorly understood. Using an integrated genomics and C-13-based targeted tracer fate association (TTFA) study, we found that NRF2 regulates miR-1 and miR-206 to direct carbon flux toward the pentose phosphate pathway (PPP) and the tricarboxylic acid (TCA) cycle, reprogramming glucose metabolism. Sustained activation of NRF2 signaling in cancer cells attenuated miR-1 and miR-206 expression, leading to enhanced expression of PPP genes. Conversely, overexpression of miR-1 and miR-206 decreased the expression of metabolic genes and dramatically impaired NADPH production, ribose synthesis, and in vivo tumor growth in mice. Loss of NRF2 decreased the expression of the redox-sensitive histone deacetylase, HDAC4, resulting in increased expression of miR-1 and miR-206, and not only inhibiting PPP expression and activity but functioning as a regulatory feedback loop that repressed HDAC4 expression. In primary tumor samples, the expression of miR-1 and miR-206 was inversely correlated with PPP gene expression, and increased expression of NRF2-dependent genes was associated with poor prognosis. Our results demonstrate that microRNA-dependent (miRNA-dependent) regulation of the PPP via NRF2 and HDAC4 represents a novel link between miRNA regulation, glucose metabolism, and ROS homeostasis in cancer cells. C1 [Singh, Anju; Happel, Christine; Kumar, Sarvesh; Nasipuri, Poonam; Biswal, Shyam] Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Manna, Soumen K.; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Acquaah-Mensah, George] Massachusetts Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Worcester, MA USA. [Carrerero, Julian; Wong, Kwok K.] Univ Valencia, Dept Physiol, Valencia, Spain. [Wakabayashi, Nobunao] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Dewi, Ruby; Girnun, Geoffrey] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Boros, Laszlo G.] SIDMAP LLC, Los Angeles, CA USA. [Boros, Laszlo G.] Harbor UCLA Med Ctr, Dept Pediat, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Gabrielson, Edward; Biswal, Shyam] Johns Hopkins Univ, Dept Oncol, Sidney Kimmel Comprehens Canc Ctr, Sch Med, Baltimore, MD 21205 USA. [Wong, Kwok K.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Biswal, S (reprint author), Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, E7624,615 North St, Baltimore, MD 21205 USA. EM asingh1@jhsph.edu; ggirnun@som.umaryland.edu; sbiswal@jhsph.edu RI Carretero, Julian/N-5214-2014; OI Carretero, Julian/0000-0001-7269-8506; Acquaah-Mensah, George/0000-0003-3984-8327 FU NIH [RO1 CA140492]; National Cancer Institute SPORE [P50 CA058184, P30ES03819, P30CA006973]; Maryland Cigarette Restitution Fund; National Research Service Award from the National Cancer Institute [NRSA-F32]; Flight Attendant Medical Research Institute; National Cancer Institute [122794, 166480, 163896, 140594, 141576]; Young Clinical Innovator Award FX This work was supported by NIH grant RO1 CA140492 (to S. Biswal); National Cancer Institute SPORE grants P50 CA058184 (to S. Biswal), P30ES03819, and P30CA006973; a research grant from the Maryland Cigarette Restitution Fund (to S. Biswal and G. Girnun); a National Research Service Award (NRSA-F32) from the National Cancer Institute (to C. Happel); a Young Clinical Innovator Award (to S. Biswal); and a Young Clinical Scientist Award (to A. Singh) from the Flight Attendant Medical Research Institute. K.K. Wong is supported by National Cancer Institute grants 122794, 166480, 163896,140594, and 141576. NR 57 TC 78 Z9 81 U1 1 U2 31 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2013 VL 123 IS 7 BP 2921 EP 2934 DI 10.1172/JCI66353 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 176PN UT WOS:000321316700020 PM 23921124 ER PT J AU Callicott, JH Feighery, EL Mattay, VS White, MG Chen, Q Baranger, DAA Berman, KF Lu, B Song, HJ Ming, GL Weinberger, DR AF Callicott, Joseph H. Feighery, Emer L. Mattay, Venkata S. White, Michael G. Chen, Qiang Baranger, David A. A. Berman, Karen F. Lu, Bai Song, Hongjun Ming, Guo-li Weinberger, Daniel R. TI DISC1 and SLC12A2 interaction affects human hippocampal function and connectivity SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID SCHIZOPHRENIA; RISK; ASSOCIATION; DYSFUNCTION; MEMORY; MICE AB Hippocampal development is coordinated by both extracellular factors like GABA neurotransmission and intracellular components like DISCI. We previously reported that SLC12A2-dependent GABA depolarization and DISC1 coregulate hippocampal neuronal development, and 2 SNPs in these genes linked to mRNA expression interactively increase schizophrenia risk. Using functional MRI, we now confirm this biological interaction in vivo by showing in 2 independent samples of healthy individuals (total N = 349) that subjects homozygous for both risk alleles evince dramatically decreased hippocampal area activation (Cohen's d = 0.78) and connectivity (d = 0.57) during a recognition memory task. These data highlight the importance of epistatic models in understanding genetic association with complex brain phenotypes. C1 [Callicott, Joseph H.; Feighery, Emer L.; Mattay, Venkata S.; White, Michael G.; Chen, Qiang; Baranger, David A. A.; Berman, Karen F.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, Div Intramural Programs, NIH, Bethesda, MD 20892 USA. [Mattay, Venkata S.; Chen, Qiang; Weinberger, Daniel R.] Lieber Inst Brain Dev, Baltimore, MD USA. [Lu, Bai] GlaxoSmithKline, R&D China, Shanghai, Peoples R China. [Song, Hongjun; Ming, Guo-li] Johns Hopkins Univ, Sch Med, Dept Neurol, Inst Cell Engn, Baltimore, MD 21205 USA. [Song, Hongjun; Ming, Guo-li] Johns Hopkins Univ, Sch Med, Dept Neurosci, Inst Cell Engn, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. RP Callicott, JH (reprint author), NIMH, Unit Dynam Imaging Genet, Clin Brain Disorders Branch, DIRP,NIH, 10 Ctr Dr,Room 3C-117,MSC 1379, Bethesda, MD 20892 USA. EM callicottj@mail.nih.gov RI Ming, Guo-li/J-7880-2013; Callicott, Joseph/C-9102-2009 OI Callicott, Joseph/0000-0003-1298-3334 FU NIMH FX Federal funding was from the NIMH Intramural Research Programs (to Daniel R. Weinberger). We would like to thank our patients and their families for participating in our research. NR 26 TC 13 Z9 13 U1 2 U2 15 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2013 VL 123 IS 7 BP 2961 EP 2964 DI 10.1172/JCI67510 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 176PN UT WOS:000321316700023 PM 23921125 ER PT J AU Gozalo, AS Zerfas, PM Starost, MF Lambert, LE Elkins, WR AF Gozalo, A. S. Zerfas, P. M. Starost, M. F. Lambert, L. E. Elkins, W. R. TI Pancreatic Endocrine Tumour with Disseminated Pulmonary Thromboembolism in an Owl Monkey (Aotus nancymae) SO JOURNAL OF COMPARATIVE PATHOLOGY LA English DT Article DE immunohistochemistry; islet cell neoplasia; non-human primate; owl monkey ID NEOPLASMS; NEUROENDOCRINE; PRIMATES; CANCER AB Pulmonary thromboembolism associated with pancreatic endocrine neoplasia is extremely uncommon in man and animals. Post-mortem examination of an adult owl monkey (Aotus nancymae) revealed extensive pulmonary arterial thromboembolism and a well-demarcated mass attached to the pancreas. Microscopically, the mass consisted of areas of interstitial fibrosis with loss of acini and islets and replacement by nests and sheets of polygonal cells with amphophilic cytoplasm, an eccentric round nucleus with stippled chromatin and, in some cells, with a single prominent eccentric nucleolus. Clusters of these cells were noted within vessels and adjacent lymph nodes. The cells did not express S100 or insulin, but were labelled strongly with SP-1/chromogranin. Rare individual cells expressed glucagon and somatostatin. A few cells in pulmonary thrombi/emboli and the adjacent lymph node also expressed SP-1/chromogranin. Based on cell morphology, location and immunohistochemistry the tumour was classified as pancreatic endocrine (islet cell) carcinoma with metastasis to regional lymph nodes and lung. Published by Elsevier Ltd. C1 [Gozalo, A. S.; Elkins, W. R.] NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. [Zerfas, P. M.; Starost, M. F.] NIH, Div Vet Resources, Off Director, Bethesda, MD 20892 USA. [Lambert, L. E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Bethesda, MD 20892 USA. [Lambert, L. E.] Chalk River Labs, Germantown, MD USA. RP Gozalo, AS (reprint author), NIAID, Comparat Med Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gozaloa@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Comparative Medicine Branch, Laboratory of Malaria Immunology and Vaccinology; Office of Research Services FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Comparative Medicine Branch, Laboratory of Malaria Immunology and Vaccinology and the Office of Research Services. We thank Dr. P. Duffy for kindly letting us use the tissues from this animal. NR 19 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9975 J9 J COMP PATHOL JI J. Comp. Pathol. PD JUL PY 2013 VL 149 IS 1 BP 132 EP 136 DI 10.1016/j.jcpa.2012.11.235 PG 5 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 174LW UT WOS:000321158000016 PM 23453490 ER PT J AU Quick, VM Byrd-Bredbenner, C AF Quick, V. M. Byrd-Bredbenner, C. TI Disturbed eating behaviours and associated psychographic characteristics of college students SO JOURNAL OF HUMAN NUTRITION AND DIETETICS LA English DT Article DE body image; college students; disturbed eating; psychographic characteristics ID DISORDER EXAMINATION QUESTIONNAIRE; BODY-IMAGE; BULIMIA-NERVOSA; SELF-ESTEEM; WOMEN; OBESITY; PREVALENCE; TRANSITION; DEPRESSION; ADULTHOOD AB Background Young adulthood is a stressful transition period that may increase the risk for disturbed eating, especially for college students. The present study aimed to explore disturbed eating behaviours and a broad array of associated psychographic characteristics in a large, diverse sample of college students. Methods College students (n=2604; 58% white; 63% female) enrolled at three large, public US universities in 2009 and 2010 were recruited to take an online survey. The survey included reliable and valid disturbed eating behaviour and associated psychographic characteristic measures. Results Many participants engaged in disturbed eating practices. For example, one-quarter of women and one-fifth of men engaged in dietary restraint. One in seven reported regularly binge eating. One-third used inappropriate compensatory behaviours (self-induced vomiting, medicine misuse and excessive exercise) as a means for controlling weight and/or shape, with the rate of these behaviours reaching clinically significant levels for 4%, 3% and 5% of participants, respectively. Examination of psychographic characteristics revealed that one-fifth had moderate levels of depression and anxiety severity and almost half engaged in at least one obsessive-compulsive disorder type behaviour. Females felt under more pressure to attain the media physical appearance standard than males. Conclusions The findings of the present study suggest that nutrition education interventions for college students may be needed to address disturbed eating behaviours and to provide guidance on how to seek professional help. The findings also suggest that it may be prudent for healthcare professionals to routinely screen college students for disturbed eating behaviours and offer interventions early when treatment is likely to be most effective. C1 [Quick, V. M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Byrd-Bredbenner, C.] Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08903 USA. RP Quick, VM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Rm 7B13E, Bethesda, MD USA. EM gingermquick@gmail.com RI Byrd-Bredbenner, Carol/F-8064-2015; OI Byrd-Bredbenner, Carol/0000-0002-8010-3987; Quick, Virginia/0000-0002-4338-963X FU Kappa Omicron Nu Research Fellowship FX This study was supported by a Kappa Omicron Nu Research Fellowship. NR 77 TC 7 Z9 7 U1 4 U2 55 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3871 EI 1365-277X J9 J HUM NUTR DIET JI J. Hum. Nutr. Diet. PD JUL PY 2013 VL 26 SU 1 SI SI BP 53 EP 63 DI 10.1111/jhn.12060 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 168RE UT WOS:000320722400008 PM 23627697 ER PT J AU Lindeman, NI Cagle, PT Beasley, MB Chitale, DA Dacic, S Giaccone, G Jenkins, RB Kwiatkowski, DJ Saldivar, JS Squire, J Thunnissen, E Ladanyi, M AF Lindeman, Neal I. Cagle, Philip T. Beasley, Mary Beth Chitale, Dhananjay Arun Dacic, Sanja Giaccone, Giuseppe Jenkins, Robert Brian Kwiatkowski, David J. Saldivar, Juan-Sebastian Squire, Jeremy Thunnissen, Erik Ladanyi, Marc TI Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; FACTOR-RECEPTOR GENE; IN-SITU-HYBRIDIZATION; POLYMERASE-CHAIN-REACTION; MUTATION-SPECIFIC ANTIBODIES; RESOLUTION MELTING ANALYSIS; PERFORMANCE LIQUID-CHROMATOGRAPHY; CHEMOTHERAPY-NAIVE PATIENTS; EML4-ALK FUSION GENE; SMART-AMPLIFICATION PROCESS AB Objective: To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Participants: Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Evidence: Three unbiased literature searches of electronic databases were performed to capture published articles from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. Consensus Process: Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). Conclusions: The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic Lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines. C1 [Lindeman, Neal I.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kwiatkowski, David J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Cagle, Philip T.] Methodist Hosp, Dept Pathol & Genom Med, Houston, TX 77030 USA. [Beasley, Mary Beth] Mt Sinai Med Ctr, Dept Pathol, New York, NY 10029 USA. [Chitale, Dhananjay Arun] Henry Ford Hosp, Dept Pathol, Detroit, MI 48202 USA. [Dacic, Sanja] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA USA. [Giaccone, Giuseppe] NIH, Med Oncol Branch, Bethesda, MD 20892 USA. [Jenkins, Robert Brian] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Jenkins, Robert Brian] Mayo Clin, Dept Lab Genet, Rochester, MN USA. [Saldivar, Juan-Sebastian] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Squire, Jeremy] Queens Univ, Dept Pathol & Mol Med, Kingston Gen Hosp, Kingston, ON, Canada. [Thunnissen, Erik] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Lindeman, NI (reprint author), Brigham & Womens Hosp, Shapiro 5020,75 Francis St, Boston, MA 02115 USA. EM nlindeman@partners.org FU College of American Pathologists (CAP); International Association for the Study of Lung Cancer (IASLC); Association for Molecular Pathology (AMP); Emory University; New York University; Oklahoma State Association of Pathologists; University of Michigan; Massachusetts General Hospital; Pennsylvania Breast Cancer Coalition; Department of Defense; Susan G. Komen for the Cure; National Institutes of Health; Millenium; Genzyme; Infinity; Sequenom; Remedica Medical Education; Merck; Pfizer; Eli Lilly; William Beaumont Symposium FX Supported by the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and Association for Molecular Pathology (AMP); no industry funds were used in the development of the guideline.; Philip T. Cagle, MD Lecture fees paid by entity Emory University; New York University; Oklahoma State Association of Pathologists; University of Michigan; Massachusetts General Hospital; Dhananjay A. Chitale, MD Grants Pennsylvania Breast Cancer Coalition; Department of Defense; Susan G. Komen for the Cure; National Institutes of Health; David J. Kwiatkowski, MD, PhD Lecture fees paid by entity Millenium; Marc Ladanyi, MD Lecture fees paid by entity Genzyme (March 2010); Infinity (July 2010); Sequenom (November 2009); Remedica Medical Education (June 2012); Erik Thunnissen, MD, PhD Lecture fees paid by entity Merck; Pfizer; Eli Lilly; Jan A. Nowak, MD, Steering Committee Lecture fees paid by entity William Beaumont Symposium NR 315 TC 163 Z9 167 U1 1 U2 26 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD JUL PY 2013 VL 15 IS 4 BP 415 EP 453 DI 10.1016/j.jmoldx.2013.03.001 PG 39 WC Pathology SC Pathology GA 176PO UT WOS:000321316800002 PM 23562183 ER PT J AU Hembrough, T Thyparambil, S Liao, WL Dafler, MM Abdo, J Bengali, KM Hewitt, SM Bender, RA Krizman, DB Burrows, J AF Hembrough, Todd Thyparambil, Sheeno Liao, Wei-Li Dafler, Marlene M. Abdo, Joseph Bengali, Kathleen M. Hewitt, Stephen M. Bender, Richard A. Krizman, David B. Burrows, Jon TI Application of Selected Reaction Monitoring for Multiplex Quantification of Clinically Validated Biomarkers in Formalin-Fixed, Paraffin-Embedded Tumor Tissue SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID TANDEM MASS-SPECTROMETRY; MESSENGER-RNA EXPRESSION; PROTEOMIC ANALYSIS; BREAST-CANCER; IMMUNOHISTOCHEMISTRY; PROTEIN; TRASTUZUMAB; PERFORMANCE; CARCINOMA; THERAPY AB One of the critical gaps in the clinical diagnostic space is the Lack of quantitative proteomic methods for use on formalin-fixed, paraffin-embedded (FFPE) tissue. Herein, we describe the development of a quantitative, multiplexed, mass spectrometry-based selected reaction monitoring (SRM) assay for four therapeutically important targets: epidermal growth factor receptor, human EGF receptor (HER)-2, HER3, and insulin-like growth factor-1 receptor. These assays were developed using the Liquid Tissue-SRM technology platform, in which FFPE tumor tissues were microdissected, completely solubilized, and then subjected to multiplexed quantitation by SRM mass spectrometry. The assays were preclinically validated by comparing Liquid Tissue-SRM quantitation of FFPE cell Lines with enzyme-Linked immunosorbent assay/electrochemiluminescence quantitation of fresh cells (R-2 > 0.95). Clinical performance was assessed on two cohorts of breast cancer tissue: one cohort of 10 samples with a wide range of HER2 expression and a second cohort of 19 HER2 IHC 3+ tissues. These clinical data demonstrate the feasibility of quantitative, multiplexed clinical analysis of proteomic markers in FFPE tissue. Our findings represent a significant advancement in cancer tissue analysis because multiplexed, quantitative analysis of protein targets in FFPE tumor tissue can be tailored to specific oncological indications to provide the following: i) complementary support for anatomical pathological diagnoses, ii) patient stratification to optimize treatment outcomes and identify drug resistance, and iii) support for the clinical development of novel therapies. C1 [Hembrough, Todd; Thyparambil, Sheeno; Liao, Wei-Li; Dafler, Marlene M.; Abdo, Joseph; Bengali, Kathleen M.; Bender, Richard A.; Krizman, David B.; Burrows, Jon] OncoPlex Diagnost Inc, Rockville, MD 20850 USA. [Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Burrows, J (reprint author), OncoPlex Diagnost Inc, 9620 Med Ctr Dr, Rockville, MD 20850 USA. EM j.burrows@oncoplexdx.com OI Hewitt, Stephen/0000-0001-8283-1788 FU OncoPlex Diagnostics, Inc. FX Supported by OncoPlex Diagnostics, Inc. NR 41 TC 20 Z9 20 U1 0 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD JUL PY 2013 VL 15 IS 4 BP 454 EP 465 DI 10.1016/j.jmoldx.2013.03.002 PG 12 WC Pathology SC Pathology GA 176PO UT WOS:000321316800003 PM 23672976 ER PT J AU Murphy, AP Ban, H Welchman, AE AF Murphy, Aidan P. Ban, Hiroshi Welchman, Andrew E. TI Integration of texture and disparity cues to surface slant in dorsal visual cortex SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE three-dimensional perception; binocular disparity; cue integration; fMRI; multivoxel pattern analysis ID POSTERIOR PARIETAL CORTEX; ANTERIOR INTRAPARIETAL AREA; INFERIOR TEMPORAL CORTEX; HUMAN BRAIN; 3D SHAPE; 3-DIMENSIONAL SHAPE; PSYCHOMETRIC FUNCTION; BINOCULAR DISPARITY; RETINAL DISPARITY; NONHUMAN-PRIMATES AB Reliable estimation of three-dimensional (3D) surface orientation is critical for recognizing and interacting with complex 3D objects in our environment. Human observers maximize the reliability of their estimates of surface slant by integrating multiple depth cues. Texture and binocular disparity are two such cues, but they are qualitatively very different. Existing evidence suggests that representations of surface tilt from each of these cues coincide at the single-neuron level in higher cortical areas. However, the cortical circuits responsible for 1) integration of such qualitatively distinct cues and 2) encoding the slant component of surface orientation have not been assessed. We tested for cortical responses related to slanted plane stimuli that were defined independently by texture, disparity, and combinations of these two cues. We analyzed the discriminability of functional MRI responses to two slant angles using multivariate pattern classification. Responses in visual area V3B/KO to stimuli containing congruent cues were more discriminable than those elicited by single cues, in line with predictions based on the fusion of slant estimates from component cues. This improvement was specific to congruent combinations of cues: incongruent cues yielded lower decoding accuracies, which suggests the robust use of individual cues in cases of large cue conflicts. These data suggest that area V3B/KO is intricately involved in the integration of qualitatively dissimilar depth cues. C1 [Murphy, Aidan P.; Ban, Hiroshi; Welchman, Andrew E.] Univ Birmingham, Sch Psychol, Birmingham B15 2TT, W Midlands, England. [Murphy, Aidan P.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, Bethesda, MD 20892 USA. [Ban, Hiroshi] Japan Soc Promot Sci, Tokyo, Japan. RP Welchman, AE (reprint author), Univ Birmingham, Sch Psychol, Birmingham B15 2TT, W Midlands, England. EM a.e.welchman@bham.ac.uk RI Welchman, Andrew/B-7542-2013 OI Welchman, Andrew/0000-0002-7559-3299 FU Wellcome Trust and National Institutes of Health studentship [WT091467MA]; Japan Society for the Promotion of Science [H22,290]; Wellcome Trust fellowship [095183/Z/10/Z] FX This work was supported by a Wellcome Trust and National Institutes of Health studentship (WT091467MA to A. P. Murphy), the Japan Society for the Promotion of Science (H22,290 to H. Ban), and a Wellcome Trust fellowship (095183/Z/10/Z to A. E. Welchman). NR 101 TC 15 Z9 15 U1 2 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 2013 VL 110 IS 1 BP 190 EP 203 DI 10.1152/jn.01055.2012 PG 14 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 174ZI UT WOS:000321197400020 PM 23576705 ER PT J AU Tosetti, P Hicks, RR Theriault, E Phillips, A Koroshetz, W Draghia-Akli, R AF Tosetti, Patrizia Hicks, Ramona R. Theriault, Elizabeth Phillips, Anthony Koroshetz, Walter Draghia-Akli, Ruxandra CA Workshop Participants TI Toward an International Initiative for Traumatic Brain Injury Research SO JOURNAL OF NEUROTRAUMA LA English DT Article DE geriatric brain injury; head trauma; human studies; pediatric brain injury ID COMMON DATA ELEMENTS; SEVERE HEAD-INJURIES; OUTCOME MEASURES; CLINICAL-TRIALS; WORKING GROUP; RECOMMENDATIONS; MANAGEMENT; CARE; MORTALITY AB The European Commission (EC) and the National Institutes of Health (NIH) jointly sponsored a workshop on October 18-20, 2011 in Brussels to discuss the feasibility and benefits of an international collaboration in the field of traumatic brain injury (TBI) research. The workshop brought together scientists, clinicians, patients, and industry representatives from around the globe as well as funding agencies from the EU, Spain, the United States, and Canada. Sessions tackled both the possible goals and governance of a future initiative and the scientific questions that would most benefit from an integrated international effort: how to optimize data collection and sharing; injury classification; outcome measures; clinical study design; and statistical analysis. There was a clear consensus that increased dialogue and coordination of research at an international level would be beneficial for advancing TBI research, treatment, and care. To this end, the EC, the NIH, and the Canadian Institutes of Health Research expressed interest in developing a framework for an international initiative for TBI Research (InTBIR). The workshop participants recommended that InTBIR initially focus on collecting, standardizing, and sharing clinical TBI data for comparative effectiveness research, which will ultimately result in better management and treatments for TBI. C1 [Tosetti, Patrizia; Draghia-Akli, Ruxandra] DG RTD, European Commiss, Brussels, Belgium. [Hicks, Ramona R.] NINDS, Bethesda, MD 20892 USA. [Theriault, Elizabeth; Phillips, Anthony; Koroshetz, Walter] Canadian Inst Hlth Res, Inst Neurosci Mental Hlth & Addict, Vancouver, BC, Canada. RP Hicks, RR (reprint author), NINDS, Ctr Neurosci, 6001 Executive Blvd,Room 2208, Bethesda, MD 20892 USA. EM hicksra@ninds.nih.gov NR 35 TC 17 Z9 19 U1 0 U2 12 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL PY 2013 VL 30 IS 14 BP 1211 EP 1222 DI 10.1089/neu.2013.2896 PG 12 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 183MV UT WOS:000321821100001 PM 23731282 ER PT J AU Ramkumar, HL Tuo, JS Shen, DF Zhang, J Cao, XG Chew, EY Chan, CC AF Ramkumar, Hema L. Tuo, Jingsheng Shen, De F. Zhang, Jun Cao, Xiaoguang Chew, Emily Y. Chan, Chi-Chao TI Nutrient Supplementation with n3 Polyunsaturated Fatty Acids, Lutein, and Zeaxanthin Decrease A2E Accumulation and VEGF Expression in the Retinas of Ccl2/Cx3cr1-Deficient Mice on Crb1(rd8) Background SO JOURNAL OF NUTRITION LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MACULAR DEGENERATION; NITRIC-OXIDE; EYE DISEASE; PHOTORECEPTOR DEGENERATION; MURINE MODEL; VITAMIN-C; CAROTENOIDS; LIPOFUSCIN; LESIONS AB The Age-Related Eye Diseases Study 2 (AREDS2) clinical trial is assessing the effects of higher dietary xanthophyll (lutein and zeaxanthin) and long-chain n3 polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake on progression to advanced age-related macular degeneration (AMD). This study's purpose was to examine the retinal effects of the AREDS2 formulation on Chemokine (C-C motif) ligand 2 (Ccl2(-/-))/CX3C chemokine receptor 1 (Cx3cr1(-/-)) mice on Crumbs homolog 1 retinal degeneration phenotype 8 (Crb1(rd8)) background (DKO), which develop focal retinal lesions with certain features similar to AMD. DKO and C57BL/6N rd8 background mice (WT) were bred and randomized into 4 groups. Two groups, WT mice on AREDS2 diet (A-WT) and DKO mice on AREDS2 diet (A-DKO), were supplemented daily with 1.76 mu mol of lutein, 35.1 mu mol of zeaxanthin, 215 mu mol EPA, and 107 mu mol of DHA, and 2 control groups, WT mice on control diet (C-WT) and DKO mice on control diet (C-DKO), were fed an isocaloric diet. All mice had monthly fundus photos and were killed after 3 mo for biochemical and histologic analyses. After 3 mo, 81% of A-DKO mice had lesion regression compared with 25% of C-DKO mice (P < 0.05). Toxic retinal 2-[2,6-dimethyl-8(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetra-enyl]-1-(2-hydroxyethyl)-4[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1-yl) 1E,3E,5E,7E-hexatrienyl]-pyridinium (A2E) concentrations were significantly lower in A-DKO compared with C-DKO mice. The outer nuclear layer thickness in A-DKO mice was significantly greater than that in C-DKO mice. Retinal expression of inducible nitric oxide synthase (iNos) tumor necrosis factor-alpha (Tnf-alpha), Cyclooxygenase-2 (Cox-2), interleukin1beta (IL-1 beta), and vascular endothelial growth factor (Vegf) was significantly lower in A-DKO compared with C-DKO mice. Xanthophylls and LCPUFAs have antiinflammatory, neuroprotective, and antiangiogenic properties. Our data provide potential mechanisms by which the AREDS2 formula has a protective effect on retinal lesions in DKO mice. C1 [Ramkumar, Hema L.; Tuo, Jingsheng; Shen, De F.; Cao, Xiaoguang; Chan, Chi-Chao] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Zhang, Jun; Chan, Chi-Chao] NEI, Histol Core, NIH, Bethesda, MD 20892 USA. [Chew, Emily Y.] NEI, NIH, Bethesda, MD 20892 USA. [Ramkumar, Hema L.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Ramkumar, Hema L.] Univ Calif San Diego, Dept Ophthalmol, Shiley Eye Ctr, San Diego, CA 92103 USA. [Cao, Xiaoguang] Peking Univ, Dept Ophthalmol, Peoples Hosp, Beijing 100871, Peoples R China. RP Chan, CC (reprint author), NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov OI Tuo, Jingsheng/0000-0002-1372-7810 FU Intramural Research Program of the National Eye Institute; NIH; Howard Hughes Medical Institute FX Supported by the Intramural Research Program of the National Eye Institute, NIH, and Howard Hughes Medical Institute. NR 52 TC 21 Z9 22 U1 0 U2 12 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUL PY 2013 VL 143 IS 7 BP 1129 EP 1135 DI 10.3945/jn.112.169649 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 170ZT UT WOS:000320894800016 PM 23677863 ER PT J AU Wu, YP Rohan, JM Martin, S Hommel, K Greenley, RN Loiselle, K Ambrosino, J Fredericks, EM AF Wu, Yelena P. Rohan, Jennifer M. Martin, Staci Hommel, Kevin Greenley, Rachel Neff Loiselle, Kristin Ambrosino, Jodie Fredericks, Emily M. TI Pediatric Psychologist Use of Adherence Assessments and Interventions SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Article DE adherence; clinical practice; dissemination; self-management; translational research ID COGNITIVE-BEHAVIORAL THERAPY; QUALITY IMPROVEMENT; HEALTH; DISSEMINATION; CHILDREN; ADOLESCENTS; TRIALS; MODEL; TRANSPORTABILITY; CLINICIAN AB Objective To document current clinical practices for medical regimen adherence assessment and intervention in the field of pediatric psychology. Methods 113 members of the Society of Pediatric Psychology completed an anonymous online survey that assessed use of adherence assessments and interventions in clinical practice, barriers and facilitators to their use, and preferred resources for obtaining information on adherence assessments and interventions. Results Respondents reported using a range of adherence assessment and intervention strategies, some of which are evidence-based. Barriers to implementing these clinical strategies included time constraints and lack of familiarity with available clinical tools. Respondents reported that education about effective clinical tools would facilitate their use of adherence assessments and interventions. Conclusions Future research and clinical efforts in adherence should consider developing practical tools for clinical practice, making accessible resources to promote dissemination of these tools, and increase understanding of clinician implementation of adherence assessments and interventions. C1 [Wu, Yelena P.; Rohan, Jennifer M.; Hommel, Kevin] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Rohan, Jennifer M.] Univ Cincinnati, Dept Psychol, Cincinnati, OH 45221 USA. [Martin, Staci] NCI, NIH, Bethesda, MD 20892 USA. [Hommel, Kevin] Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. [Greenley, Rachel Neff] Rosalind Franklin Univ Med & Sci, Chicago, IL USA. [Loiselle, Kristin] Univ Georgia, Athens, GA 30602 USA. [Ambrosino, Jodie] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Fredericks, Emily M.] Univ Michigan Hlth Syst, Ann Arbor, MI USA. RP Wu, YP (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Behav Med & Clin Psychol, Ctr Promot Treatment Adherence & Self Management, MLC-7039,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM yelena.wu@cchmc.org FU Intramural NIH HHS; NIDDK NIH HHS [K23 DK090202, DK090202] NR 39 TC 4 Z9 5 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-8693 EI 1465-735X J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD JUL PY 2013 VL 38 IS 6 SI SI BP 595 EP 604 DI 10.1093/jpepsy/jst025 PG 10 WC Psychology, Developmental SC Psychology GA 178QR UT WOS:000321463000002 PM 23658375 ER PT J AU De Jesus, LC Pappas, A Shankaran, S Li, L Das, A Bell, EF Stoll, BJ Laptook, AR Walsh, MC Hale, EC Newman, NS Bara, R Higgins, RD AF De Jesus, Lilia C. Pappas, Athina Shankaran, Seetha Li, Lei Das, Abhik Bell, Edward F. Stoll, Barbara J. Laptook, Abbot R. Walsh, Michele C. Hale, Ellen C. Newman, Nancy S. Bara, Rebecca Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst TI Outcomes of Small for Gestational Age Infants Born at < 27 Weeks' Gestation SO JOURNAL OF PEDIATRICS LA English DT Article ID INTRAUTERINE GROWTH RESTRICTION; BIRTH-WEIGHT INFANTS; PRETERM INFANTS; NEURODEVELOPMENTAL OUTCOMES; BRAIN-DEVELOPMENT; CEREBRAL-PALSY; FETAL-GROWTH; MORTALITY; DEXAMETHASONE; BETAMETHASONE AB Objective To determine whether small for gestational age (SGA) infants born at <27 weeks gestational age (GA) are at increased risk for mortality, morbidity, and growth and neurodevelopmental impairment at 18-22 months corrected age. Study design This was a retrospective cohort study from National Institute of Child Health and Human Development Neonatal Research Network's Generic Database and Follow-Up Studies. Infants born at <27 weeks GA between January 2006 and July 2008 were included. SGA was defined as birth weight <10th percentile for GA based on Olsen growth curves. Infants with birth weight >= 10th percentile for GA were classified as non-SGA. Maternal and infant characteristics, neonatal outcomes, and neurodevelopmental data were compared in SGA and non-SGA infants. Neurodevelopmental impairment was defined as any of the following: cognitive score <70 on the Bayley Scales of Infant Development III, moderate or severe cerebral palsy, bilateral hearing loss (with and without amplification), or blindness (bilateral vision <20/200). Logistic regression analysis was applied to evaluate the associations between SGA status and death or neurodevelopmental impairment. Results The SGA group comprised 385 infants; the non-SGA group, 2586 infants. Compared with mothers of non-SGA infants, mothers of SGA infants were more likely to have a high school education, prenatal care, cesarean delivery, pregnancy-induced hypertension, and antenatal corticosteroid exposure. Compared with non-SGA infants, SGA infants had higher mortality and were more likely to have postnatal growth failure, prolonged mechanical ventilation, and postnatal steroid use. SGA status was associated with increased risk of death or neurodevelopmental impairment (OR, 3.91; 95% CI, 2.91-5.25; P < .001). Conclusion SGA status in infants born at <27 weeks GA is associated with an increased likelihood of postnatal steroid use, mortality, growth failure, and neurodevelopmental impairment at 18-22 months corrected age. C1 [De Jesus, Lilia C.; Pappas, Athina; Shankaran, Seetha; Bara, Rebecca] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Li, Lei; Das, Abhik] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Stoll, Barbara J.; Hale, Ellen C.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Laptook, Abbot R.] Brown Univ, Dept Pediat, Providence, RI 02912 USA. [Walsh, Michele C.; Newman, Nancy S.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Hlth & Human Dev, Bethesda, MD USA. RP De Jesus, LC (reprint author), Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. FU The National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Center for Research Resources; National Center for Advancing Translational Sciences FX The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Center for Research Resources, and the National Center for Advancing Translational Sciences provided grant support for the Neonatal Research Network's Generic Database and Follow-up Studies. Data collected at participating sites of the NICHD Neonatal Research Network were transmitted to RTI International, the data coordinating center for the network; which stored, managed and analyzed the data for this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no conflicts of interest. NR 30 TC 22 Z9 23 U1 0 U2 13 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD JUL PY 2013 VL 163 IS 1 BP 55 EP U436 DI 10.1016/j.jpeds.2012.12.097 PG 9 WC Pediatrics SC Pediatrics GA 179BZ UT WOS:000321494000014 PM 23415614 ER PT J AU Movsas, TZ Pinto-Martin, JA Whitaker, AH Feldman, JF Lorenz, JM Korzeniewski, SJ Levy, SE Paneth, N AF Movsas, Tammy Z. Pinto-Martin, Jennifer A. Whitaker, Agnes H. Feldman, Judith F. Lorenz, John M. Korzeniewski, Steven J. Levy, Susan E. Paneth, Nigel TI Autism Spectrum Disorder Is Associated with Ventricular Enlargement in a Low Birth Weight Population SO JOURNAL OF PEDIATRICS LA English DT Article ID CRANIAL ULTRASOUND ABNORMALITIES; WHITE-MATTER; PRETERM INFANTS; INTRAVENTRICULAR HEMORRHAGE; CEREBRAL-PALSY; SCREENING QUESTIONNAIRE; LIKELIHOOD ESTIMATION; COGNITIVE OUTCOMES; PREMATURE-INFANTS; CHILDREN BORN AB Objective To determine the relation of neonatal cranial ultrasound abnormalities to autism spectrum disorders (ASD) in low birth weight (LBW) adult survivors, a population at increased ASD risk. Study design This is a secondary analysis of a prospectively-followed regional birth cohort of 1105 LBW infants systematically screened for perinatal brain injury with cranial ultrasound in the first week of life and later assessed for ASD using a two-stage process [screening at age 16 years (n = 623) followed by diagnostic assessment at age 21 years of a systematically selected subgroup of those screened (n = 189)]; 14 cases of ASD were identified. For this analysis, cranial ultrasound abnormalities were defined as ventricular enlargement (indicative of diffuse white matter injury), parenchymal lesions (indicative of focal white matter injury), and isolated germinal matrix/intraventricular hemorrhage. Results Compared with no cranial ultrasound abnormalities, any type of white matter injury (ventricular enlargement and/or parenchymal lesion) tripled the risk for screening positively for ASD [3.0 (2.2, 4.1)]. However, the risk of being diagnosed with ASD depended on type of white matter injury. With ventricular enlargement, the risk of ASD diagnosis was almost seven-fold that of no cranial ultrasound abnormality [6.7 (2.3, 19.7)], and no elevated risk was found for parenchymal lesion without ventricular enlargement [1.8 (0.2, 13.6)]. Isolated germinal matrix/intraventricular hemorrhage did not increase risk for a positive ASD screen or diagnosis. Conclusion In LBW neonates, cranial ultrasound evidence of ventricular enlargement is a strong and significant risk factor for subsequent development of rigorously-diagnosed ASD. C1 [Movsas, Tammy Z.] Midland Cty Dept Publ Hlth, Midland, MI USA. [Movsas, Tammy Z.] Michigan State Univ, Dept Pediat & Human Dev, Midland, MI 48640 USA. [Pinto-Martin, Jennifer A.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Pinto-Martin, Jennifer A.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Whitaker, Agnes H.; Feldman, Judith F.] Columbia Univ, Med Ctr, New York State Psychiat Inst, Div Child & Adolescent Psychiat,Dept Psychiat, New York, NY 10027 USA. [Lorenz, John M.] Columbia Univ, Dept Pediat, Coll Phys & Surg, Med Ctr, New York, NY 10027 USA. [Korzeniewski, Steven J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatal Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Korzeniewski, Steven J.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Levy, Susan E.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Paneth, Nigel] Michigan State Univ, Dept Epidemiol & Biostat, Coll Human Med, Midland, MI 48640 USA. RP Movsas, TZ (reprint author), Michigan State Univ, Midland Cty Dept Publ Hlth Pediat & Human Dev, 220 West Ellsworth St, Midland, MI 48640 USA. EM tmovsas@gmail.com FU National Institutes of Health (T32 Perinatal Epidemiology Training Grant) [2T32HD046377] FX T.M. was funded by the National Institutes of Health (T32 Perinatal Epidemiology Training Grant 2T32HD046377). The authors declare no conflicts of interest. NR 39 TC 18 Z9 18 U1 1 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD JUL PY 2013 VL 163 IS 1 BP 73 EP 78 DI 10.1016/j.jpeds.2012.12.084 PG 6 WC Pediatrics SC Pediatrics GA 179BZ UT WOS:000321494000017 PM 23410601 ER PT J AU Kent, EE Alfano, CM Smith, AW Bernstein, L McTiernan, A Baumgartner, KB Ballard-Barbash, R AF Kent, Erin E. Alfano, Catherine M. Smith, Ashley Wilder Bernstein, Leslie McTiernan, Anne Baumgartner, Kathy B. Ballard-Barbash, Rachel TI The Roles of Support Seeking and Race/Ethnicity in Posttraumatic Growth Among Breast Cancer Survivors SO JOURNAL OF PSYCHOSOCIAL ONCOLOGY LA English DT Article DE breast cancer; cancer survivor; support group; patient-provider support; posttraumatic growth ID AFRICAN-AMERICAN WOMEN; QUALITY-OF-LIFE; SOCIAL SUPPORT; PROSTATE-CANCER; HEALTH; DIAGNOSIS; BENEFIT; PARTICIPATION; INTERVENTION; DISPARITIES AB Posttraumatic growth (PTG) after cancer can minimize the emotional impact of disease and treatment; however, the facilitators of PTG, including support seeking, are unclear. The authors examined the role of support seeking on PTG among 604 breast cancer survivors ages 40 to 64 from the Health Eating, Activity, and Lifestyle (HEAL) Study. Multivariable linear regression was used to examine predictors of support seeking (participation in support groups and confiding in health care providers) as well as the relationship between support seeking and PTG. Support program participation was moderate (61.1%) compared to the high rates of confiding in health professionals (88.6%), and African Americans were less likely to report participating than non-Hispanic Whites (odds ratio = .14, confidence intervals [0.08, 0.23]). The mean (SD) PTG score was 48.8 (27.4) (range 0-105). Support program participation ( = 10.4) and confiding in health care providers ( = 12.9) were associated (p < .001) with higher PTG. In analyses stratified by race/ethnicity, PTG was significantly higher in non-Hispanic Whites and African American support program participants (p < .01), but not significantly higher in Hispanics/Latinas. Confiding in a health care provider was only associated with PTG for non-Hispanic Whites (p = .02). Support program experiences and patient-provider encounters should be examined to determine which attributes facilitate PTG in diverse populations. C1 [Kent, Erin E.; Alfano, Catherine M.; Smith, Ashley Wilder; Ballard-Barbash, Rachel] NCI, Div Canc Control & Populat Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kent, Erin E.] NCI, Ctr Canc Training, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Dept Canc Etiol, Duarte, CA 91010 USA. [McTiernan, Anne] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98195 USA. [McTiernan, Anne] Univ Washington, Sch Med, Seattle, WA USA. [McTiernan, Anne] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Baumgartner, Kathy B.] Univ Louisville, Dept Epidemiol & Clin Informat Sci, Louisville, KY 40292 USA. RP Kent, EE (reprint author), NCI, Outcomes Res Branch, 9609 Med Ctr Dr,3E 430, Bethesda, MD 20892 USA. EM Erin.Kent@nih.gov FU NCI NIH HHS [N01-CN-05228, N01-CN-75036-20, N01 CN005228, N01 PC067010] NR 51 TC 3 Z9 4 U1 0 U2 9 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0734-7332 J9 J PSYCHOSOC ONCOL JI J. Psychosoc. Oncol. PD JUL 1 PY 2013 VL 31 IS 4 BP 393 EP 412 DI 10.1080/07347332.2013.798759 PG 20 WC Psychology, Social SC Psychology GA 180PJ UT WOS:000321606800003 PM 23844921 ER PT J AU Xu, JF Zheng, G Yuan, A AF Xu, Jinfeng Zheng, Gang Yuan, Ao TI Case-control genome-wide joint association study using semiparametric empirical model and approximate Bayes factor SO JOURNAL OF STATISTICAL COMPUTATION AND SIMULATION LA English DT Article DE approximate Bayes factor; association study; empirical likelihood; genetic model; Hardy-Weinberg equilibrium; profile likelihood; robustness; side information ID MAXIMUM-LIKELIHOOD; DISEASE; INDEPENDENCE; REGRESSION; TESTS AB We propose a semiparametric approach for the analysis of case-control genome-wide association study. Parametric components are used to model both the conditional distribution of the case status given the covariates and the distribution of genotype counts, whereas the distribution of the covariates are modelled nonparametrically. This yields a direct and joint modelling of the case status, covariates and genotype counts, and gives a better understanding of the disease mechanism and results in more reliable conclusions. Side information, such as the disease prevalence, can be conveniently incorporated into the model by an empirical likelihood approach and leads to more efficient estimates and a powerful test in the detection of disease-associated SNPs. Profiling is used to eliminate a nuisance nonparametric component, and the resulting profile empirical likelihood estimates are shown to be consistent and asymptotically normal. For the hypothesis test on disease association, we apply the approximate Bayes factor (ABF) which is computationally simple and most desirable in genome-wide association studies where hundreds of thousands to a million genetic markers are tested. We treat the approximate Bayes factor as a hybrid Bayes factor which replaces the full data by the maximum likelihood estimates of the parameters of interest in the full model and derive it under a general setting. The deviation from Hardy-Weinberg Equilibrium (HWE) is also taken into account and the ABF for HWE using cases is shown to provide evidence of association between a disease and a genetic marker. Simulation studies and an application are further provided to illustrate the utility of the proposed methodology. C1 [Xu, Jinfeng] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117546, Singapore. [Zheng, Gang] NHLBI, Off Biostat Res, DPPS, Bethesda, MD 20892 USA. [Yuan, Ao] Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. RP Yuan, A (reprint author), Howard Univ, Natl Human Genome Ctr, 2216 6th St NW, Washington, DC 20059 USA. EM yuanao@hotmail.com OI Xu, Jinfeng/0000-0002-3165-2015 FU National Center for Research Resources at NIH [2G12RR003048] FX This work is supported in part by the National Center for Research Resources at NIH grant 2G12RR003048. NR 22 TC 0 Z9 0 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0094-9655 EI 1563-5163 J9 J STAT COMPUT SIM JI J. Stat. Comput. Simul. PD JUL 1 PY 2013 VL 83 IS 7 BP 1191 EP 1209 DI 10.1080/00949655.2011.654119 PG 19 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 181TE UT WOS:000321690600001 PM 24532860 ER PT J AU Lindeman, NI Cagle, PT Beasley, MB Chitale, DA Dacic, S Giaccone, G Jenkins, RB Kwiatkowski, DJ Saldivar, JS Squire, J Thunnissen, E Ladanyi, M AF Lindeman, Neal I. Cagle, Philip T. Beasley, Mary Beth Chitale, Dhananjay Arun Dacic, Sanja Giaccone, Giuseppe Jenkins, Robert Brian Kwiatkowski, David J. Saldivar, Juan-Sebastian Squire, Jeremy Thunnissen, Erik Ladanyi, Marc TI Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; FACTOR-RECEPTOR GENE; IN-SITU-HYBRIDIZATION; POLYMERASE-CHAIN-REACTION; MUTATION-SPECIFIC ANTIBODIES; RESOLUTION MELTING ANALYSIS; PERFORMANCE LIQUID-CHROMATOGRAPHY; CHEMOTHERAPY-NAIVE PATIENTS; EML4-ALK FUSION GENE; SMART-AMPLIFICATION PROCESS AB Objective: To establish evidence-based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Participants: Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Evidence: Three unbiased literature searches of electronic databases were performed to capture articles published published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. Consensus Process: Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). Conclusions: The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines. C1 [Lindeman, Neal I.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kwiatkowski, David J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Cagle, Philip T.] Methodist Hosp, Dept Pathol & Genom Med, Houston, TX 77030 USA. [Beasley, Mary Beth] Mt Sinai Med Ctr, Dept Pathol, New York, NY 10029 USA. [Chitale, Dhananjay Arun] Henry Ford Hosp, Dept Pathol, Detroit, MI 48202 USA. [Dacic, Sanja] Univ Pittsburgh, Dept Pathol, Med Ctr, Pittsburgh, PA USA. [Giaccone, Giuseppe] NIH, Med Oncol Branch, Bethesda, MD 20892 USA. [Jenkins, Robert Brian] Mayo Clin, Dept Lab Genet, Dept Lab Med & Pathol, Rochester, MN USA. [Saldivar, Juan-Sebastian] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Squire, Jeremy] Queens Univ, Kingston Gen Hosp, Dept Pathol & Mol Med, Kingston, ON, Canada. [Thunnissen, Erik] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Lindeman, NI (reprint author), Brigham & Womens Hosp, Shapiro 5020,75 Francis St, Boston, MA 02115 USA. EM nlindeman@part-ners.org RI Mendez, Pedro /J-8955-2016; Giaccone, Giuseppe/E-8297-2017 OI Mendez, Pedro /0000-0001-6713-7907; Giaccone, Giuseppe/0000-0002-5023-7562 FU NCI NIH HHS [P01 CA129243] NR 318 TC 255 Z9 265 U1 6 U2 37 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JUL PY 2013 VL 8 IS 7 BP 823 EP 859 DI 10.1097/JTO.0b013e318290868f PG 37 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 170VY UT WOS:000320884100010 PM 23552377 ER PT J AU Ankerst, DP Till, C Boeck, A Goodman, P Tangen, CM Feng, ZD Partin, AW Chan, DW Sokoll, L Kagan, J Wei, JT Thompson, IM AF Ankerst, Donna P. Till, Cathee Boeck, Andreas Goodman, Phyllis Tangen, Catherine M. Feng, Ziding Partin, Alan W. Chan, Daniel W. Sokoll, Lori Kagan, Jacob Wei, John T. Thompson, Ian M. TI The Impact of Prostate Volume, Number of Biopsy Cores and American Urological Association Symptom Score on the Sensitivity of Cancer Detection Using the Prostate Cancer Prevention Trial Risk Calculator SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; risk; algorithms; early detection of cancer ID DETECTION RESEARCH NETWORK; COLLABORATIVE GROUP; VALIDATION; ANTIGEN AB Purpose: We assessed the independent predictive value of prostate volume, number of biopsy cores and AUASS (American Urological Association symptom score) compared to risk factors included in the PCPTRC (Prostate Cancer Prevention Trial risk calculator for prostate cancer) and PCPTHG (Prostate Cancer Prevention Trial risk calculator for high grade cancer [Gleason grade 7 or greater]). Materials and Methods: Of 5,519 PCPT (Prostate Cancer Prevention Trial) participants used to construct the PCPTRC 4,958 with AUASS and prostate specific antigen 10 ng/ml or less were included on logistic regression analysis. Risk algorithms were evaluated in 571 EDRN (Early Detection Research Network) participants using the ROC AUC. Results: A total of 1,094 participants (22.1%) had prostate cancer, of whom 232 (21.2%) had high grade disease. For prostate cancer prediction higher prostate specific antigen, abnormal digital rectal examination, family history of prostate cancer and number of cores were associated with increased risk, while volume was associated with decreased risk. Excluding prostate volume and number of cores, a history of negative biopsy and increased AUASS were also associated with lower risk. For high grade cancer higher prostate specific antigen, abnormal digital rectal examination, black race and number of cores were associated with increased risk and volume, while AUASS was associated with decreased risk. The AUC of the PCPTRC adjusted for volume and number of cores was 72.7% (using EDRN data), 68.2% when adjusted for AUASS alone and 67.6% PCPTRC. For high grade disease the AUCs were 74.8%, 74.0% and 73.5% (PCPTHG), respectively. Conclusions: Adjusted PCPT risk calculators for volume, number of cores and AUASS improve cancer detection. C1 [Ankerst, Donna P.; Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Ankerst, Donna P.; Boeck, Andreas] Tech Univ Munich, Dept Math, Garching, Germany. [Ankerst, Donna P.; Thompson, Ian M.] Tech Univ Munich, Dept Life Sci, Garching, Germany. [Till, Cathee; Goodman, Phyllis; Tangen, Catherine M.] Fred Hutchinson Canc Res Ctr, SW Oncol Grp, Ctr Stat, Seattle, WA 98104 USA. [Feng, Ziding] Fred Hutchinson Canc Res Ctr, Program Biostat & Biomath, Seattle, WA 98104 USA. [Partin, Alan W.; Chan, Daniel W.; Sokoll, Lori] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Partin, Alan W.; Chan, Daniel W.; Sokoll, Lori] Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. [Kagan, Jacob] NCI, Canc Biomarkers Res Grp, Canc Prevent Div, Rockville, MD USA. [Wei, John T.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. RP Ankerst, DP (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM ankerst@uthscsa.edu RI Wei, John/E-8967-2012 FU [U01CA86402]; [U24CA115102]; [5P30 CA0541474-18] FX Supported by Grants U01CA86402, U24CA115102 and 5P30 CA0541474-18. NR 12 TC 17 Z9 17 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2013 VL 190 IS 1 BP 70 EP 76 DI 10.1016/j.juro.2012.12.108 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 178GH UT WOS:000321432900022 PM 23313212 ER PT J AU Fwu, CW Eggers, PW Kaplan, SA Kirkali, Z Lee, JY Kusek, JW AF Fwu, Chyng-Wen Eggers, Paul W. Kaplan, Steven A. Kirkali, Ziya Lee, Jeannette Y. Kusek, John W. TI Long-Term Effects of Doxazosin, Finasteride and Combination Therapy on Quality of Life in Men with Benign Prostatic Hyperplasia SO JOURNAL OF UROLOGY LA English DT Article DE lower urinary tract symptoms; prostatic hyperplasia; quality of life; doxazosin; finasteride ID URINARY-TRACT SYMPTOMS; MEDICAL THERAPY; HEALTH-STATUS; IMPACT INDEX; TRIAL; TOLERABILITY; DUTASTERIDE; TAMSULOSIN; EFFICACY; COMBAT AB Purpose: We examined the effects of doxazosin, finasteride and combination therapy among men with benign prostatic hyperplasia on quality of life assessed with MOS-SF-36 (Medical Outcomes Study Short-Form 36) and 2 disease specific instruments (BII, benign prostatic hyperplasia Impact Index and I-PSS-QoL, International Prostate Symptom Score-QoL) during 4 years. Materials and Methods: The MTOPS (Medical Therapy of Prostatic Symptoms) study was a multicenter, randomized, double-blind, placebo controlled clinical trial with a primary outcome of time to benign prostatic hyperplasia progression. Change in quality of life was a secondary outcome. A total of 2,872 men enrolled in the MTOPS study who had 3 baseline quality of life measures and at least 1 followup measure by any of the quality of life instruments were analyzed. Results: Compared with men assigned to placebo, men assigned to doxazosin and combination experienced a statistically significant improvement in the BII at year 4. Men assigned to each of the drug groups also experienced a significant improvement in the I-PSS-QoL compared with those assigned to placebo. Considering longitudinal changes during 4 years, a significant improvement in BII and I-PSS-QoL scores was observed in men assigned to the drug groups compared with those assigned to placebo. However, there were no significant differences for the MOS-SF-36 subscales and summary scores when drug groups were compared with the placebo group. Conclusions: The quality of life of men treated with doxazosin, finasteride, and the drugs combined generally improved when assessed with the BII and the I-PSS-QoL compared with those treated with placebo. Quality of life did not show improvement when measured by the MOS-SF-36. C1 [Fwu, Chyng-Wen] Social & Sci Syst Inc, Silver Spring, MD 20910 USA. [Eggers, Paul W.; Kirkali, Ziya; Kusek, John W.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. [Kaplan, Steven A.] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA. [Lee, Jeannette Y.] Univ Arkansas Med Sci, Dept Biostat, Little Rock, AR 72205 USA. RP Fwu, CW (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM cfwu@s-3.com FU National Institute of Diabetes and Digestive and Kidney Diseases [HHSN 276201200161U] FX Supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (HHSN 276201200161U). NR 26 TC 4 Z9 6 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2013 VL 190 IS 1 BP 187 EP 193 DI 10.1016/j.juro.2013.01.061 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 178GH UT WOS:000321432900057 PM 23357210 ER PT J AU Bertin, FR Baseler, LJ Wilson, CR Kritchevsky, JE Taylor, SD AF Bertin, F. R. Baseler, L. J. Wilson, C. R. Kritchevsky, J. E. Taylor, S. D. TI Arsenic Toxicosis in Cattle: Meta-Analysis of 156 Cases SO JOURNAL OF VETERINARY INTERNAL MEDICINE LA English DT Article DE Bovine; Heavy metal; Poisoning ID BEEF-CATTLE; WEST-BENGAL; HERD; INDIA; WATER AB Background: Arsenic toxicosis is uncommon in cattle and successful treatment is rarely reported. Objectives: This analysis reviews all cases of acute arsenic toxicosis in cattle reported in the literature and describes cases from Purdue University that had a favorable outcome. Clinical presentation of the disease, treatments, and variables associated with survival are described. Animals: One hundred and fifty-six cattle with arsenic toxicosis from 16 outbreaks. Methods: Meta-analysis. Results: The most common clinical signs were sudden death (68%), diarrhea (33%), ataxia (29%), dehydration (22%), and respiratory distress (4%). The most common clinicopathologic abnormalities included azotemia (100%), hematuria (100%), increased liver enzyme activity (86%), and increased hematocrit (60%). One percent of cattle survived and the survival time for nonsurvivors ranged from 20 hours to 21 days. None of the clinical signs or clinicopathologic findings was associated with survival. Treatment was attempted in 24% of cases and was not associated with survival (P=.055), but administration of an antidote and administration of fluids were associated with better outcome (P=.036 and P=.009, respectively). In the animals presented to Purdue University, treatment with IV fluids and sodium thiosulfate resulted in decreased blood arsenic concentrations in all animals (P=.009) and a survival rate of 50%. Conclusions and Clinical Importance: Although acute arsenic toxicosis has a poor prognosis, survival is possible if aggressive fluid therapy and antidotes are administered. C1 [Bertin, F. R.; Kritchevsky, J. E.; Taylor, S. D.] Purdue Univ, Dept Vet Clin Sci, Coll Vet Med, W Lafayette, IN 47907 USA. [Baseler, L. J.] NIAID, Rocky Mt Labs, NIH, Comparat Biomed Scientist Training Program, Hamilton, MT 59840 USA. [Wilson, C. R.] Purdue Univ, Coll Vet Med, W Lafayette, IN 47907 USA. RP Taylor, SD (reprint author), Purdue Univ, Dept Vet Clin Sci, Coll Vet Med, W Lafayette, IN 47907 USA. EM taylo248@purdue.edu RI Bertin, Francois-Rene/O-6342-2016 OI Bertin, Francois-Rene/0000-0002-2820-8431 NR 19 TC 1 Z9 1 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0891-6640 J9 J VET INTERN MED JI J. Vet. Intern. Med. PD JUL PY 2013 VL 27 IS 4 BP 977 EP 981 DI 10.1111/jvim.12124 PG 5 WC Veterinary Sciences SC Veterinary Sciences GA 182SY UT WOS:000321765800032 PM 23758199 ER PT J AU Brown, P Gipson, C AF Brown, Patricia Gipson, Chester TI A word from OLAW and USDA SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. [Gipson, Chester] USDA, APHIS, AC, Tucson, AZ USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD JUL PY 2013 VL 42 IS 7 BP 244 EP 244 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 174MJ UT WOS:000321159400016 PM 23783311 ER PT J AU Hillengass, J Landgren, O AF Hillengass, Jens Landgren, Ola TI Challenges and opportunities of novel imaging techniques in monoclonal plasma cell disorders: imaging "early myeloma" SO LEUKEMIA & LYMPHOMA LA English DT Review DE Multiple myeloma; imaging; PET/CT; MRI; early myeloma; whole-body PET/MRI ID WHOLE-BODY MRI; POSITRON-EMISSION-TOMOGRAPHY; DIAGNOSED MULTIPLE-MYELOMA; MULTIDETECTOR COMPUTED-TOMOGRAPHY; BONE-MARROW INFILTRATION; COMPRESSION FRACTURES; SKELETAL SURVEY; CONVENTIONAL RADIOGRAPHY; PROGNOSTIC-SIGNIFICANCE; EXTRAMEDULLARY DISEASE AB After decades of virtually no progress, multiple myeloma survival has improved significantly in the last 10 years. Indeed, multiple myeloma has perhaps seen more remarkable progress in treatment and patient outcomes than any other cancer during the last decade. Despite significant limitations, conventional radiological skeletal survey still remains the gold standard to rule out bone disease in patients with monoclonal plasma cell diseases. This is even more remarkable, as myeloma is actually a disease of the bone marrow and bone destruction is a secondary complication of advanced disease. Novel imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) allow morphological and functional characterization including information on disease distribution (bone marrow, bone and extramedullary disease), disease activity and minimal residual disease after given therapy. The present review summarizes data on novel imaging techniques and discusses their clinical value and future opportunities for patients with monoclonal plasma cell diseases. C1 [Hillengass, Jens] Heidelberg Univ, Multiple Myeloma Sect, Dept Hematol Oncol & Rheumatol, Heidelberg, Germany. [Landgren, Ola] NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov NR 68 TC 22 Z9 23 U1 2 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUL PY 2013 VL 54 IS 7 BP 1355 EP 1363 DI 10.3109/10428194.2012.740559 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 168IE UT WOS:000320698300006 PM 23289361 ER PT J AU Dong, HY Wang, WJ Uldrick, TS Gangi, M AF Dong, Henry Y. Wang, Wenjing Uldrick, Thomas S. Gangi, Maryann TI Human herpesvirus 8-and Epstein-Barr virus-associated solitary B cell lymphoma with a T cell immunophenotype SO LEUKEMIA & LYMPHOMA LA English DT Letter ID PRIMARY EFFUSION LYMPHOMA; POSITIVE PATIENTS; HIV; BOWEL; NODE C1 [Dong, Henry Y.; Gangi, Maryann] Esoterix Genet Labs LLC, New York, NY 10019 USA. [Wang, Wenjing] St Vincent Hosp, New York, NY USA. [Uldrick, Thomas S.] NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Dong, HY (reprint author), Esoterix Genet Labs LLC, 521 West 57th St, New York, NY 10019 USA. EM dongy@labcorp.com NR 17 TC 4 Z9 4 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUL PY 2013 VL 54 IS 7 BP 1560 EP 1563 DI 10.3109/10428194.2012.747680 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 168IE UT WOS:000320698300040 PM 23228024 ER PT J AU Jose, GS Jackson, ER Uh, E Johny, C Haymond, A Lundberg, L Pinkham, C Kehn-Hall, K Boshoff, HI Couch, RD Dowd, CS AF Jose, Geraldine San Jackson, Emily R. Uh, Eugene Johny, Chinchu Haymond, Amanda Lundberg, Lindsay Pinkham, Chelsea Kehn-Hall, Kylene Boshoff, Helena I. Couch, Robin D. Dowd, Cynthia S. TI Design of potential bisubstrate inhibitors against Mycobacterium tuberculosis (Mtb) 1-deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr)-evidence of a novel binding mode SO MEDCHEMCOMM LA English DT Article ID SUBSTITUTED FOSMIDOMYCIN ANALOGS; ISOPRENOID BIOSYNTHESIS; NONMEVALONATE PATHWAY; ANTIMALARIAL-DRUGS; ESCHERICHIA-COLI; PHOSPHONIC ACID; MEP SYNTHASE; FR900098; DXR; RESISTANCE AB In most bacteria, the nonmevalonate pathway is used to synthesize isoprene units. Dxr, the second step in the pathway, catalyzes the NADPH-dependent reductive isomerization of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol-4-phosphate (MEP). Dxr is inhibited by natural products fosmidomycin and FR900098, which bind in the DXP binding site. These compounds, while potent inhibitors of Dxr, lack whole cell activity against Mycobacterium tuberculosis (Mtb) due to their polarity. Our goal was to use the Mtb Dxr-fosmidomycin co-crystal structure to design bisubstrate ligands to bind to both the DXP and NADPH sites. Such compounds would be expected to demonstrate improved whole cell activity due to increased lipophilicity. Two series of compounds were designed and synthesized. Compounds from both series inhibited Mtb Dxr. The most potent compound (8) has an IC50 of 17.8 mu M. Analysis shows 8 binds to Mtb Dxr via a novel, non-bisubstrate mechanism. Further, the diethyl ester of 8 inhibits Mtb growth making this class of compounds interesting lead molecules in the search for new antitubercular agents. C1 [Jose, Geraldine San; Jackson, Emily R.; Uh, Eugene; Dowd, Cynthia S.] George Washington Univ, Dept Chem, Washington, DC 20052 USA. [Johny, Chinchu; Haymond, Amanda; Couch, Robin D.] George Mason Univ, Dept Chem & Biochem, Manassas, VA 20110 USA. [Johny, Chinchu; Haymond, Amanda; Lundberg, Lindsay; Pinkham, Chelsea; Kehn-Hall, Kylene; Couch, Robin D.] George Mason Univ, Natl Ctr Biodef & Infect Dis, Manassas, VA 20110 USA. [Boshoff, Helena I.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Dowd, CS (reprint author), George Washington Univ, Dept Chem, Washington, DC 20052 USA. EM kkhall@gmu.edu; hboshoff@niaid.nih.gov; rcouch@gmu.edu; cdowd@gwu.edu RI Kehn-Hall, Kylene/I-5752-2013 FU Intramural Research Program of NIAID/NIH; George Washington University Department of Chemistry; GWU University Facilitating Fund; NIH [AI086453]; George Mason University's Department of Chemistry and Biochemistry; U.S. Army Medical Research and Materiel Command [W23RYX1291N601] FX This work was supported by the Intramural Research Program of NIAID/NIH, the George Washington University Department of Chemistry, the GWU University Facilitating Fund, and NIH (AI086453 to CSD). RDC was supported by George Mason University's Department of Chemistry and Biochemistry and the U.S. Army Medical Research and Materiel Command W23RYX1291N601. NR 41 TC 6 Z9 6 U1 0 U2 16 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-2503 J9 MEDCHEMCOMM JI MedChemComm PD JUL PY 2013 VL 4 IS 7 BP 1099 EP 1104 DI 10.1039/c3md00085k PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 171RZ UT WOS:000320948100007 ER PT J AU Huo, ZM Summers, RM Paquerault, S Lo, J Hoffmeister, J Armato, SG Freedman, MT Lin, J Lo, SCB Petrick, N Sahiner, B Fryd, D Yoshida, H Chan, HP AF Huo, Zhimin Summers, Ronald M. Paquerault, Sophie Lo, Joseph Hoffmeister, Jeffrey Armato, Samuel G., III Freedman, Matthew T. Lin, Jesse Lo, Shih-Chung Ben Petrick, Nicholas Sahiner, Berkman Fryd, David Yoshida, Hiroyuki Chan, Heang-Ping TI Quality assurance and training procedures for computer-aided detection and diagnosis systems in clinical use SO MEDICAL PHYSICS LA English DT Article DE computer-aided diagnosis; computer-aided detection; quality assurance; user training ID CT COLONOGRAPHY; SCREENING MAMMOGRAPHY; CAD; METHODOLOGIES; PERFORMANCE AB Computer-aided detection/diagnosis (CAD) is increasingly used for decision support by clinicians for detection and interpretation of diseases. However, there are no quality assurance (QA) requirements for CAD in clinical use at present. QA of CAD is important so that end users can be made aware of changes in CAD performance both due to intentional or unintentional causes. In addition, end-user training is critical to prevent improper use of CAD, which could potentially result in lower overall clinical performance. Research on QA of CAD and user training are limited to date. The purpose of this paper is to bring attention to these issues, inform the readers of the opinions of the members of the American Association of Physicists in Medicine (AAPM) CAD subcommittee, and thus stimulate further discussion in the CAD community on these topics. The recommendations in this paper are intended to be work items for AAPM task groups that will be formed to address QA and user training issues on CAD in the future. The work items may serve as a framework for the discussion and eventual design of detailed QA and training procedures for physicists and users of CAD. Some of the recommendations are considered by the subcommittee to be reasonably easy and practical and can be implemented immediately by the end users; others are considered to be "best practice" approaches, which may require significant effort, additional tools, and proper training to implement. The eventual standardization of the requirements of QA procedures for CAD will have to be determined through consensus from members of the CAD community, and user training may require support of professional societies. It is expected that high-quality CAD and proper use of CAD could allow these systems to achieve their true potential, thus benefiting both the patients and the clinicians, and may bring about more widespread clinical use of CAD for many other diseases and applications. It is hoped that the awareness of the need for appropriate CAD QA and user training will stimulate new ideas and approaches for implementing such procedures efficiently and effectively as well as funding opportunities to fulfill such critical efforts. (C) 2013 American Association of Physicists in Medicine. C1 [Huo, Zhimin] Carestream Hlth Inc, Rochester, NY 14615 USA. [Summers, Ronald M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Paquerault, Sophie; Petrick, Nicholas; Sahiner, Berkman] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Lo, Joseph] Duke Univ, Med Ctr, Durham, NC 27705 USA. [Hoffmeister, Jeffrey] ICAD Inc, Nashua, NH 03062 USA. [Armato, Samuel G., III] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Freedman, Matthew T.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Lin, Jesse] FUJIFILM Med Syst USA Inc, Stamford, CT 06902 USA. [Lo, Shih-Chung Ben] Georgetown Univ, Washington, DC 20057 USA. [Fryd, David] Riverain Med, Miamisburg, OH 45342 USA. [Yoshida, Hiroyuki] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yoshida, Hiroyuki] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Chan, Heang-Ping] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. RP Chan, HP (reprint author), Univ Michigan, Dept Radiol, 1500 East Med Ctr Dr,MIB C477, Ann Arbor, MI 48109 USA. EM chanhp@umich.edu FU Intramural Research Program of the National Institutes of Health (NIH), Clinical Center; University of Chicago; Riverain Technologies through The University of Chicago; iCAD; Riverain Technologies through Georgetown University Medical Center FX The authors are grateful to the members and participants of the CADSC who have contributed to the stimulating discussions during many meetings and teleconferences. R.M.S. is supported by the Intramural Research Program of the National Institutes of Health (NIH), Clinical Center; the views expressed in this paper are the opinions of the authors and do not necessarily represent the views of the National Institutes of Health or Department of Health and Human Services. S. G. A. and H.Y. receive royalties and licensing fees through the University of Chicago related to CAD. S. G. A. receives research funding from Riverain Technologies through The University of Chicago. R.M.S. receives patent royalties and research support related to CAD from iCAD. M.T.F. and S.C.B.L. receive funding from Riverain Technologies through Georgetown University Medical Center. NR 14 TC 4 Z9 4 U1 1 U2 10 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUL PY 2013 VL 40 IS 7 AR 077001 DI 10.1118/1.4807642 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 175ZK UT WOS:000321272200059 PM 23822459 ER PT J AU Matsushita, K Tamura, M Tanaka, N Tomonaga, T Matsubara, H Shimada, H Levens, D He, LS Liu, JH Yoshida, M Nomura, F AF Matsushita, Kazuyuki Tamura, Mai Tanaka, Nobuko Tomonaga, Takeshi Matsubara, Hisahiro Shimada, Hideaki Levens, David He, Liusheng Liu, Juhong Yoshida, Minoru Nomura, Fumio TI Interactions between SAP155 and FUSE-Binding Protein-Interacting Repressor Bridges c-Myc and P27Kip1 Expression SO MOLECULAR CANCER RESEARCH LA English DT Article ID FAR-UPSTREAM ELEMENT; GENE-EXPRESSION; MESSENGER-RNA; SUPPRESSOR; CANCER; TRANSCRIPTION; CELLS; CDK2; ARREST; TFIIH AB Oncogenic c-Myc plays a critical role in cell proliferation, apoptosis, and tumorigenesis, but the precise mechanisms that drive this activity remain largely unknown. P27Kip1 (CDKN1B) arrests cells in G1, and SAP155 (SF3B1), a subunit of the essential splicing factor 3b (SF3b) subcomplex of the spliceosome, is required for proper P27 pre-mRNA splicing. FUSE-binding protein-interacting repressor (FIR), a splicing variant of PUF60 lacking exon5, is a c-Myc transcriptional target that suppresses the DNA helicase p89 (ERCC3) and is alternatively spliced in colorectal cancer lacking the transcriptional repression domain within exon 2 (FIR Delta exon2). FIR and FIR Delta exon2 form a homo- or hetero-dimer that complexes with SAP155. Our study indicates that the FIR/FIR Delta exon2/SAP155 interaction bridges c-Myc and P27 expression. Knockdown of FIR/FIR Delta exon2 or SAP155 reduced p27 expression, inhibited its pre-mRNA splicing, and reduced CDK2/Cyclin E expression. Moreover, spliceostatin A, a natural SF3b inhibitor, markedly inhibited P27 expression by disrupting its pre-mRNA splicing and reduced CDK2/Cyclin E expression. The expression of P89, another FIR target, was increased in excised human colorectal cancer tissues. Knockdown of FIR reduced P89; however, the effects on P27 and P89 expression are not simply or directly related to altered FIR expression levels, indicating that the mechanical or physical interaction of the SAP155/FIR/FIR Delta exon2 complex is potentially essential for sustained expression of both P89 and P27. Together, the interaction between SAP155 and FIR/FIR Delta exon2 not only integrates cell-cycle progression and c-Myc transcription by modifying P27 and P89 expression but also suggests that the interaction is a potential target for cancer screening and treatment. C1 [Matsushita, Kazuyuki; Tamura, Mai; Tanaka, Nobuko; Nomura, Fumio] Chiba Univ, Grad Sch Med, Dept Mol Diag F8, Chiba 2608670, Japan. [Matsubara, Hisahiro] Chiba Univ, Grad Sch Med, Dept Frontier Surg M9, Chiba 2608670, Japan. [Tomonaga, Takeshi] Natl Inst Biomed Innovat, Proteome Res Ctr, Ibaraki, Osaka, Japan. [Shimada, Hideaki] Toho Univ, Sch Med, Dept Surg, Tokyo, Japan. [Yoshida, Minoru] RIKEN, Chem Genet Lab, Wako, Saitama, Japan. [Levens, David; He, Liusheng; Liu, Juhong] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Matsushita, K (reprint author), Chiba Univ, Grad Sch Med, Dept Mol Diag F8, Chuo Ku, 1-8-1 Inohana, Chiba 2608670, Japan. EM kmatsu@faculty.chiba-u.jp RI Levens, David/C-9216-2009; Yoshida, Minoru/C-8049-2014; OI Levens, David/0000-0002-7616-922X; Matsushita, Kazuyuki/0000-0001-6742-0761 FU Ministry of Education, Science, Sports, and Culture of Japan [18591453]; Seed Finding Programs; "Mini-Feasibility Study Project" of the JST (Japan Science and Technology) Agency; Japan Society for the Promotion of Science FX This study was supported in part by Grant-in-Aid 18591453 for priority areas in cancer research from the Ministry of Education, Science, Sports, and Culture of Japan and "Seed Finding Programs" and "Mini-Feasibility Study Project" of the JST (Japan Science and Technology) Agency (to K. Matsushita), and a Grant-in-Aid for Scientific Research (S) from the Japan Society for the Promotion of Science (to M. Yoshida). NR 33 TC 9 Z9 9 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD JUL PY 2013 VL 11 IS 7 BP 689 EP 698 DI 10.1158/1541-7786.MCR-12-0673 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 185DL UT WOS:000321945300001 PM 23594796 ER PT J AU Tilly, K Bestor, A Rosa, PA AF Tilly, Kit Bestor, Aaron Rosa, Patricia A. TI Lipoprotein succession in Borrelia burgdorferi: similar but distinct roles for OspC and VlsE at different stages of mammalian infection SO MOLECULAR MICROBIOLOGY LA English DT Article ID OUTER-SURFACE-PROTEIN; LYME-DISEASE SPIROCHETE; GENE-EXPRESSION; CRYSTAL-STRUCTURE; TICK VECTOR; MONOCLONAL-ANTIBODY; ANTIGENIC VARIATION; LINEAR PLASMID-25; HOST; KINETICS AB Borrelia burgdorferi alternates between ticks and mammals, requiring variable gene expression and protein production to adapt to these diverse niches. These adaptations include shifting among the major outer surface lipoproteins OspA, OspC, and VlsE at different stages of the infectious cycle. We hypothesize that these proteins carry out a basic but essential function, and that OspC and VlsE fulfil this requirement during early and persistent stages of mammalian infection respectively. Previous work by other investigators suggested that several B. burgdorferi lipoproteins, including OspA and VlsE, could substitute for OspC at the initial stage of mouse infection, when OspC is transiently but absolutely required. In this study, we assessed whether vlsE and ospA could restore infectivity to an ospC mutant, and found that neither gene product effectively compensated for the absence of OspC during early infection. In contrast, we determined that OspC production was required by B. burgdorferi throughout SCID mouse infection if the vlsE gene were absent. Together, these results indicate that OspC can substitute for VlsE when antigenic variation is unnecessary, but that these two abundant lipoproteins are optimized for their related but specific roles during early and persistent mammalian infection by B. burgdorferi. C1 [Tilly, Kit; Bestor, Aaron; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Tilly, K (reprint author), NIAID, Lab Zoonot Pathogens, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. EM ktilly@niaid.nih.gov FU NIH, NIAID FX We thank John Leong for insightful suggestions and discussion. We thank Adeline Porter, Frank Deleo, and Claire Checroun for help assessing B. burgdorferi susceptibility to mouse and human immune cells and serum. We thank Sandy Stewart, Karin Peterson, Sarah Ward, and members of the Rosa lab for helpful comments on the manuscript. We thank Brian Stevenson (University of Kentucky) for providing the polyclonal rabbit anti-VlsE antibody. Anita Mora and Heather Murphy provided expert graphics assistance. This research was supported by the Intramural Research Program of the NIH, NIAID. NR 68 TC 19 Z9 20 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 2013 VL 89 IS 2 BP 216 EP 227 DI 10.1111/mmi.12271 PG 12 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 176YT UT WOS:000321343400003 PM 23692497 ER PT J AU Gong, R Wang, YP Ying, TL Peng, Y Streaker, E Prabakaran, P Dimitrov, DS AF Gong, Rui Wang, Yanping Ying, Tianlei Peng, Yang Streaker, Emily Prabakaran, Ponraj Dimitrov, Dimiter S. TI N-Terminal Truncation of an Isolated Human IgG1 CH2 Domain Significantly Increases Its Stability and Aggregation Resistance SO MOLECULAR PHARMACEUTICS LA English DT Article DE IgG; Fc; CH2 domain; stability; aggregation resistance ID NEONATAL-FC-RECEPTOR; COMPLEMENTARITY-DETERMINING REGIONS; HUMAN-ANTIBODY; CRYSTAL-STRUCTURE; THERAPEUTIC ANTIBODIES; CONSTANT DOMAINS; DESIGN; HIV-1; IMMUNOGLOBULIN; PROTEINS AB Isolated human immunoglobulin G (IgG) CH2 domains are promising scaffolds for novel candidate therapeutics. Unlike other human IgG domains, CH2 is not involved in strong interchain interactions, and isolated, CH2 is relatively stable. However, isolated single CH2 is prone to aggregation. In native IgG and Fc molecules, the N-terminal residues of CH2 from the two heavy chains interact with each other and form hinge regions. By contrast; the N-terminal residues are highly disordered in isolated CH2. We have hypothesized that the removal of the CH2 N-terminal residues may not Only increase its stability but also its aggregation resistance. To test this hypothesis we constructed a shortened variant of IgG1 CH2 (CH2s) where the first seven residues of the N-terminus were deleted. We found that the thermal stability, of CH2s was increased by 5 degrees C compared to CH2. Importantly, we demonstrated that CH2s is significantly less prone to aggregation than CH2 as measured by Thioflavin T (ThT) fluorescence, turbidity, and light scattering. We also found that the CH2s exhibited pH-dependent binding to a soluble single-chain human neonatal Fc receptor (shFcRn) which was significantly stronger than the very weak binding of CH2 to shFcRn as measured by flow cytometry. Computer modeling suggested a possible mode of CH2 aggregation involving its N-terminal residues. Therefore, deletion of the N-terminal residues could increase drugability of CH2-based therapeutic candidates. This strategy to increase stability and aggregation resistance could also be applicable to other Ig-related proteins. C1 [Gong, Rui] Chinese Acad Sci, Wuhan Inst Virol, Ctr Emerging Infect Dis, Antibody Engn Grp, Wuhan 430071, Hubei, Peoples R China. [Gong, Rui; Wang, Yanping; Ying, Tianlei; Peng, Yang; Streaker, Emily; Prabakaran, Ponraj; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, NIH, Frederick, MD 21702 USA. [Wang, Yanping; Streaker, Emily; Prabakaran, Ponraj] Sci Applicat Int Corp Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Gong, R (reprint author), Chinese Acad Sci, Wuhan Inst Virol, Ctr Emerging Infect Dis, 1 Xiaohongshan,Rm 522, Wuhan 430071, Hubei, Peoples R China. EM gongr@wh.iov.cn; dimiter.dimitrov@nih.gov FU Wuhan Key Laboratory on Emerging Infectious Diseases and Biosafety; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [N01-CO-12400] FX We thank Dr. Sergey G. Tarasov and Ms. Marzena A. Dyba of the Biophysics Resource in the Structural Biophysics Laboratory, NCI-Frederick for technical help and the Wuhan Key Laboratory on Emerging Infectious Diseases and Biosafety for support. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. 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 46 TC 8 Z9 8 U1 0 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD JUL PY 2013 VL 10 IS 7 BP 2642 EP 2652 DI 10.1021/mp400075f PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 178UD UT WOS:000321472000013 PM 23641816 ER PT J AU Cortes, A Hadler, J Pointon, JP Robinson, PC Karaderi, T Leo, P Cremin, K Pryce, K Harris, J Lee, S Joo, KB Shim, SC Weisman, M Ward, M Zhou, XD Garchon, HJ Chiocchia, G Nossent, J Lie, BA Forre, O Tuomilehto, J Laiho, K Jiang, L Liu, Y Wu, X Bradbury, LA Elewaut, D Burgos-Vargas, R Stebbings, S Appleton, L Farrah, C Lau, J Kenna, TJ Haroon, N Ferreira, MA Yang, J Mulero, J Fernandez-Sueiro, JL Gonzalez-Gay, MA Lopez-Larrea, C Deloukas, P Donnelly, P Bowness, P Gafney, K Gaston, H Gladman, DD Rahman, P Maksymowych, WP Xu, HJ Crusius, JBA van der Horst-Bruinsma, IE Chou, CT Valle-Onate, R Romero-Sanchez, C Hansen, IM Pimentel-Santos, FM Inman, RD Videm, V Martin, J Breban, M Reveille, JD Evans, DM Kim, TH Wordsworth, BP Brown, MA AF Cortes, Adrian Hadler, Johanna Pointon, Jenny P. Robinson, Philip C. Karaderi, Tugce Leo, Paul Cremin, Katie Pryce, Karena Harris, Jessica Lee, Seunghun Joo, Kyung Bin Shim, Seung-Cheol Weisman, Michael Ward, Michael Zhou, Xiaodong Garchon, Henri-Jean Chiocchia, Gilles Nossent, Johannes Lie, Benedicte A. Forre, Oystein Tuomilehto, Jaakko Laiho, Kari Jiang, Lei Liu, Yu Wu, Xin Bradbury, Linda A. Elewaut, Dirk Burgos-Vargas, Ruben Stebbings, Simon Appleton, Louise Farrah, Claire Lau, Jonathan Kenna, Tony J. Haroon, Nigil Ferreira, Manuel A. Yang, Jian Mulero, Juan Fernandez-Sueiro, Jose Luis Gonzalez-Gay, Miguel A. Lopez-Larrea, Carlos Deloukas, Panos Donnelly, Peter Bowness, Paul Gafney, Karl Gaston, Hill Gladman, Dafna D. Rahman, Proton Maksymowych, Walter P. Xu, Huji Crusius, J. Bart A. van der Horst-Bruinsma, Irene E. Chou, Chung-Tei Valle-Onate, Raphael Romero-Sanchez, Consuelo Hansen, Inger Myrnes Pimentel-Santos, Fernando M. Inman, Robert D. Videm, Vibeke Martin, Javier Breban, Maxime Reveille, John D. Evans, David M. Kim, Tae-Hwan Wordsworth, Bryan Paul Brown, Matthew A. CA Int Genetics Ankylosing Australo-Anglo-Amer GFEGS Nord-Trondelag Hlth Study HUNT Spondyloarthrit Res Consortium WTCCC2 TI Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; DISEASE SUSCEPTIBILITY LOCI; HLA CLASS-I; T-CELL; ENDOPLASMIC-RETICULUM; GENETIC SUSCEPTIBILITY; BEHCETS-DISEASE; COMMON; ERAP1; ACTIVATION AB Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression. C1 [Cortes, Adrian; Hadler, Johanna; Robinson, Philip C.; Leo, Paul; Cremin, Katie; Pryce, Karena; Harris, Jessica; Bradbury, Linda A.; Kenna, Tony J.; Yang, Jian; Brown, Matthew A.] Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia. [Pointon, Jenny P.; Karaderi, Tugce; Appleton, Louise; Farrah, Claire; Lau, Jonathan; Bowness, Paul; Wordsworth, Bryan Paul] Nuffield Orthopaed Ctr, Oxford Musculoskeletal Biomed Res Unit, NIHR, Oxford OX3 7LD, England. [Lee, Seunghun; Joo, Kyung Bin; Kim, Tae-Hwan] Hanyang Univ Hosp Rheumat Dis, Dept Rheumatol, Seoul, South Korea. [Shim, Seung-Cheol] Eulji Univ Hosp, Div Rheumatol, Dept Med, Taejon, South Korea. [Weisman, Michael] Cedars Sinai Med Ctr, Dept Med Rheumatol, Los Angeles, CA 90048 USA. [Ward, Michael] NIAMSD, US NIH, Bethesda, MD 20892 USA. [Zhou, Xiaodong; Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Garchon, Henri-Jean; Chiocchia, Gilles; Breban, Maxime] Univ Paris 05, Inst Cochin, CNRS,INSERM, UMR 8104,U1016, Paris, France. [Garchon, Henri-Jean; Breban, Maxime] Versailles St Quentin En Yvelines Univ, Hop Ambroise Pare, AP HP, Div Rheumatol, Boulogne, France. [Nossent, Johannes] Univ Hosp North Norway, Tromso, Norway. [Nossent, Johannes] Royal Darwin Hosp, Div Med, Darwin, NT, Australia. [Lie, Benedicte A.] Univ Oslo, Dept Med Genet, Oslo, Norway. [Lie, Benedicte A.] Oslo Univ Hosp, Oslo, Norway. [Lie, Benedicte A.] Oslo Univ Hosp, Dept Immunol, Oslo, Norway. [Forre, Oystein] Univ Hosp Oslo, Dept Rheumatol, Oslo, Norway. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Tuomilehto, Jaakko] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia. [Laiho, Kari] Paijat Hame Cent Hosp, Lahti, Finland. [Jiang, Lei; Liu, Yu; Wu, Xin; Xu, Huji] Second Mil Med Univ, Shanghai Changzheng Hosp, Dept Rheumatol & Immunol, Shanghai, Peoples R China. [Elewaut, Dirk] Ghent Univ Hosp, Dept Rheumatol, Ghent, Belgium. [Burgos-Vargas, Ruben] Univ Nacl Autonoma Mexico, Fac Med, Hosp Gen Mexico, Dept Rheumatol, Mexico City 04510, DF, Mexico. [Stebbings, Simon] Univ Otago, Dunedin Sch Med, Dept Med, Dunedin, New Zealand. [Haroon, Nigil; Inman, Robert D.] Toronto Western Hosp, Div Rheumatol, Toronto, ON M5T 2S8, Canada. [Ferreira, Manuel A.] Univ Queensland, Royal Brisbane Hosp, Queensland Inst Med Res, Herston, Qld, Australia. [Mulero, Juan] Hosp Puerta de Hierro, Dept Rheumatol, Madrid, Spain. [Fernandez-Sueiro, Jose Luis] Complejo Hosp La Coruna, Dept Rheumatol, Inst Invest Biomed A Coruna INIBIC, La Coruna, Spain. [Gonzalez-Gay, Miguel A.] Hosp Marques de Valcecilla, IFIMAV, Dept Rheumatol, Santander, Spain. [Lopez-Larrea, Carlos] Asturias Cent Univ Hosp, Dept Immunol, Oviedo, Spain. [Lopez-Larrea, Carlos] Fdn Renal Inigo Alvarez Toledo, Madrid, Spain. [Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Donnelly, Peter] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Gafney, Karl] Norfolk & Norwich Univ Hosp, Dept Rheumatol, Norwich, Norfolk, England. [Gaston, Hill] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England. [Gladman, Dafna D.] Univ Toronto, Div Rheumatol, Toronto, ON, Canada. [Gladman, Dafna D.] Toronto Western Res Inst, Toronto, ON, Canada. [Gladman, Dafna D.] Univ Hlth Network, Psoriat Arthrit Program, Toronto, ON, Canada. [Rahman, Proton] Mem Univ Newfoundland, St John, NF, Canada. [Maksymowych, Walter P.] Univ Alberta, Dept Med, Edmonton, AB, Canada. [Crusius, J. Bart A.] Vrije Univ Amsterdam Med Ctr, Dept Med Microbiol & Infect Control, Lab Immunogenet, Amsterdam, Netherlands. [van der Horst-Bruinsma, Irene E.] Vrije Univ Amsterdam Med Ctr, Dept Rheumatol, Amsterdam, Netherlands. [Chou, Chung-Tei] Taipei Vet Gen Hosp, Dept Med, Div Allergy, Taipei, Taiwan. [Chou, Chung-Tei] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Valle-Onate, Raphael; Romero-Sanchez, Consuelo] Univ La Sabana, Hosp Mil Cent, Div Rheumatol, Spondyloarthropathy Grp, Bogota, Colombia. [Hansen, Inger Myrnes] Helgelandssykehuset, Mo I Rana, Norway. [Pimentel-Santos, Fernando M.] Univ Nova Lisboa, Fac Ciencias Med, Chron Dis Res Ctr CEDOC, P-1200 Lisbon, Portugal. [Videm, Vibeke] Norwegian Univ Sci & Technol, Dept Lab Med Childrens & Womens Hlth, N-7034 Trondheim, Norway. [Videm, Vibeke] Univ Trondheim Hosp, Dept Immunol & Transfus Med, Trondheim, Norway. [Martin, Javier] CSIC, Inst Parasitol Biomed Lopez Neyra, Granada, Spain. [Evans, David M.] MRC, Ctr Causal Anal Translat Epidemiol, Sch Social & Community Med, Bristol, Avon, England. RP Brown, MA (reprint author), Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia. EM matt.brown@uq.edu.au RI Deloukas, Panos/B-2922-2013; Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013; Kenna, Tony/A-6035-2011; Robinson, Philip/B-8319-2011; Leo, Paul/B-3470-2011; Ferreira, Manuel/D-3609-2013; Gonzalez-Gay, Miguel/B-2306-2008; Martin, Javier/B-8141-2008; chiocchia, gilles/F-6287-2013; Yang, Jian/A-5852-2010; Elewaut, Dirk/K-6831-2014 OI Brown, Matthew A/0000-0003-0538-8211; Evans, David/0000-0003-0663-4621; Deloukas, Panos/0000-0001-9251-070X; Pimentel-Santos, Fernando/0000-0002-2816-7705; Kenna, Tony/0000-0001-6844-3463; Robinson, Philip/0000-0002-3156-3418; Leo, Paul/0000-0001-8325-4134; Gonzalez-Gay, Miguel/0000-0002-7924-7406; chiocchia, gilles/0000-0001-9973-0940; Yang, Jian/0000-0003-2001-2474; FU Wellcome Trust [083948/Z/07/Z, 068545/Z/02, 076113]; Medical Research Council [G0000934]; Wellcome Trust; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [P01-052915, R01-AR046208]; University of Texas at Houston Clinical and Translational Science Award (CTSA) [UL1RR024188]; Cedars-Sinai General Clinical Research Center (GCRC) [MO1-RR00425]; Intramural Research Program, NIAMS, US National Institutes of Health and the Rebecca Cooper Foundation (Australia); Arthritis Research UK [19536, 18797]; Oxford Comprehensive Biomedical Research Centre [A91202]; National Natural Science Foundation of China [81020108029, 30872339]; Bolsa Investigacao da Sociedade Portuguesa de Reumatologia/Schering-Plough; European Union [FICYT PC-10-70-Fondos FEDER]; Agence Nationale de Recherche GEnetics, Microbiota, Inflammation and Spondyloarthritis (GEMISA) [ANR-10-MIDI-0002]; Krembil Foundation; Arthritis Society; National Health and Medical Research Council (Australia) (NHMRC); Arthritis Australia; NHMRC [613672, 1011506]; Intramural Research Program, NIAMS, US National Institutes of Health; search council of Ghent University; Fund for Scientific Research Flanders; National Health and Medical Research Council (Australia) Senior Principal Research Fellowship; National Health and Medical Research Council (Australia) [566938, 569829]; Australian Cancer Research Foundation; Rebecca Cooper Medical Research Foundation; National Ankylosing Spondylitis Society (UK); Spondyloarthritis Association of America; NIHR Oxford Musculoskeletal Biomedical Research Unit; NIHR Thames Valley Comprehensive Local Research; Abbott Laboratories FX We thank all participating subjects with ankylosing spondylitis and healthy individuals who provided the DNA and clinical information necessary for this study. The Wellcome Trust Case Control Consortium 2 project is funded by the Wellcome Trust (083948/Z/07/Z). We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and of the UK National Blood Service controls, funded by the Wellcome Trust. We thank J.C. Barrett for contributing the design of the Immunochip and for helpful analytical discussion, as well as E. Gray, S. Bumpstead, D. Simpkin and the staff of the Wellcome Trust Sanger Institute Sample Management and Genotyping teams for their genotyping and analytical contributions. The Australo-Anglo-American Spondyloarthritis Consortium (TASC) study was funded by National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants P01-052915 and R01-AR046208. Funding was also received from University of Texas at Houston Clinical and Translational Science Award (CTSA) UL1RR024188, Cedars-Sinai General Clinical Research Center (GCRC) grant MO1-RR00425, the Intramural Research Program, NIAMS, US National Institutes of Health and the Rebecca Cooper Foundation (Australia). This study was funded, in part, by Arthritis Research UK (grants 19536 and 18797), by the Wellcome Trust (grant 076113) and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (theme A91202). We thank A. Harrison (University of Otago) for his contribution to the New Zealand ankylosing spondylitis cohort. H. X. was funded by National Natural Science Foundation of China grants 81020108029 and 30872339. Portuguese sample collection was performed by COnhecer a Realidade PORtuguesa sobre a Espondilite Anquilosante (CORPOREA Study Group), coordinated by F.M.P.-S. and supported by Bolsa Investigacao da Sociedade Portuguesa de Reumatologia/Schering-Plough 2007. The Spanish ankylosing spondylitis case collection was supported by Spanish grant FICYT PC-10-70-Fondos FEDER European Union. The Spondyloarthritis Research Consortium of Canada (SPARCC) was funded by a National Research Initiative Award from the Arthritis Society (Canada). French sample collection was performed by the Groupe Francaise d'Etude Genetique des Spondylarthrites, coordinated by R. Said-Nahal and funded by Agence Nationale de Recherche GEnetics, Microbiota, Inflammation and Spondyloarthritis (GEMISA) grant ANR-10-MIDI-0002. We thank the Norwegian Bone Marrow Donor registry for providing data from healthy Norwegian controls. W. P. M. is a Medical Scientist of Alberta Innovates-Health Solutions. The Psoriatic Arthritis Program is supported by the Krembil Foundation and the Arthritis Society. P. C. R. is funded by the National Health and Medical Research Council (Australia) (NHMRC) and Arthritis Australia. J.Y. is supported by NHMRC grants 613672 and 1011506. M. Ward is supported by the Intramural Research Program, NIAMS, US National Institutes of Health. D. E. is supported by the research council of Ghent University and by the Fund for Scientific Research Flanders. M. A. B. is funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship, and support for this study was received from a National Health and Medical Research Council (Australia) program grant (566938) and project grant (569829) and from the Australian Cancer Research Foundation and the Rebecca Cooper Medical Research Foundation. We thank A.; Gardiner and the Brisbane Convention and Exhibition Centre for their assistance in preparing the manuscript. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and the Spondyloarthritis Association of America in case recruitment. Additional financial and technical support for subject recruitment was provided by the NIHR Oxford Musculoskeletal Biomedical Research Unit and NIHR Thames Valley Comprehensive Local Research and by an unrestricted educational grant from Abbott Laboratories. NR 68 TC 172 Z9 175 U1 3 U2 57 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUL PY 2013 VL 45 IS 7 BP 730 EP + DI 10.1038/ng.2667 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 172LQ UT WOS:000321005200007 ER PT J AU Savage, SA Mirabello, L Wang, ZM Gastier-Foster, JM Gorlick, R Khanna, C Flanagan, AM Tirabosco, R Andrulis, IL Wunder, JS Gokgoz, N Patino-Garcia, A Sierrasesumaga, L Lecanda, F Kurucu, N Ilhan, IE Sari, N Serra, M Hattinger, C Picci, P Spector, LG Barkauskas, DA Marina, N de Toledo, SRC Petrilli, AS Amary, MF Halai, D Thomas, DM Douglass, C Meltzer, PS Jacobs, K Chung, CC Berndt, SI Purdue, MP Caporaso, NE Tucker, M Rothman, N Landi, MT Silverman, DT Kraft, P Hunter, DJ Malats, N Kogevinas, M Wacholder, S Troisi, R Helman, L Fraumeni, JF Yeager, M Hoover, RN Chanock, SJ AF Savage, Sharon A. Mirabello, Lisa Wang, Zhaoming Gastier-Foster, Julie M. Gorlick, Richard Khanna, Chand Flanagan, Adrienne M. Tirabosco, Roberto Andrulis, Irene L. Wunder, Jay S. Gokgoz, Nalan Patino-Garcia, Ana Sierrasesumaga, Luis Lecanda, Fernando Kurucu, Nilgun Ilhan, Inci Ergurhan Sari, Neriman Serra, Massimo Hattinger, Claudia Picci, Piero Spector, Logan G. Barkauskas, Donald A. Marina, Neyssa Caminada de Toledo, Silvia Regina Petrilli, Antonio S. Amary, Maria Fernanda Halai, Dina Thomas, David M. Douglass, Chester Meltzer, Paul S. Jacobs, Kevin Chung, Charles C. Berndt, Sonja I. Purdue, Mark P. Caporaso, Neil E. Tucker, Margaret Rothman, Nathaniel Landi, Maria Teresa Silverman, Debra T. Kraft, Peter Hunter, David J. Malats, Nuria Kogevinas, Manolis Wacholder, Sholom Troisi, Rebecca Helman, Lee Fraumeni, Joseph F., Jr. Yeager, Meredith Hoover, Robert N. Chanock, Stephen J. TI Genome-wide association study identifies two susceptibility loci for osteosarcoma SO NATURE GENETICS LA English DT Article ID GENETIC-VARIATION; RECOMBINATION HOTSPOTS; LINKAGE DISEQUILIBRIUM; BONE CANCER; POLYMORPHISMS; CHILDREN; RECEPTOR; COMMON; TUMOR; RATES AB Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 x 10(-9)) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 x 10(-8) and 2.9 x 10(-7), respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma. C1 [Savage, Sharon A.; Mirabello, Lisa; Berndt, Sonja I.; Purdue, Mark P.; Caporaso, Neil E.; Tucker, Margaret; Rothman, Nathaniel; Landi, Maria Teresa; Silverman, Debra T.; Wacholder, Sholom; Troisi, Rebecca; Fraumeni, Joseph F., Jr.; Hoover, Robert N.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, US NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Jacobs, Kevin; Chung, Charles C.; Yeager, Meredith] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, SAIC Frederick Inc,NCI Frederick, Frederick, MD 21701 USA. [Gastier-Foster, Julie M.] Nationwide Childrens Hosp, Columbus, OH USA. [Gastier-Foster, Julie M.] Ohio State Univ, Dept Pathol & Pediat, Columbus, OH 43210 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Albert Einstein Coll Med, Bronx, NY USA. [Khanna, Chand; Meltzer, Paul S.; Helman, Lee] NCI, Ctr Canc Res, US NIH, Bethesda, MD 20892 USA. [Flanagan, Adrienne M.] UCL, Inst Canc, London, England. [Flanagan, Adrienne M.; Tirabosco, Roberto; Amary, Maria Fernanda; Halai, Dina] Royal Natl Orthopaed Hosp NHS Trust, Stanmore, Middx, England. [Andrulis, Irene L.; Wunder, Jay S.; Gokgoz, Nalan] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Patino-Garcia, Ana; Sierrasesumaga, Luis; Lecanda, Fernando] Univ Navarra, Univ Navarra Clin, Dept Pediat, E-31080 Pamplona, Spain. [Kurucu, Nilgun; Ilhan, Inci Ergurhan; Sari, Neriman] AY Ankara Oncol Training & Res Hosp, Dept Pediat Oncol, Ankara, Turkey. [Serra, Massimo; Hattinger, Claudia; Picci, Piero] Orthopaed Rizzoli Inst, Expt Oncol Lab, Bologna, Italy. [Spector, Logan G.] Univ Minnesota, Dept Pediat, Div Epidemiol & Clin Res, Minneapolis, MN 55455 USA. [Barkauskas, Donald A.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Marina, Neyssa] Stanford Univ, Palo Alto, CA 94304 USA. [Marina, Neyssa] Lucile Packard Childrens Hosp, Dept Pediat Hematol Oncol, Palo Alto, CA USA. [Caminada de Toledo, Silvia Regina; Petrilli, Antonio S.] Univ Fed Sao Paulo UNIFESP, Grp Apoio Adolescente & Crianca Com Canc GRAACC, Pediat Oncol Inst, Sao Paulo, Brazil. [Thomas, David M.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, East Melbourne, Vic, Australia. [Douglass, Chester; Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Malats, Nuria] Ctr Nacl Invest Oncol, Madrid, Spain. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Kogevinas, Manolis] IMIM Hosp Mar Med Res Inst, Barcelona, Spain. [Kogevinas, Manolis] Network Biomed Res Ctr Epidemiol & Publ Hlth CIBE, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. RP Savage, SA (reprint author), NCI, Div Canc Epidemiol & Genet, US NIH, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Picci, Piero/J-5979-2016; Petrilli, Antonio/B-7906-2012; Andrulis, Irene/E-7267-2013; Tucker, Margaret/B-4297-2015; Hattinger, Claudia/Q-1212-2016; Toledo, Silvia/C-2470-2012; Kogevinas, Manolis/C-3918-2017; Malats, Nuria/H-7041-2015; Patino-Garcia, Ana/I-4299-2012; Purdue, Mark/C-9228-2016; Savage, Sharon/B-9747-2015; Serra, Massimo/J-4878-2016 OI Picci, Piero/0000-0002-8519-4101; Spector, Logan/0000-0003-2516-0222; Hattinger, Claudia/0000-0002-9316-5095; Malats, Nuria/0000-0003-2538-3784; Purdue, Mark/0000-0003-1177-3108; Savage, Sharon/0000-0001-6006-0740; Serra, Massimo/0000-0003-0742-1177 FU Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health; Bone Cancer Research Trust UK; National Cancer Institute, US National Institutes of Health [U10 CA98543, U24 CA114766]; WWWW (QuadW) Foundation to the Children's Oncology Group; Ontario Research Fund; Canadian Foundation for Innovation; Regione Emilia-Romagna; Royal National Orthopaedic Hospital Musculoskeletal Research Programme; Biobank; National Institute for Health Research UCL Hospitals (UCLH) Biomedical Research Centre; UCL Experimental Cancer Centre; Fondo de Investigacion Sanitaria (FIS); Instituto de Salud Carlos III (ISCIII); Caja de Ahorros de Navarra (CAN) Programme 'Tu eliges, tu decides'; Asociacion Espanola Contra el Cancer (AECC) project; [PI10/01580] FX This study was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health and the Bone Cancer Research Trust UK. Research is supported by the Chair's Grant U10 CA98543 and Human Specimen Banking Grant U24 CA114766 to the Children's Oncology Group from the National Cancer Institute, US National Institutes of Health. Additional support for research is provided by a grant from the WWWW (QuadW) Foundation to the Children's Oncology Group. This work was supported by grants to I. L. A. and J.S.W. from the Ontario Research Fund and Canadian Foundation for Innovation. This study was also supported by biobank grants from the Regione Emilia-Romagna and by the infrastructure and personnel of the Royal National Orthopaedic Hospital Musculoskeletal Research Programme and Biobank. Support was also provided to A. M. F. by the National Institute for Health Research UCL Hospitals (UCLH) Biomedical Research Centre and the UCL Experimental Cancer Centre. Funding was also provided by PI10/01580, the Fondo de Investigacion Sanitaria (FIS), the Instituto de Salud Carlos III (ISCIII) and the Caja de Ahorros de Navarra (CAN) Programme 'Tu eliges, tu decides' to A. P.-G. and L. S. and by an Asociacion Espanola Contra el Cancer (AECC) project to F.L. NR 43 TC 68 Z9 69 U1 1 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JUL PY 2013 VL 45 IS 7 BP 799 EP + DI 10.1038/ng.2645 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 172LQ UT WOS:000321005200015 PM 23727862 ER PT J AU Rehermann, B AF Rehermann, Barbara TI Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells SO NATURE MEDICINE LA English DT Review ID C VIRUS-INFECTION; NATURAL-KILLER-CELLS; ADAPTIVE IMMUNE-RESPONSES; ACTIVATED STELLATE CELLS; CHRONIC HBV INFECTION; B-VIRUS; HCV INFECTION; INTERFERON-ALPHA; LIVER FIBROSIS; IN-VIVO AB Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections account for 57% of cases of liver cirrhosis and 78% of cases of primary liver cancer worldwide and cause a million deaths per year. Although HBV and HCV differ in their genome structures, replication strategies and life cycles, they have common features, including their noncytopathic nature and their capacity to induce chronic liver disease, which is thought to be immune mediated. However, the rate of disease progression from chronic hepatitis to cirrhosis varies greatly among infected individuals, and the factors that regulate it are largely unknown. This review summarizes our current understanding of the roles of antigen-specific and nonspecific immune cells in the pathogenesis of chronic hepatitis B and C and discusses recent findings that identify natural killer cells as regulators of T cell function and liver inflammation. C1 NIDDK, Immunol Sect, Liver Dis Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. EM rehermann@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health FX This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health. NR 165 TC 149 Z9 158 U1 7 U2 60 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2013 VL 19 IS 7 BP 859 EP 868 DI 10.1038/nm.3251 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 179YB UT WOS:000321557700029 PM 23836236 ER PT J AU Liang, TJ AF Liang, T. Jake TI Current progress in development of hepatitis C virus vaccines SO NATURE MEDICINE LA English DT Review ID T-CELL RESPONSES; ADAPTIVE IMMUNE-RESPONSES; NATURAL-KILLER-CELLS; NEUTRALIZING ANTIBODIES; UNITED-STATES; SPONTANEOUS CLEARANCE; HEALTHY-VOLUNTEERS; GENETIC-VARIATION; ENVELOPE PROTEIN; VIRAL CLEARANCE AB Despite major advances in the understanding and treatment of hepatitis C, a preventive vaccine remains elusive. The marked genetic diversity and multiple mechanisms of persistence of hepatitis C virus, combined with the relatively poor immune response of the infected host against the virus, are major barriers. The lack of robust and convenient model systems further hampers the effort to develop an effective vaccine. Advances in our understanding of virus-host interactions and protective immunity in hepatitis C virus infection provide an important roadmap to develop potent and broadly directed vaccine candidates targeting both humoral and cellular immune responses. Multiple approaches to generating and testing viral immunogens have met with variable success. Several candidates have advanced to clinical trials based on promising results in chimpanzees. The ultimate path to a successful preventive vaccine requires comprehensive evaluations of all aspects of protective immunity, innovative application of state-of-the-art vaccine technology and properly designed vaccine trials that can affirm definitive endpoints of efficacy. C1 NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. RP Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. EM jliang@nih.gov RI Cheng, Yushao/E-6256-2011 FU Intramural Research Program of the US National Institute of Diabetes and Digestive and Kidney Diseases FX This work is supported by the Intramural Research Program of the US National Institute of Diabetes and Digestive and Kidney Diseases. NR 121 TC 62 Z9 67 U1 1 U2 35 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2013 VL 19 IS 7 BP 869 EP 878 DI 10.1038/nm.3183 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 179YB UT WOS:000321557700030 PM 23836237 ER PT J AU Ranasinghe, S Cutler, S Davis, I Lu, R Soghoian, DZ Qi, Y Sidney, J Kranias, G Flanders, MD Lindqvist, M Kuhl, B Alter, G Deeks, SG Walker, BD Gao, XJ Sette, A Carrington, M Streeck, H AF Ranasinghe, Srinika Cutler, Sam Davis, Isaiah Lu, Richard Soghoian, Damien Z. Qi, Ying Sidney, John Kranias, Gregory Flanders, Michael D. Lindqvist, Madelene Kuhl, Bjorn Alter, Galit Deeks, Steven G. Walker, Bruce D. Gao, Xiaojiang Sette, Alessandro Carrington, Mary Streeck, Hendrik TI Association of HLA-DRB1-restricted CD4(+) T cell responses with HIV immune control SO NATURE MEDICINE LA English DT Article ID INFECTION; PROGRESSION; MOLECULES; PROTEINS; EPITOPES AB The contribution of HLA class II-restricted CD4(+) T cell responses to HIV immune control is poorly defined. Here, we delineated previously uncharacterized peptide-DRB1 restrictions in functional assays and analyzed the host genetic effects of HLA-DRB1 alleles on HIV viremia in a large cohort of HIV controllers and progressors. We found distinct stratifications in the effect of HLA-DRB1 alleles on HIV viremia, with HLA-DRB1*15:02 significantly associated with low viremia and HLA-DRB1*03:01 significantly associated with high viremia. Notably, a subgroup of HLA-DRB1 variants linked with low viremia showed the ability to promiscuously present a larger breadth of peptides with lower functional avidity when compared to HLA-DRB1 variants linked with high viremia. Our data provide systematic evidence that HLA-DRB1 variant expression has a considerable impact on the control of HIV replication, an effect that seems to be mediated primarily by the protein specificity of CD4(+) T cell responses to HIV Gag and Nef. C1 [Ranasinghe, Srinika; Cutler, Sam; Davis, Isaiah; Lu, Richard; Soghoian, Damien Z.; Kranias, Gregory; Flanders, Michael D.; Lindqvist, Madelene; Kuhl, Bjorn; Alter, Galit; Walker, Bruce D.; Carrington, Mary; Streeck, Hendrik] MIT, Ragon Inst MGH, Cambridge, MA 02139 USA. [Ranasinghe, Srinika; Cutler, Sam; Davis, Isaiah; Lu, Richard; Soghoian, Damien Z.; Kranias, Gregory; Flanders, Michael D.; Lindqvist, Madelene; Kuhl, Bjorn; Alter, Galit; Walker, Bruce D.; Carrington, Mary; Streeck, Hendrik] Harvard Univ, Cambridge, MA 02138 USA. [Qi, Ying; Gao, Xiaojiang; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. [Sidney, John; Sette, Alessandro] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. [Deeks, Steven G.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Streeck, H (reprint author), Walter Reed Army Inst Res, US Mil HIV Res Program, Henry M Jackson Fdn, Silver Spring, MD USA. EM hstreeck@hivresearch.org FU US National Institutes of Health (NIH) [R01 AI091450, R01 AI094602]; Henry M. Jackson Foundation; US Department of Defense [W81XWH-07-2-0067]; NIH/National Institute of Allergy and Infectious Diseases (NIAID) [5P30AI060354-09]; Center for HIV/AIDS Immunology and Immunogen Discovery (CHAVI-ID); MGH Executive Committee on Research Fund for Medical Discovery; US Intramural Research Program of the US National Institutes of Health, National Cancer Institute (NCI), Center for Cancer Research [HHSN261200800001E]; Centers for AIDS Research at UCSF [PO AI27763]; CFAR Network of Integrated Systems [R24 AI067039]; UCSF Clinical and Translational Science Institute [UL1 RR024131]; NIAID [RO1 AI087145, K24 AI069994]; Mark and Lisa Schwartz Foundation; Bill & Melinda Gates Foundation; AIDS Healthcare Foundation; CFAR, an NIH [P30 AI060354]; NIH; NIAID; NCI; National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute; National Institute on Drug Abuse; National Institute of Mental Health; National Institute on Aging; Fogarty International Center; Organization for Autism Research FX We thank all individuals whose participation enabled this study. This study was funded by the US National Institutes of Health (NIH) (R01 AI091450 and R01 AI094602). H. S. is funded through R01 AI091450 and R01 AI094602 and the Henry M. Jackson Foundation by a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Department of Defense (W81XWH-07-2-0067). S. R. is supported by a Harvard CFAR Scholar Award (NIH/National Institute of Allergy and Infectious Diseases (NIAID) 5P30AI060354-09), Center for HIV/AIDS Immunology and Immunogen Discovery (CHAVI-ID) and MGH Executive Committee on Research Fund for Medical Discovery. This project has also been funded in part with federal funds from the US Intramural Research Program of the US National Institutes of Health, National Cancer Institute (NCI), Center for Cancer Research, under contract HHSN261200800001E. The UCSF SCOPE cohort was supported by the Centers for AIDS Research at UCSF (PO AI27763), CFAR Network of Integrated Systems (R24 AI067039), the UCSF Clinical and Translational Science Institute (UL1 RR024131), and NIAID (RO1 AI087145 and K24 AI069994). The MGH cohort was supported by the Mark and Lisa Schwartz Foundation and the Collaboration of AIDS Vaccine Discovery of the Bill & Melinda Gates Foundation. This research has been supported in part by the International HIV Controllers Study, funded by the Bill & Melinda Gates Foundation, the AIDS Healthcare Foundation and CFAR, an NIH-funded program (P30 AI060354) that is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, National Institute of Child Health and Human Development, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health, National Institute on Aging, Fogarty International Center and Organization for Autism Research. We thank M. Ghebremichael for statistical assistance and Y. Yuki for HLA genotyping. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 21 TC 33 Z9 33 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2013 VL 19 IS 7 BP 930 EP + DI 10.1038/nm.3229 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 179YB UT WOS:000321557700038 PM 23793098 ER PT J AU Renton, AE Traynor, BJ AF Renton, Alan E. Traynor, Bryan J. TI CRESTing the ALS mountain SO NATURE NEUROSCIENCE LA English DT Editorial Material ID AMYOTROPHIC-LATERAL-SCLEROSIS; PRION-LIKE DOMAINS; NEURODEGENERATIVE DISEASE; MUTATIONS; CHROMATIN; GENE; PROTEINS; FUS AB Chesi et al. use exome sequencing of trios consisting of subjects with amyotrophic lateral sclerosis and their parents to find de novo variants in 25 genes, one of which is the chromatin regulator SS18L1 (CREST). C1 [Renton, Alan E.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Traynor, Bryan J.] Johns Hopkins Univ Hosp, Dept Neurol, Brain Sci Inst, Baltimore, MD 21287 USA. RP Renton, AE (reprint author), NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM alan.renton@nih.gov RI Traynor, Bryan/G-5690-2010 FU Intramural NIH HHS [ZIA AG000933-02] NR 15 TC 0 Z9 0 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD JUL PY 2013 VL 16 IS 7 BP 774 EP 775 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 174UM UT WOS:000321180900003 PM 23799466 ER PT J AU Schoenbaum, G Esber, GR Iordanova, MD AF Schoenbaum, Geoffrey Esber, Guillem R. Iordanova, Mihaela D. TI Dopamine signals mimic reward prediction errors SO NATURE NEUROSCIENCE LA English DT Editorial Material ID SUFFICIENT; RESPONSES; NEURONS AB Modern theories of associative learning center on a prediction error. A study finds that artificial activation of dopamine neurons can substitute for missing reward prediction errors to rescue blocked learning. C1 [Schoenbaum, Geoffrey; Esber, Guillem R.] NIDA, Behav Neurosci Branch, Intramural Res Branch, US Natl Inst Hlth, Baltimore, MD USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Iordanova, Mihaela D.] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. RP Schoenbaum, G (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Branch, US Natl Inst Hlth, Baltimore, MD USA. EM geoffrey.schoenbaum@nih.gov OI Iordanova, Mihaela/0000-0001-6232-448X FU Intramural NIH HHS [ZIA DA000587-01, ZIA DA000587-02, Z99 DA999999] NR 15 TC 3 Z9 3 U1 1 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD JUL PY 2013 VL 16 IS 7 BP 777 EP 779 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 174UM UT WOS:000321180900005 PM 23799468 ER PT J AU Dayan, E Censor, N Buch, ER Sandrini, M Cohen, LG AF Dayan, Eran Censor, Nitzan Buch, Ethan R. Sandrini, Marco Cohen, Leonardo G. TI Noninvasive brain stimulation: from physiology to network dynamics and back SO NATURE NEUROSCIENCE LA English DT Review ID HUMAN MOTOR CORTEX; TRANSCRANIAL MAGNETIC STIMULATION; THETA-BURST-STIMULATION; PAIRED ASSOCIATIVE STIMULATION; HIGH-FREQUENCY STIMULATION; POSTERIOR PARIETAL CORTEX; VENTRAL PREMOTOR CORTEX; CORTICAL STIMULATION; PREFRONTAL CORTEX; SYNAPTIC PLASTICITY AB Noninvasive brain stimulation techniques have been widely used for studying the physiology of the CNS, identifying the functional role of specific brain structures and, more recently, exploring large-scale network dynamics. Here we review key findings that contribute to our understanding of the mechanisms underlying the physiological and behavioral effects of these techniques. We highlight recent innovations using noninvasive stimulation to investigate global brain network dynamics and organization. New combinations of these techniques, in conjunction with neuroimaging, will further advance the utility of their application. C1 [Dayan, Eran; Censor, Nitzan; Buch, Ethan R.; Sandrini, Marco; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Neurorehabil Sect, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Buch, Ethan R.; Sandrini, Marco] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol & Neurorehabil Sect, US Natl Inst Hlth, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov RI Sandrini, Marco/J-2276-2014; OI Sandrini, Marco/0000-0002-1664-5722; Dayan, Eran/0000-0001-9710-9210 FU Intramural Research Program of the US National Institute of Neurological Disorders and Stroke (NINDS; US National Institutes of Health); US Department of Defense in the Center for Neuroscience and Regenerative Medicine; NINDS Ruth L. Kirschstein National Research Service Award FX We thank S.-L. Liew for suggestions. This work was supported by the Intramural Research Program of the US National Institute of Neurological Disorders and Stroke (NINDS; US National Institutes of Health) and by funding from US Department of Defense in the Center for Neuroscience and Regenerative Medicine to M.S. and E.R.B. N.C. was supported by an NINDS Ruth L. Kirschstein National Research Service Award. NR 100 TC 124 Z9 124 U1 9 U2 67 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD JUL PY 2013 VL 16 IS 7 BP 838 EP 844 DI 10.1038/nn.3422 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 174UM UT WOS:000321180900014 PM 23799477 ER PT J AU Bushnell, MC Ceko, M Low, LA AF Bushnell, M. Catherine Ceko, Marta Low, Lucie A. TI Cognitive and emotional control of pain and its disruption in chronic pain SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID IRRITABLE-BOWEL-SYNDROME; ANTERIOR CINGULATE CORTEX; CHRONIC BACK-PAIN; NOXIOUS THERMAL-STIMULATION; MU-OPIOID RECEPTOR; POSITRON-EMISSION-TOMOGRAPHY; POSTERIOR PARIETAL CORTEX; VOXEL-BASED MORPHOMETRY; TRAUMATIC BRAIN-INJURY; LONG-TERM POTENTIATION AB Chronic pain is one of the most prevalent health problems in our modern world, with millions of people debilitated by conditions such as back pain, headache and arthritis. To address this growing problem, many people are turning to mind-body therapies, including meditation, yoga and cognitive behavioural therapy. This article will review the neural mechanisms underlying the modulation of pain by cognitive and emotional states -important components of mind-body therapies. It will also examine the accumulating evidence that chronic pain itself alters brain circuitry, including that involved in endogenous pain control, suggesting that controlling pain becomes increasingly difficult as pain becomes chronic. C1 [Bushnell, M. Catherine; Ceko, Marta; Low, Lucie A.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Bushnell, MC (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 35 Convent Dr,Room 1C917,MSC 3711, Bethesda, MD 20892 USA. EM bushnellmc@mail.nih.gov OI CEKO, MARTA/0000-0001-8679-8145; Low, Lucie/0000-0001-6082-8625 FU Intramural NIH HHS [ZIA AT000024-01] NR 183 TC 191 Z9 196 U1 13 U2 141 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JUL PY 2013 VL 14 IS 7 BP 502 EP 511 DI 10.1038/nrn3516 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 172YY UT WOS:000321044900012 PM 23719569 ER PT J AU Fan, Q He, JF Wang, QR Cai, HB Sun, XG Zhou, XX Qin, HD Shugart, YY Jia, WH AF Fan, Qin He, Jun-Fang Wang, Qi-Rui Cai, Hong-Bing Sun, Xue-Gang Zhou, Xin-Xi Qin, Hai-De Shugart, Yin Yao Jia, Wei-Hua TI Functional polymorphism in the 5 '-UTR of CR2 is associated with susceptibility to nasopharyngeal carcinoma SO ONCOLOGY REPORTS LA English DT Article DE nasopharyngeal carcinoma; complement receptor 2; single-nucleotide polymorphism; susceptibility; case-control study ID BARR-VIRUS RECEPTOR; MESSENGER-RNA; 5'-UNTRANSLATED REGION; TRANSLATION EFFICIENCY; GENETIC POLYMORPHISMS; RISK; VARIANTS; EXPRESSION; CANTONESE; DISEASE AB Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is a squamous cell cancer endemic in Southern China and Southeast Asia. It has been shown that inflammatory and immune responses during EBV infection contribute to the development of NPC. The complement receptor 2 (CR2) gene plays central roles during inflammatory and immune responses and, therefore, is a good candidate susceptibility gene for NPC. We performed PCR-based sequencing to identify multiple single-nucleotide polymorphisms (SNPs) within the exon regions of the CR2 gene in a Cantonese population. Two SNPs were screened in 528 NPC patients and 408 normal individuals to perform a case-control study matched according to age, gender and residence. Furthermore, we cloned the entire 5'-UTR and entire CR2 promoter into a luciferase report system and compared the luciferase activities between the different allelic constructs. A SNP in the 5'-UTR of CR2 (24 TIC, rs3813946) showed a significant association (P<0.01) with NPC in the Cantonese population studied. The subjects were categorized into 2 age groups: group 1, age <= 45 years and group 2, age >45 years. In group 1, the allelic frequencies of 24 TIC in the patients were significantly different from those of the controls (P=0.0034). The odds ratio (OR=1.81) also indicated a higher risk of NPC in individuals who carried the minor allele C. All constructs exerted allelic differences on luciferase activities, but only the susceptible allele +24C construct showed increased activity. Our findings implicate CR2 as a susceptibility gene for NPC and suggest that enhanced CR2 expression may be involved in the oncogenesis and development of NPC. C1 [Fan, Qin; Wang, Qi-Rui; Cai, Hong-Bing; Sun, Xue-Gang] Southern Med Univ, Coll Tradit Chinese Med, Guangzhou 510515, Guangdong, Peoples R China. [He, Jun-Fang; Zhou, Xin-Xi; Qin, Hai-De; Jia, Wei-Hua] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol Southern China, Guangzhou 510060, Guangdong, Peoples R China. [He, Jun-Fang; Zhou, Xin-Xi; Qin, Hai-De; Jia, Wei-Hua] Sun Yat Sen Univ, Ctr Canc, Dept Expt Res, Guangzhou 510060, Guangdong, Peoples R China. [He, Jun-Fang] Sun Yat Sen Univ, Dept Immunol, Guangzhou 510080, Guangdong, Peoples R China. [Shugart, Yin Yao] NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Jia, WH (reprint author), Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol Southern China, Guangzhou 5100605, Guangdong, Peoples R China. EM jiaweih@mail.sysu.edu.cn FU National Natural Science Foundation [30000141, 81173616]; National Key Basic Research Projects (973 Projects) [G19980510]; National Science and Technology Project of China [2002BA711A03] FX This study was supported by the National Natural Science Foundation (30000141 and 81173616), the National Key Basic Research Projects (973 Projects, G19980510) and the National Science and Technology Project (2002BA711A03) of China. We thank Lizhen Chen and Qisheng Feng for providing the clinical data and we also thank Ruhua Zhang for the DNA sequencing. NR 32 TC 4 Z9 4 U1 1 U2 6 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD JUL PY 2013 VL 30 IS 1 BP 11 EP 16 DI 10.3892/or.2013.2421 PG 6 WC Oncology SC Oncology GA 173KD UT WOS:000321077500002 PM 23612877 ER PT J AU Kauffman, EC Robinson, BD Downes, M Marcinkiewicz, K Vourganti, S Scherr, DS Gudas, LJ Mongan, NP AF Kauffman, Eric C. Robinson, Brian D. Downes, Martin Marcinkiewicz, Katarzyna Vourganti, Srinivas Scherr, Douglas S. Gudas, Lorraine J. Mongan, Nigel P. TI Estrogen receptor-beta expression and pharmacological targeting in bladder cancer SO ONCOLOGY REPORTS LA English DT Article DE epigenetic; hormonal; urothelial; transitional cell ID TRANSITIONAL-CELL CARCINOMA; RADICAL CYSTECTOMY; URINARY-BLADDER; ER-BETA; RISK; MORTALITY; RECURRENCE; GENDER; ROLES; ALPHA AB A role for estrogen signaling in urothelial carcinoma of the bladder (UCB) is suggested to be associated with more advanced disease with worse outcomes in women. Estrogen receptor beta (ER beta) is the predominant receptor in bladder tissues. We aimed to ascertain whether ER beta correlates with clinicopathological predictors of aggressive bladder cancer and worse survival outcomes. ER beta was measured by immunohistochemistry in malignant and adjacent benign bladder tissues in patients (N=72) with UCB who underwent radical cystectomy. ER beta expression was tested for statistical association with clinicopathological variables and patient survival. ER beta expression was determined in bladder cancer cell lines, and the effects of the selective estrogen modulator tamoxifen and the ER beta agonist diarylpropionitrile on cell growth were determined. The ER beta level was significantly higher in malignant vs. benign urothelium (P<0.001) and was strongly associated with aggressive tumor histology characterized by lymphovascular (P=0.008) and perineural (P=0.006) invasion, and clinical histories of pelvic irradiation (P=0.005), hydronephrosis (P=0.022) and no intravesical chemotherapy (P=0.038). All patients with a high (>70%) percentage of ER beta positivity in tissue with >3-month follow-up developed recurrent disease (P=0.009). Higher ER beta level was predictive of worse recurrence-free and overall survival following cystectomy, after adjustment for tumor stage, and remained significantly associated with recurrence-free survival in the multivariable analysis including tumor stage, nodal stage and lymphovascular invasion. Activation of ER beta in bladder cancer cell lines led to significant increases in proliferation, while pharmacological inhibition with tamoxifen blocked cell growth. Our study supports a role for ER beta in aggressive UCB. Pharmacological targeting of ER beta warrants further investigation as a therapeutic strategy in UCB. C1 [Kauffman, Eric C.; Robinson, Brian D.; Scherr, Douglas S.] Weill Cornell Med Coll, Dept Urol, New York, NY 10065 USA. [Kauffman, Eric C.] Roswell Pk Canc Inst, Dept Urol, Buffalo, NY 14263 USA. [Kauffman, Eric C.] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. [Robinson, Brian D.; Mongan, Nigel P.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. [Downes, Martin; Mongan, Nigel P.] Univ Nottingham, Fac Med & Hlth Sci, Sch Vet Med & Sci, Loughborough LE12 5RD, Leics, England. [Marcinkiewicz, Katarzyna; Gudas, Lorraine J.] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA. [Vourganti, Srinivas] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Gudas, LJ (reprint author), Weill Cornell Med Coll, Dept Pharmacol, 1300 York Ave, New York, NY 10065 USA. EM ljgudas@med.cornell.edu; nigel.mongan@nottingham.ac.uk RI Mongan, Nigel/B-7410-2011 FU Weill Cornell Medical College; University of Nottingham; NIH (NIDCR) FX The authors gratefully acknowledge the institutional financial support of Weill Cornell Medical College, the University of Nottingham and an F31 Fellowship from NIH (NIDCR) (K.M). NR 31 TC 8 Z9 8 U1 0 U2 7 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD JUL PY 2013 VL 30 IS 1 BP 131 EP 138 DI 10.3892/or.2013.2416 PG 8 WC Oncology SC Oncology GA 173KD UT WOS:000321077500019 PM 23612777 ER PT J AU Shepperd, JA Klein, WMP Waters, EA Weinstein, ND AF Shepperd, James A. Klein, William M. P. Waters, Erika A. Weinstein, Neil D. TI Taking Stock of Unrealistic Optimism SO PERSPECTIVES ON PSYCHOLOGICAL SCIENCE LA English DT Article DE unrealistic optimism; comparative optimism; optimistic bias; risk judgments ID TASK-COMPLETION TIMES; PROTECTION MOTIVATION THEORY; COMPARATIVE RISK JUDGMENTS; FUTURE LIFE-EVENTS; PERSONAL RISK; PLANNING FALLACY; PERCEIVED VULNERABILITY; CIGARETTE SMOKERS; POSITIVITY BIAS; ATTITUDE-CHANGE AB Researchers have used terms such as unrealistic optimism and optimistic bias to refer to concepts that are similar but not synonymous. Drawing from 3 decades of research, we discuss critically how researchers define unrealistic optimism, and we identify four types that reflect different measurement approaches: unrealistic absolute optimism at the individual and group levels and unrealistic comparative optimism at the individual and group levels. In addition, we discuss methodological criticisms leveled against research on unrealistic optimism and note that the criticisms are primarily relevant to only one type: the group form of unrealistic comparative optimism. We further clarify how the criticisms are not nearly as problematic as they might seem, even for unrealistic comparative optimism. Finally, we note boundary conditions on the different types of unrealistic optimism and reflect on five broad questions that deserve further attention. C1 [Shepperd, James A.] Univ Florida, Gainesville, FL 32611 USA. [Klein, William M. P.] NCI, Bethesda, MD 20892 USA. [Waters, Erika A.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Weinstein, Neil D.] Rutgers State Univ, Piscataway, NJ 08855 USA. RP Shepperd, JA (reprint author), Univ Florida, Dept Psychol, POB 112250, Gainesville, FL 32611 USA. EM shepperd@ufl.edu OI Waters, Erika/0000-0001-7402-0133 FU NIMHD NIH HHS [L60 MD006280] NR 99 TC 44 Z9 44 U1 3 U2 57 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1745-6916 J9 PERSPECT PSYCHOL SCI JI Perspect. Psychol. Sci. PD JUL PY 2013 VL 8 IS 4 BP 395 EP 411 DI 10.1177/1745691613485247 PG 17 WC Psychology, Multidisciplinary SC Psychology GA 179BU UT WOS:000321493400003 PM 26045714 ER PT J AU Perrino, T Howe, G Sperling, A Beardslee, W Sandler, I Shern, D Pantin, H Kaupert, S Cano, N Cruden, G Bandiera, F Brown, CH AF Perrino, Tatiana Howe, George Sperling, Anne Beardslee, William Sandler, Irwin Shern, David Pantin, Hilda Kaupert, Sheila Cano, Nicole Cruden, Gracelyn Bandiera, Frank Brown, C. Hendricks TI Advancing Science Through Collaborative Data Sharing and Synthesis SO PERSPECTIVES ON PSYCHOLOGICAL SCIENCE LA English DT Article DE collaborative research; data sharing; data synthesis; scientific equity; integrative data analysis ID RANDOMIZED CONTROLLED-TRIAL; INTEGRATIVE DATA-ANALYSIS; DEPRESSIVE SYMPTOMS; PREVENTIVE INTERVENTION; SUBSTANCE USE; ADOLESCENTS; CHILDREN; FAMILY; METAANALYSIS; EFFICACY AB The demand for researchers to share their data has increased dramatically in recent years. There is a need to replicate and confirm scientific findings to bolster confidence in many research areas. Data sharing also serves the critical function of allowing synthesis of findings across trials. As innovative statistical methods have helped resolve barriers to synthesis analyses, data sharing and synthesis can help answer research questions that cannot be answered by individual trials alone. However, the sharing of data among researchers remains challenging and infrequent. This article aims to (a) increase support for data sharing and synthesis collaborations among researchers to advance scientific knowledge and (b) provide a model for establishing these collaborations using the example of the ongoing National Institute of Mental Health's Collaborative Data Synthesis on Adolescent Depression Trials. This study brings together datasets from existing prevention and treatment trials in adolescent depression, as well as researchers and stakeholders, to answer questions about for whom interventions work and by what pathways interventions have their effects. This is critical to improving interventions, including increasing knowledge about intervention efficacy among minority populations, or what we call scientific equity. The collaborative model described is relevant to fields with research questions that can only be addressed by synthesizing individual-level data. C1 [Perrino, Tatiana; Pantin, Hilda; Kaupert, Sheila; Cano, Nicole; Cruden, Gracelyn; Brown, C. Hendricks] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Howe, George] George Washington Univ, Washington, DC 20052 USA. [Sperling, Anne] NIMH, Bethesda, MD 20892 USA. [Beardslee, William] Childrens Hosp, Boston, MA 02115 USA. [Beardslee, William] Harvard Univ, Cambridge, MA 02138 USA. [Sandler, Irwin] Arizona State Univ, Tempe, AZ 85287 USA. [Shern, David] Mental Hlth Amer, Alexandria, VA USA. [Bandiera, Frank] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Perrino, T (reprint author), Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, 1425 NW 10th Ave,307F R-669, Miami, FL 33136 USA. EM tperrino@med.miami.edu RI chen, zhu/K-5923-2013; OI Brown, C Hendricks/0000-0002-0294-2419 NR 45 TC 15 Z9 15 U1 3 U2 14 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1745-6916 J9 PERSPECT PSYCHOL SCI JI Perspect. Psychol. Sci. PD JUL PY 2013 VL 8 IS 4 BP 433 EP 444 DI 10.1177/1745691613491579 PG 12 WC Psychology, Multidisciplinary SC Psychology GA 179BU UT WOS:000321493400007 ER PT J AU Hafko, R Villapol, S Nostramo, R Symes, A Sabban, EL Inagami, T Saavedra, JM AF Hafko, Roman Villapol, Sonia Nostramo, Regina Symes, Aviva Sabban, Esther L. Inagami, Tadashi Saavedra, Juan M. TI Commercially Available Angiotensin II At-2 Receptor Antibodies Are Nonspecific SO PLOS ONE LA English DT Article ID GENE-DISRUPTED MICE; TYPE-2 AT(2) RECEPTOR; MESSENGER-RNA; RAT-KIDNEY; CONVERTING-ENZYME; ADRENAL-GLAND; BIOCHEMICAL-PROPERTIES; ADRENERGIC-RECEPTORS; ANTERIOR-PITUITARY; AT(1) RECEPTORS AB Commercially available angiotensin II AT(2) receptor antibodies are widely employed for receptor localization and quantification, but they have not been adequately validated. In this study, we characterized three commercially available AT(2) receptor antibodies: 2818-1 from Epitomics, sc-9040 from Santa Cruz Biotechnology, Inc., and AAR-012 from Alomone Labs. Using western blot analysis the immunostaining patterns observed were different for every antibody tested, and in most cases consisted of multiple immunoreactive bands. Identical immunoreactive patterns were present in wild-type and AT(2) receptor knockout mice not expressing the target protein. In the mouse brain, immunocytochemical studies revealed very different cellular immunoreactivity for each antibody tested. While the 2818-1 antibody reacted only with endothelial cells in small parenchymal arteries, the sc-9040 antibody reacted only with ependymal cells lining the cerebral ventricles, and the AAR-012 antibody reacted only with multiple neuronal cell bodies in the cerebral cortex. Moreover, the immunoreactivities were identical in brain tissue from wildtype or AT(2) receptor knockout mice. Furthermore, in both mice and rat tissue extracts, there was no correlation between the observed immunoreactivity and the presence or absence of AT(2) receptor binding or gene expression. We conclude that none of these commercially available AT(2) receptor antibodies tested met the criteria for specificity. In the absence of full antibody characterization, competitive radioligand binding and determination of mRNA expression remain the only reliable approaches to study AT(2) receptor expression. C1 [Hafko, Roman; Saavedra, Juan M.] NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Villapol, Sonia; Symes, Aviva] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Villapol, Sonia; Symes, Aviva] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. [Nostramo, Regina; Sabban, Esther L.] New York Med Coll, Dept Biochem & Mol Biol, Valhalla, NY 10595 USA. [Inagami, Tadashi] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. EM Saavedrj@mail.nih.gov RI Symes, Aviva/S-7471-2016 OI Symes, Aviva/0000-0003-2557-9939 FU Intramural Research Program of the National Institute of Mental Health [MH002762-16]; Center for Neuroscience and Regenerative Medicine [300604 11.060855]; American Heart Association [10GRNT442001]; NIH [HL58205] FX Juan M. Saavedra was funded by the Intramural Research Program of the National Institute of Mental Health: MH002762-16 (2012). Sonia Villapol and Aviva Symes were funded by: Center for Neuroscience and Regenerative Medicine (grant no: 300604 11.060855), http://www.usuhs.mil/cnrm/. Drs. Esther Sabban and Regina Nostramu were funded by the American Heart Association, Grant # 10GRNT442001 to Esther L. Sabban. Tadashi Inagami was funded by grant HL58205 from NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 20 Z9 20 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 1 PY 2013 VL 8 IS 7 AR UNSP e69234 DI 10.1371/journal.pone.0069234 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 175ZH UT WOS:000321271900050 PM 23840911 ER PT J AU Chaudhary, KR Zordoky, BNM Edin, ML Alsaleh, N El-Kadi, AOS Zeldin, DC Seubert, JM AF Chaudhary, Ketul R. Zordoky, Beshay N. M. Edin, Matthew L. Alsaleh, Nasser El-Kadi, Ayman O. S. Zeldin, Darryl C. Seubert, John M. TI Differential effects of soluble epoxide hydrolase inhibition and CYP2J2 overexpression on postischemic cardiac function in aged mice SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article DE Epoxyeicosatrienoic acids; Cytochrome P450; Aging; Ischemia reperfusion injury; Soluble epoxide hydrolase inhibitor; Leukotoxin diol ID ISCHEMIA-REPERFUSION INJURY; LINOLEIC-ACID METABOLITES; CA2+-ACTIVATED K+ CHANNELS; HEART CONTRACTILE FUNCTION; RAT VENTRICULAR MYOCYTES; PROTEIN PHOSPHATASE 2A; EPOXYEICOSATRIENOIC ACIDS; ENDOTHELIAL-CELLS; MITOCHONDRIAL DYSFUNCTION; INDUCED CARDIOPROTECTION AB Cardioprotective effects of epoxyeicosatrienoic acids (EETs) have been demonstrated in models of young mice with either the cardiomyocyte specific over-expression of cytochrome P450 2J2 (CYP2J2 Tr) or deletion of soluble epoxide hydrolase (sEH null). In this study we examined differences in EET-induced cardioprotection in young (2 months) and aged (12 months) CYP2J2 Tr and sEHnull mice using Langendorff isolated perfused heart model. Improved postischemic functional recovery was observed in both young and aged sEH null mice compared to age matched WT. Conversely, the cardioprotective effect observed in young CYP2J2 Tr was lost in aged CYP2J2 Tr mice. The loss of cardioprotection in aged CYP2J2 Tr was regained following perfusion with the sEH inhibitor t-AUCB. Data demonstrated increased levels of leukotoxin dial (DiHOME) and oxidative stress as well decreased protein phosphatase 2A (PP2A) activation in aged CYP2J2 Tr. In conclusion, inhibition of sEH and EET-induced cardioprotection is maintained in aged mice. However, the loss of protective effects observed in aged CYP2J2 Tr might be attributed to increased levels of DiHOME, oxidative stress and/or decreased PP2A activity. (C) 2012 Elsevier Inc. All rights reserved. C1 [Chaudhary, Ketul R.; Zordoky, Beshay N. M.; Alsaleh, Nasser; El-Kadi, Ayman O. S.; Seubert, John M.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2E1, Canada. [Seubert, John M.] Univ Alberta, Fac Med, Dept Pharmacol, Edmonton, AB T6G 2E1, Canada. [Edin, Matthew L.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Durham, NC USA. RP Seubert, JM (reprint author), Univ Alberta, Fac Pharm & Pharmaceut Sci, Katz Ctr Pharm & Hlth Res 2 020M, Edmonton, AB T6G 2E1, Canada. EM jseubert@pharmacy.ualberta.ca OI Edin, Matthew/0000-0002-7042-500X; Zordoky, Beshay/0000-0002-9358-4185 FU Heart and Stroke Foundation of Canada; Alberta Innovates-Health Solutions FX KRC is the recipient of the Doctoral Research Award from the Heart and Stroke Foundation of Canada and the Studentship award from the Alberta Innovates-Health Solutions. JMS is the recipient of a New Investigator Award from the Heart and Stroke Foundation of Canada and a Health Scholar Award from the Alberta Innovates-Health Solutions. This work was supported by grant from Heart and Stroke Foundation of Canada (JMS). NR 47 TC 4 Z9 4 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD JUL-AUG PY 2013 VL 104 SI SI BP 8 EP 17 DI 10.1016/j.prostaglandins.2012.08.001 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 183GM UT WOS:000321802500003 PM 22922020 ER PT J AU Strauss, KI Gruzdev, A Zeldin, DC AF Strauss, Kenneth I. Gruzdev, Artiom Zeldin, Darryl C. TI Altered behavioral phenotypes in soluble epoxide hydrolase knockout mice: Effects of traumatic brain injury SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article DE Brain injury recovery; Behavior; Cytochrome P450 eicosanoids; Arachidonic acid metabolism ID EPOXYEICOSATRIENOIC ACID METABOLISM; BLOOD-PRESSURE REGULATION; ARACHIDONIC-ACID; FUNCTIONAL HYPEREMIA; PHOSPHATASE-ACTIVITY; RAT; INHIBITORS; EPOXYGENASE; MODEL; CYTOCHROME-P-450 AB After traumatic brain injury (TBI), arachidonic acid (ArA) is released from damaged cell membranes and metabolized to many bioactive eicosanoids, including several epoxyeicosatrienoic acids (EETs). Soluble epoxide hydrolase (Ephx2, sEH) appears to be the predominant pathway for EET metabolism to less active dihydroxyeicosatrienoates (DHETs). Prior studies indicate that brain levels of EETs increase transiently after TBI and EETs have antiinflammatory and neuroprotective activities which may benefit the injured brain. If the net effect of increased EET levels in the injured brain is beneficial to recovery, then Ephx2 gene disruption would be expected to enhance elevated EET levels and improve recovery in the injured brain. Thus, Ephx2-KO (Ephx2(-/-) bred onto pure C57Bl/6 background) mice were compared to wild-type controls in a unilateral controlled cortical impact model of TBI. Before injury, animals behaved comparably in open field activity and neurologic reflexes. Interestingly, the Ephx2-KO mice showed improved motor coordination on a beam walk task, yet showed indications of defective learning in a test of working spatial memory. After surgery, brain-injured Ephx2-KO mice again had less of a deficit in the beam walk than wild-type, and the difference in latency (post - pre) showed a trend of protection for Ephx2-KO mice after TBI. Brain-injured mice showed no genotype differences in working memory. Surprisingly, sham-operated Ephx2-KO mice exhibited an injured phenotype for working memory, compared to sham-operated wild-type mice. Brain eicosanoid levels were measured using liquid chromatography with tandem mass spectrometry. Of the 20 eicosanoids evaluated, only 8,9-EET was elevated in the Ephx2-KO cerebral cortex (37 d post-surgery, in both sham and injured). Tissue DHET levels were below the limit of quantification. These results reflect a significant contribution of sEH deficiency in coordination of ambulatory movements and working spatial memory in the mouse. Further investigation of differential sEH expression and EET levels at earlier time points and across other brain regions may shed light on these behavioral differences. (C) 2012 Published by Elsevier Inc. C1 [Strauss, Kenneth I.] Michigan State Univ, Coll Human Med, Grand Rapids, MI 49503 USA. [Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Strauss, KI (reprint author), Michigan State Univ, Coll Human Med, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA. EM kenneth.strauss@hc.msu.edu; artiom.gruzdev@nih.gov; zeldin@niehs.nih.gov FU NINDS [NS054890] FX This work was funded in part by NINDS Grant NS054890 (KIS). The authors would like to thank Laura Miller, J. Alyce Bradbury and Joan P. Graves for managing the animal colony, confirming genotypes and coordinating shipments. Thanks also to Analise Sauro and Jaimie Pineda for excellent technical assistance in the completion of this work. NR 36 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 EI 2212-196X J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD JUL-AUG PY 2013 VL 104 SI SI BP 18 EP 24 DI 10.1016/j.prostaglandins.2012.07.005 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 183GM UT WOS:000321802500004 PM 22922090 ER PT J AU Oni-Orisan, A Deng, YM Schuck, RN Theken, KN Edin, ML Lih, FB Molnar, K DeGraff, L Tomer, KB Zeldin, DC Lee, CR AF Oni-Orisan, Akinyemi Deng, Yangmei Schuck, Robert N. Theken, Katherine N. Edin, Matthew L. Lih, Fred B. Molnar, Kimberly DeGraff, Laura Tomer, Kenneth B. Zeldin, Darryl C. Lee, Craig R. TI Dual modulation of cyclooxygenase and CYP epoxygenase metabolism and acute vascular inflammation in mice SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article DE CYP2J2; Soluble epoxide hydrolase; Cyclooxygenase; Vascular inflammation; Epoxyeicosatrienoic acid; Prostaglandin ID SOLUBLE EPOXIDE HYDROLASE; NF-KAPPA-B; EPOXYEICOSATRIENOIC ACIDS; CYTOCHROME-P450 EPOXYGENASES; ENDOTHELIAL EXPRESSION; PROSTAGLANDIN E-2; BLOOD-PRESSURE; IN-VIVO; INHIBITORS; ENDOTOXIN AB Cyclooxygenase (COX)-derived prostaglandins and cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids are important regulators of inflammation; however, functional interactions' between these pathways in the regulation of vascular inflammation in vivo have not been studied. We investigated the relative and additive effects of endothelial CYP2J2 overexpression (Tie2-CYP2J2-Tr), global sEH disruption (Ephx2(-/-)), and pharmacologic COX inhibition with indomethacin on the acute vascular inflammatory response to endotoxin in mice. Compared to vehicle-treated wild-type C57BL/6 controls, induction of myeloperoxidase (MPO) activity in lung and liver was similarly attenuated in Tie2-CYP2J2-Tr mice, Ephx2(-/-) mice and wild-type mice treated with moderate dose indomethacin. Dual modulation of both pathways, however, did not produce an additive anti-inflammatory effect. These findings demonstrate that both COX and CYP epoxygenase-mediated eicosanoid metabolism are important regulators of the acute vascular inflammatory response in vivo, and suggest that the anti-inflammatory effects of modulating each pathway may be mediated, at least in part, by overlapping mechanisms. (C) 2012 Elsevier Inc. All rights reserved. C1 [Oni-Orisan, Akinyemi; Deng, Yangmei; Schuck, Robert N.; Theken, Katherine N.; Molnar, Kimberly; Lee, Craig R.] Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Edin, Matthew L.; Lih, Fred B.; DeGraff, Laura; Tomer, Kenneth B.; Zeldin, Darryl C.] NIEHS, Lab Resp Biol, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Lee, CR (reprint author), Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, Eshelman Sch Pharm, CB 7569 Kerr Hall, Chapel Hill, NC 27599 USA. EM craig_lee@unc.edu OI Edin, Matthew/0000-0002-7042-500X; Lee, Craig/0000-0003-3595-5301 FU University of North Carolina at Chapel Hill Royster Society of Fellows Chancellor's Fellowship; American Heart Association [T32 HL069768]; American Foundation for Pharmaceutical Education; Intramural Research Program of the NIH/NIEHS [Z01 ES050167, Z01 ES025034]; [R01 GM088199]; [R01 GM088199-S1] FX This publication was made possible by a University of North Carolina at Chapel Hill Royster Society of Fellows Chancellor's Fellowship to Dr. Oni-Orisan, a predoctoral training program in Integrative Vascular Biology (T32 HL069768) and predoctoral fellowship from the American Heart Association to Dr. Schuck, a predoctoral fellowship from the American Foundation for Pharmaceutical Education to Dr. Theken, funds from the Intramural Research Program of the NIH/NIEHS to Dr. Tomer (Z01 ES050167) and Dr. Zeldin (Z01 ES025034), and grants R01 GM088199 and R01 GM088199-S1 to Dr. Lee. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 36 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD JUL-AUG PY 2013 VL 104 SI SI BP 67 EP 73 DI 10.1016/j.prostaglandins.2012.09.003 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 183GM UT WOS:000321802500010 PM 23000418 ER PT J AU Li, H Edin, ML Gruzdev, A Cheng, J Bradbury, JA Graves, JP DeGraff, LM Zeldin, DC AF Li, Hong Edin, Matthew L. Gruzdev, Artiom Cheng, Jennifer Bradbury, J. Alyce Graves, Joan P. DeGraff, Laura M. Zeldin, Darryl C. TI Regulation of T helper cell subsets by cyclooxygenases and their metabolites SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Review DE Cyclooxygenases; T helper cells; Prostanoids; PGE2 ID ASPIRIN-INDUCED ASTHMA; HUMAN TH17 CELLS; ANTIGEN-PRESENTING CELLS; EXACERBATED RESPIRATORY-DISEASE; ALLERGIC AIRWAY INFLAMMATION; PROSTAGLANDIN E-2 PRODUCTION; SELECTIVE COX-2 INHIBITOR; TH2 IMMUNE-RESPONSES; IFN-GAMMA PRODUCTION; DENDRITIC CELLS AB Cyclooxygenases and their metabolites are important regulators of inflammatory responses and play critical roles in regulating the differentiation of T helper cell subsets in inflammatory diseases. In this review, we highlight new information on regulation of T helper cell subsets by cyclooxygenases and their metabolites. Prostanoids influence cytokine production by both antigen presenting cells and T cells to regulate the differentiation of naive CD4(+) T cells to Th1, Th2 and Th17 cell phenotypes. Cyclooxygenases and PGE(2) generally exacerbate Th2 and Th17 phenotypes, while suppressing Th1 differentiation. Thus, cycloxygenases may play a critical role in diseases that involve immune cell dysfunction. Targeting of cyclooxygenases and their eicosanoid products may represent a new approach for treatment of inflammatory diseases, tumors and autoimmune disorders. Published by Elsevier Inc. C1 [Li, Hong; Edin, Matthew L.; Gruzdev, Artiom; Cheng, Jennifer; Bradbury, J. Alyce; Graves, Joan P.; DeGraff, Laura M.; Zeldin, Darryl C.] NIEHS, Lab Resp Biol, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Zeldin, DC (reprint author), NIEHS, Div Intramural Res, NIH, 111 TW Alexander Dr,Bldg 101,Room A214, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov OI Edin, Matthew/0000-0002-7042-500X FU Intramural NIH HHS [Z01 ES025043-09] NR 127 TC 8 Z9 8 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD JUL-AUG PY 2013 VL 104 SI SI BP 74 EP 83 DI 10.1016/j.prostaglandins.2012.11.002 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 183GM UT WOS:000321802500011 PM 23201570 ER PT J AU Sutin, AR Costa, PT Chan, W Milaneschi, Y Eaton, WW Zonderman, AB Ferrucci, L Terracciano, A AF Sutin, Angelina R. Costa, Paul T., Jr. Chan, Wayne Milaneschi, Yuri Eaton, William W. Zonderman, Alan B. Ferrucci, Luigi Terracciano, Antonio TI I Know Not To, but I Can't Help It: Weight Gain and Changes in Impulsivity-Related Personality Traits SO PSYCHOLOGICAL SCIENCE LA English DT Article DE health; personality; impulsiveness; deliberation; body mass index ID EPIDEMIOLOGIC CATCHMENT-AREA; SOCIOECONOMIC-STATUS; OBESE ADULTS; BODY-MASS; FOLLOW-UP; OVERWEIGHT; LIFE; DEPRESSION; CHILDHOOD; STABILITY AB Reciprocal relations between weight and psychological factors suggest that there are deep connections between mind and body. Personality traits are linked to weight gain; weight gain may likewise be associated with personality change. Using data from two diverse longitudinal samples (N = 1,919) collected at two time points an average of 10 years apart, we showed that significant weight gain is associated with increases in both impulsiveness and deliberation: In both samples, middle-aged adults who gained 10% or more of their baseline body weight by follow-up increased in their tendency to give in to temptation, yet were more thoughtful about the consequences of their actions. The present research moves beyond life events to implicate health status in adult personality development. The findings also suggest that interventions focusing on the emotional component of impulse control may be more effective because even people who become more thoughtful about the consequences of their actions may have limited success at inhibiting their behavior. C1 [Sutin, Angelina R.] Florida State Univ, Coll Med, Dept Med Humanities & Social Sci, Tallahassee, FL 32306 USA. [Sutin, Angelina R.; Costa, Paul T., Jr.; Chan, Wayne; Zonderman, Alan B.; Terracciano, Antonio] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Chan, Wayne] Rutgers State Univ, Dept Psychol, Piscataway, NJ 08855 USA. [Milaneschi, Yuri; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Milaneschi, Yuri] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Eaton, William W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Terracciano, Antonio] Florida State Univ, Coll Med, Dept Genet, Tallahassee, FL 32306 USA. RP Sutin, AR (reprint author), Florida State Univ, Coll Med, 1115 W Call St, Tallahassee, FL 32306 USA. EM angelina.sutin@med.fsu.edu RI terracciano, antonio/B-1884-2008; OI Chan, Wayne/0000-0001-5061-1713; Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS [Z99 AG999999, ZIA AG000183-22, ZIA AG000197-03, ZIA AG000197-04, ZIA AG000183-23]; PHS HHS [DAO26652] NR 27 TC 20 Z9 20 U1 3 U2 34 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD JUL PY 2013 VL 24 IS 7 BP 1323 EP 1328 DI 10.1177/0956797612469212 PG 6 WC Psychology, Multidisciplinary SC Psychology GA 181XC UT WOS:000321702500030 PM 23630223 ER PT J AU Burns, JE Yao, J Wiese, TS Munoz, HE Jones, EC Summers, RM AF Burns, Joseph E. Yao, Jianhua Wiese, Tatjana S. Munoz, Hector E. Jones, Elizabeth C. Summers, Ronald M. TI Automated Detection of Sclerotic Metastases in the Thoracolumbar Spine at CT SO RADIOLOGY LA English DT Article ID COMPUTER-AIDED DETECTION; SUPPORT VECTOR MACHINES; SKELETAL-RELATED EVENTS; PROSTATE-CANCER; BONE-DISEASE; LUNG NODULES; VERTEBRAE; DIAGNOSIS; RECOGNITION; PERFORMANCE AB Purpose: To design and validate a computer system for automated detection and quantitative characterization of sclerotic metastases of the thoracolumbar spine on computed tomography (CT) images. Materials and Methods: This retrospective study was approved by the institutional review board and was HIPAA compliant; informed consent was waived. The data set consisted of CT examinations in 49 patients (14 female, 35 male patients; mean age, 57.0 years; range, 12-77 years), demonstrating a total of 532 sclerotic lesions of the spine of greater than 0.3 cm(3) in volume, and in 10 control case patients (four women, six men; mean age, 55.2 years; range, 19-70 years) without spinal lesions. CT examinations were divided into training and test sets, and images were analyzed according to prototypical fully-automated computer-aided detection (CAD) software. Free-response receiver operating characteristic analysis was performed. Results: Lesion detection sensitivity on images in the training set was 90%, relative to reference-standard marked lesions (95% confidence interval [CI]: 83%, 97%), at a false-positive rate (FPR) of 10.8 per patient (95% CI: 6.6, 15.0). For images in the testing set, sensitivity was 79% (95% CI: 74%, 84%), with an FPR of 10.9 per patient (95% CI: 8.5, 13.3). False-negative findings were most commonly (37 [40%] of 93) a result of endplate proximity, with 32 (34% of 93) caused by low CT attenuation. Marginal sclerosis caused by degenerative change (174 [28.1%] of 620 actual detections) was the most common cause of false-positive detections, followed by partial volume averaging with vertebral endplates (173 [27.9%] of 620) and pedicle cortex parallel to the axial imaging plane (121 [19.5%] 620). Conclusion: This CAD system successfully identified and segmented sclerotic lesions in the thoracolumbar spine. (C) RSNA, 2013 C1 [Burns, Joseph E.] Univ Calif Irvine, Dept Radiol Sci, Orange, CA 92668 USA. [Yao, Jianhua; Wiese, Tatjana S.; Munoz, Hector E.; Jones, Elizabeth C.; Summers, Ronald M.] NIH, Imaging Biomarkers & Computer Aided Detect Lab, Ctr Clin, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Computer Aided Detect Lab, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C224D,MSC1182, Bethesda, MD 20892 USA. EM rms@nih.gov FU National Institutes of Health [1Z01 CL040004] FX This research was supported by the National Institutes of Health (grant 1Z01 CL040004), and the authors are employees of the National Institutes of Health. NR 40 TC 9 Z9 9 U1 0 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2013 VL 268 IS 1 BP 69 EP 78 DI 10.1148/radiol.13121351 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 169ER UT WOS:000320761400008 PM 23449957 ER PT J AU Turkbey, B Mani, H Aras, O Ho, J Hoang, A Rastinehad, AR Agarwal, H Shah, V Bernardo, M Pang, YX Daar, D McKinney, YL Linehan, WM Kaushal, A Merino, MJ Wood, BJ Pinto, PA Choyke, PL AF Turkbey, Baris Mani, Haresh Aras, Omer Ho, Jennifer Hoang, Anthony Rastinehad, Ardeshir R. Agarwal, Harsh Shah, Vijay Bernardo, Marcelino Pang, Yuxi Daar, Dagane McKinney, Yolanda L. Linehan, W. Marston Kaushal, Aradhana Merino, Maria J. Wood, Bradford J. Pinto, Peter A. Choyke, Peter L. TI Prostate Cancer: Can Multiparametric MR Imaging Help Identify Patients Who Are Candidates for Active Surveillance? SO RADIOLOGY LA English DT Article ID RADICAL PROSTATECTOMY; PATHOLOGICAL FEATURES; MEN; RISK; CRITERIA; PREDICTION; EXPERIENCE; MANAGEMENT; OUTCOMES; ANTIGEN AB Purpose: To determine whether multiparametric magnetic resonance (MR) imaging can help identify patients with prostate cancer who would most appropriately be candidates for active surveillance (AS) according to current guidelines and to compare the results with those of conventional clinical assessment scoring systems, including the D'Amico, Epstein, and Cancer of the Prostate Risk Assessment (CAPRA) systems, on the basis of findings at prostatectomy. Materials and Methods: This institutional review board-approved HIPAA-compliant retrospectively designed study included 133 patients (mean age, 59.3 years) with a mean prostate-specific antigen level of 6.73 ng/mL (median, 4.39 ng/mL) who underwent multiparametric MR imaging at 3.0 T before radical prostatectomy. Informed consent was obtained from all patients. Patients were then retrospectively classified as to whether they would have met AS eligibility criteria or were better served by surgery. AS eligibility criteria for prostatectomy specimens were a dominant tumor smaller than 0.5 mL without Gleason 4 or 5 patterns or extracapsular or seminal vesicle invasion. Conventional clinical assessment scores (the D'Amico, Epstein, and CAPRA scoring systems) were compared with multiparametric MR imaging findings for predicting AS candidates. The level of significance of difference between scoring systems was determined by using the chi(2) test for categoric variables with the level of significance set at P<.05. Results: Among 133 patients, 14 were eligible for AS on the basis of prostatectomy results. The sensitivity, positive predictive value (PPV), and overall accuracy, respectively, were 93%, 25%, and 70% for the D'Amico system, 64%, 45%, and 88% for the Epstein criteria, and 93%, 20%, and 59% for the CAPRA scoring system for predicting AS candidates (P<.005 for all, chi(2) test), while multiparametric MR imaging had a sensitivity of 93%, a PPV of 57%, and an overall accuracy of 92% (P<.005). Conclusion: Multiparametric MR imaging provides useful additional information to existing clinicopathologic scoring systems of prostate cancer and improves the assignment of treatment (eg, AS or active treatment). (C) RSNA, 2013 C1 [Turkbey, Baris; Aras, Omer; Bernardo, Marcelino; Daar, Dagane; McKinney, Yolanda L.; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Mani, Haresh; Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Ho, Jennifer; Kaushal, Aradhana] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Hoang, Anthony; Rastinehad, Ardeshir R.; Linehan, W. Marston; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Agarwal, Harsh] Philips Res North Amer, Briarcliff Manor, NY USA. [Shah, Vijay] VirtualScopics, Rochester, NY USA. [Bernardo, Marcelino; Daar, Dagane] NCI, Dept Imaging Phys, SAIC Frederick, Frederick, MD 21701 USA. [Pang, Yuxi] Philips Healthcare, Cleveland, OH USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr,MSC 1182 Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM pchoyke@mail.nih.gov RI Shah, Vijay/D-4083-2014 OI Shah, Vijay/0000-0003-3856-156X FU National Institutes of Health [Z01 BC 011023, Z01 BC 011081] FX B.T., H. M., O.A., J.H., A. H., A. R. R., M. B., D. D., Y.L.M., W. M. L., A. K., M.J.M., B.J.W., P. A. P., and P. L. C. are employees of the National Institutes of Health. This research was supported by the National Institutes of Health (grants Z01 BC 011023 and Z01 BC 011081). NR 27 TC 88 Z9 90 U1 1 U2 6 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2013 VL 268 IS 1 BP 144 EP 152 DI 10.1148/radiol.13121325 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 169ER UT WOS:000320761400016 PM 23468576 ER PT J AU Qian, CQ Yu, X Chen, DY Dodd, S Bouraoud, N Pothayee, N Chen, Y Beeman, S Bennett, K Murphy-Boesch, J Koretsky, A AF Qian, Chunqi Yu, Xin Chen, Der-Yow Dodd, Stephen Bouraoud, Nadia Pothayee, Nikorn Chen, Yun Beeman, Scott Bennett, Kevin Murphy-Boesch, Joseph Koretsky, Alan TI Wireless Amplified Nuclear MR Detector (WAND) for High-Spatial-Resolution MR Imaging of Internal Organs: Preclinical Demonstration in a Rodent Model SO RADIOLOGY LA English DT Article ID NMR; COIL; SAMPLES AB Purpose: To assess the feasibility of imaging deep-lying internal organs at high spatial resolution by imaging kidney glomeruli in a rodent model with use of a newly developed, wireless amplified nuclear magnetic resonance (MR) detector. Materials and Methods: This study was approved by the Animal Care and Use Committee at the National Institutes of Health/National Institute of Neurologic Disorder and Stroke. As a preclinical demonstration of this new detection technology, five different millimeter-scale wireless amplified nuclear MR detectors configured as double frequency resonators were chronically implanted on the medial surface of the kidney in five Sprague-Dawley rats for MR imaging at 11.7 T. Among these rats, two were administered gadopentetate dimeglumine to visualize renal tubules on T1-weighted gradient-refocused echo (GRE) images, two were administered cationized ferritin to visualize glomeruli on T2*-weighted GRE images, and the remaining rat was administered both gadopentetate dimeglumine and cationized ferritin to visualize the interleaved pattern of renal tubules and glomeruli. The image intensity in each pixel was compared with the local tissue signal intensity average to identify regions of hyper- or hypointensity. Results: T1-weighted images with 70-mm in-plane resolution and 200-mm section thickness were obtained within 3.2 minutes to image renal tubules, and T2*-weighted images of the same resolution were obtained within 5.8 minutes to image the glomeruli. Hyperintensity from gadopentetate dimeglumine enabled visualization of renal tubules, and hypointensity from cationic ferritin enabled visualization of the glomeruli. Conclusion: High-spatial-resolution images have been obtained to observe kidney microstructures in vivo with a wireless amplified nuclear MR detector. (C) RSNA, 2013 C1 [Qian, Chunqi; Yu, Xin; Chen, Der-Yow; Dodd, Stephen; Bouraoud, Nadia; Chen, Yun; Murphy-Boesch, Joseph; Koretsky, Alan] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Beeman, Scott; Bennett, Kevin] Arizona State Univ, Sch Biol & Hlth Syst Engn, Tempe, AZ USA. RP Qian, CQ (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,Room 1D48, Bethesda, MD 20892 USA. EM qianc2@ninds.nih.gov RI Koretsky, Alan/C-7940-2015 OI Chen, Yun/0000-0001-6917-7814; Koretsky, Alan/0000-0002-8085-4756 FU National Institutes of Health [Z01999999] FX This research was supported by the National Institutes of Health (grant Z01999999). NR 25 TC 10 Z9 10 U1 0 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2013 VL 268 IS 1 BP 228 EP 236 DI 10.1148/radiol.13121352 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 169ER UT WOS:000320761400025 PM 23392428 ER PT J AU Li, YS Xu, JJ Mao, LH Liu, Y Gao, RT Zheng, ZM Chen, WJ Le, A Shi, ST Wang, SL AF Li, Yunsheng Xu, Junji Mao, Lisha Liu, Yi Gao, Runtao Zheng, Zongmei Chen, Wanjun Le, Anh Shi, Songtao Wang, Songlin TI Allogeneic Mesenchymal Stem Cell Therapy for Bisphosphonate-Related Jaw Osteonecrosis in Swine SO STEM CELLS AND DEVELOPMENT LA English DT Article ID HUMAN AQUAPORIN-1 CDNA; PIG PAROTID-GLANDS; STROMAL CELLS; MINIATURE PIG; ZOLEDRONIC ACID; FLUID SECRETION; TISSUE-REPAIR; DIFFERENTIATION; IMMUNOTHERAPY; MODEL AB Bisphosphonates (BPs), which are used to treat a variety of clinical disorders, have the side effect of jawbone necrosis. Currently, there is no reliable treatment for BP-related osteonecrosis of the jaw (BRONJ) due to a lack of understanding of its pathogenesis. To investigate the pathogenesis of BRONJ and observe the treatment effect of bone marrow mesenchymal stem cell (BMMSC) transplantation, we established a preclinical animal model of BRONJ in miniature pigs (minipigs). After treatment with zoledronic acid, the clinical and radiographic manifestations of BRONJ could be observed in minipigs after first premolar extraction. The biological and immunological properties of BMMSCs were impaired in the BP-treated minipigs. Moreover, the ratio of Foxp3-positive regulatory T-cells (Tregs) in peripheral blood decreased, and interleukin (IL)-17 increased in the serum of BP-treated minipigs. After allogeneic BMMSC transplantation via intravenous infusion, mucosal healing and bone reconstruction were observed; IL-17 levels were reduced; and Tregs were elevated. In summary, we established a clinically relevant BRONJ model in minipigs and tested a promising allogeneic BMMSC-based therapy, which may have potential clinical applications for treating BRONJ. C1 [Li, Yunsheng; Xu, Junji; Mao, Lisha; Liu, Yi; Gao, Runtao; Zheng, Zongmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Beijing Key Lab Tooth Regenerat & Funct Reconstru, Mol Lab Gene Therapy & Tooth Regenerat, Beijing 100050, Peoples R China. [Li, Yunsheng] Coal Gen Hosp, Dept Stomatol, Beijing, Peoples R China. [Chen, Wanjun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, NIH, Bethesda, MD USA. [Le, Anh; Shi, Songtao] Univ So Calif, Ctr Craniofacial Mol Biol, Herman Ostrow Sch Dent, Los Angeles, CA 90089 USA. [Wang, Songlin] Capital Med Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Beijing 100050, Peoples R China. RP Wang, SL (reprint author), Capital Med Univ, Sch Stomatol, Tian Tan Xi Li 4, Beijing 100050, Peoples R China. EM songtaos@usc.edu; slwang@ccmu.edu.cn FU Beijing Municipal Committee for Science and Technology [Z121100005212004]; National Basic Research Program of China [2007CB947304, 2010CB944801]; Beijing Municipality [PHR20090510, PXM 2009-014226-074691, PXM2011-014226-07-000066]; NIDCR [R01DE017449] FX This work was supported by the Beijing Municipal Committee for Science and Technology no. Z121100005212004, National Basic Research Program of China no. 2007CB947304 and no. 2010CB944801; Beijing Municipality no. PHR20090510, no. PXM 2009-014226-074691, and no. PXM2011-014226-07-000066; and a grant from NIDCR no. R01DE017449. NR 26 TC 15 Z9 16 U1 4 U2 14 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 EI 1557-8534 J9 STEM CELLS DEV JI Stem Cells Dev. PD JUL PY 2013 VL 22 IS 14 BP 2047 EP 2056 DI 10.1089/scd.2012.0615 PG 10 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 174WE UT WOS:000321186700007 PM 23461552 ER PT J AU Lu, XW Sail, D Kovac, P AF Lu, Xiaowei Sail, Deepak Kovac, Pavol TI 4 ',6 '-O-Benzylidene- and 4 ',6 '-O-p-Methoxybenzylidene-alpha,beta-cellobiose and Their Hexa-O-beta-benzoyl Derivatives SO SYNTHESIS-STUTTGART LA English DT Article DE synthetic methods; carbohydrate chemistry; protecting groups; regioselectivity ID DIMETHYL SULFATE ADDUCT; 4,6-O-BENZYLIDENE ACETALS; BENZYLIDENE ACETALS; N-BROMOSUCCINIMIDE; SUGARS; RING; REGIOSELECTIVITY; TRIETHYLSILANE AB The preparation of 4',6'-O-benzylidenecellobiose has been improved and its p-methoxybenzylidene counterpart was prepared in a similar way. As with other alkylidene derivatives of sugars, the corresponding per-O-benzoates are versatile intermediates in carbohydrate synthesis, allowing, after hydrolytic cleavage or opening of the phenylidene ring, regioselective manipulation of hydroxyl groups in cellobiose, or access to various derivatives of lactose. C1 [Lu, Xiaowei; Sail, Deepak; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov FU Intramural Research Program of the NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 21 TC 0 Z9 0 U1 2 U2 8 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0039-7881 EI 1437-210X J9 SYNTHESIS-STUTTGART JI Synthesis PD JUL PY 2013 VL 45 IS 14 BP 1946 EP 1949 DI 10.1055/s-0033-1339174 PG 4 WC Chemistry, Organic SC Chemistry GA 180RH UT WOS:000321612300004 ER PT J AU Birnbaum, LS AF Birnbaum, Linda S. TI When environmental chemicals act like uncontrolled medicine SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Editorial Material DE endocrine disruptor; environment; development; regulation ID EXPOSURE; CHILDREN; HEALTH; OBESITY; DISEASE; GIRLS; AGE AB In the same way as medicines are delivered to produce effects in the endocrine system, environmental chemicals can be similarly delivered to produce unwanted endocrine effects, resulting in a staggering increase in several diseases. These effects on endocrine and other physiological systems can have significant population-level impacts and thus require public health approaches to disease control. C1 [Birnbaum, Linda S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Birnbaum, LS (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov NR 19 TC 15 Z9 15 U1 1 U2 12 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD JUL PY 2013 VL 24 IS 7 BP 321 EP 323 DI 10.1016/j.tem.2012.12.005 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 183EB UT WOS:000321795900001 PM 23660158 ER PT J AU Subbarao, K Matsuoka, Y AF Subbarao, Kanta Matsuoka, Yumiko TI The prospects and challenges of universal vaccines for influenza SO TRENDS IN MICROBIOLOGY LA English DT Review DE influenza virus; universal vaccine ID VIRUS-LIKE PARTICLE; IMPROVED CROSS-PROTECTION; MEMORY B-CELLS; A-VIRUS; EXTRACELLULAR DOMAIN; MATRIX PROTEIN-2; PANDEMIC INFLUENZA; M2 PROTEIN; MONOCLONAL-ANTIBODIES; NEUTRALIZING EPITOPE AB Vaccination is the most effective way to reduce the impact of epidemic as well as pandemic influenza. However, the licensed inactivated influenza vaccine induces strain-specific immunity and must be updated annually. When novel viruses appear, matched vaccines are not likely to be available in time for the first wave of a pandemic. Yet, the enormous diversity of influenza A viruses in nature makes it impossible to predict which subtype or strain will cause the next pandemic. Several recent scientific advances have generated renewed enthusiasm and hope for universal vaccines that will induce broad protection from a range of influenza viruses. C1 [Subbarao, Kanta; Matsuoka, Yumiko] NIAID, NIH, Bethesda, MD 20892 USA. RP Subbarao, K (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov FU Intramural Research Program of the MAID, NTH FX The authors work is supported by the Intramural Research Program of the MAID, NTH. NR 90 TC 22 Z9 25 U1 3 U2 36 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD JUL PY 2013 VL 21 IS 7 BP 350 EP 358 DI 10.1016/j.tim.2013.04.003 PG 9 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 183DN UT WOS:000321794300008 PM 23685068 ER PT J AU Mideo, N Kennedy, DA Carlton, JM Bailey, JA Juliano, JJ Read, AF AF Mideo, Nicole Kennedy, David A. Carlton, Jane M. Bailey, Jeffrey A. Juliano, Jonathan J. Read, Andrew F. TI Ahead of the curve: next generation estimators of drug resistance in malaria infections SO TRENDS IN PARASITOLOGY LA English DT Review ID FALCIPARUM CIRCUMSPOROZOITE PROTEIN; PLASMODIUM-FALCIPARUM; ARTEMISININ RESISTANCE; PARASITE CLEARANCE; WESTERN CAMBODIA; NO EVIDENCE; IN-VIVO; EPIDEMIOLOGY; DIVERSITY; DYNAMICS AB Drug resistance is a major obstacle to controlling infectious diseases. A key challenge is detecting the early signs of drug resistance when little is known about its genetic basis. Focusing on malaria parasites, we propose a way to do this. Newly developing or low level resistance at low frequency in patients can be detected through a phenotypic signature: individual parasite variants clearing more slowly following drug treatment. Harnessing the abundance and resolution of deep sequencing data, our 'selection differential' approach addresses some limitations of extant methods of resistance detection, should allow for the earliest detection of resistance in malaria or other multi-clone infections, and has the power to uncover the true scale of the drug resistance problem. C1 [Mideo, Nicole; Kennedy, David A.; Read, Andrew F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Kennedy, David A.; Read, Andrew F.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Carlton, Jane M.] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA. [Bailey, Jeffrey A.] Univ Massachusetts, Sch Med, Div Transfus Med, Worcester, MA 01655 USA. [Bailey, Jeffrey A.] Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA 01655 USA. [Juliano, Jonathan J.] Univ N Carolina, Sch Med, Div Infect Dis, Chapel Hill, NC 27599 USA. [Read, Andrew F.] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. RP Mideo, N (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, Univ Pk, University Pk, PA 16802 USA. EM nlm12@psu.edu FU National Institute of Allergy and Infectious Diseases; NIH [R01AI089819, U19AI089676]; Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship FX We thank members of the Research and Policy in Infectious Disease Dynamics Program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International. Center, National Institutes of Health (NTH) for discussion, and four anonymous reviewers for helping to substantially improve this manuscript. This study was funded by National Institute of Allergy and Infectious Diseases, NIH grants R01AI089819 to J.J.J. and U19AI089676 to J.M.C., and a Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship to N.M. NR 65 TC 7 Z9 8 U1 0 U2 21 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 J9 TRENDS PARASITOL JI Trends Parasitol. PD JUL PY 2013 VL 29 IS 7 BP 321 EP 328 DI 10.1016/j.pt.2013.05.004 PG 8 WC Parasitology SC Parasitology GA 184IM UT WOS:000321883300004 PM 23746748 ER PT J AU Yang, P Cai, GQ Cai, YQ Fei, J Liu, GX AF Yang, Ping Cai, Guoqiang Cai, Youqing Fei, Jian Liu, Guoxiang TI Gamma aminobutyric acid transporter subtype 1 gene knockout mice: a new model for attention deficit/hyperactivity disorder SO ACTA BIOCHIMICA ET BIOPHYSICA SINICA LA English DT Article DE GAT1; gene knockout mice; ADHD; learning problems; motor coordination ID DEFICIT HYPERACTIVITY DISORDER; GABA TRANSPORTER; HYPERDOPAMINERGIC MICE; MOLECULAR-GENETICS; RAT-BRAIN; DOPAMINE; ADHD; EXPRESSION; IMPULSIVITY; SEROTONIN AB Attention deficit/hyperactivity disorder (ADHD) is characterized by hyperactivity, impaired sustained attention, impulsivity, and is usually accompanied by varying degrees of learning difficulties and lack of motor coordination. However, the pathophysiology and etiology of ADHD remain inconclusive so far. Our previous studies have demonstrated that the gamma aminobutyric acid transporter subtype 1 (GAT1) gene knockout (ko) mouse (gat1/) is hyperactive and exhibited impaired memory performance in the Morris water maze. In the current study, we found that the gat1/ mice showed low levels of attentional focusing and increased impulsivity. In addition, the gat1/ mice displayed ataxia characterized by defects in motor coordination and balance skills. The hyperactivity in the ko mice was reduced by both methylphenidate and amphetamine. Collectively, these results suggest that GAT1 ko mouse is a new animal model for ADHD studying and GAT1 may be a new target to treat ADHD. C1 [Yang, Ping; Fei, Jian] Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China. [Cai, Guoqiang; Cai, Youqing] Shanghai Res Ctr Model Organisms, Shanghai 201210, Peoples R China. [Liu, Guoxiang] NIA, Transgen Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Liu, GX (reprint author), NIA, Transgen Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM liuguoxi@mail.nih.gov RI liu, guoxiang/I-8174-2013; CAI, YOU-QING/A-4315-2013 OI CAI, YOU-QING/0000-0002-1440-6779 FU National Natural Science Foundation of China [81171300]; National Key Project [2010CB945501, 2010CB912604]; E-Institutes of Shanghai Municipal Education Commission [E03003] FX This work was supported by the grants from the National Natural Science Foundation of China (81171300), the National Key Project (2010CB945501, 2010CB912604), and the E-Institutes of Shanghai Municipal Education Commission (E03003). NR 47 TC 6 Z9 6 U1 3 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1672-9145 J9 ACTA BIOCH BIOPH SIN JI Acta Biochim. Biophys. Sin. PD JUL PY 2013 VL 45 IS 7 BP 578 EP 585 DI 10.1093/abbs/gmt043 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 173DT UT WOS:000321059000007 PM 23656791 ER PT J AU Redd, AD Wendel, SK Grabowski, MK Ocama, P Kiggundu, V Bbosa, F Boaz, I Balagopal, A Reynolds, SJ Gray, RH Serwadda, D Kirk, GD Quinn, TC Stabinski, L AF Redd, Andrew D. Wendel, Sarah K. Grabowski, Mary K. Ocama, Ponsiano Kiggundu, Valerian Bbosa, Francis Boaz, Iga Balagopal, Ashwin Reynolds, Steven J. Gray, Ronald H. Serwadda, David Kirk, Gregory D. Quinn, Thomas C. Stabinski, Lara TI Liver Stiffness Is Associated With Monocyte Activation in HIV-Infected Ugandans Without Viral Hepatitis SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID MICROBIAL TRANSLOCATION; DISEASE PROGRESSION; TRANSIENT ELASTOGRAPHY; FIBROSIS; IMMUNODEFICIENCY; DISCORDANCE; MORTALITY; RAKAI; CELLS AB A high prevalence of liver stiffness, as determined by elevated transient elastography liver stiffness measurement, was previously found in a cohort of HIV-infected Ugandans in the absence of chronic viral hepatitis. Given the role of immune activation and microbial translocation in models of liver disease, a shared immune mechanism was hypothesized in the same cohort without other overt causes of liver disease. This study examined whether HIV-related liver stiffness was associated with markers of immune activation or microbial translocation (MT). A retrospective case-control study of subjects with evidence of liver stiffness as defined by a transient elastography stiffness measurement >= 9.3 kPa (cases = 133) and normal controls (n = 133) from Rakai, Uganda was performed. Cases were matched to controls by age, gender, HIV, hepatitis B virus (HBV), and highly active antiretroviral therapy (HAART) status. Lipopolysaccharide (LPS), endotoxin IgM antibody, soluble CD14 (sCD14), C-reactive protein (CRP), and D-dimer levels were measured. Conditional logistic regression was used to estimate adjusted matched odds ratios (adjMOR) and 95% confidence intervals. Higher sCD14 levels were associated with a 19% increased odds of liver stiffness (adjMOR = 1.19, p = 0.002). In HIV-infected individuals, higher sCD14 levels were associated with a 54% increased odds of having liver stiffness (adjMOR = 1.54, p < 0.001); however, the opposite was observed in HIV-negative individuals (adjMOR = 0.57, p = 0.001). No other biomarker was significantly associated with liver stiffness, and only one subject was found to have detectable LPS. Liver stiffness in HIV-infected Ugandans is associated with increased sCD14 indicative of monocyte activation in the absence of viral hepatitis or microbial translocation, and suggests that HIV may be directly involved in liver disease. C1 [Redd, Andrew D.; Wendel, Sarah K.; Reynolds, Steven J.; Quinn, Thomas C.; Stabinski, Lara] NIAID, Immunoregulat Lab, NIH, Baltimore, MD 21205 USA. [Grabowski, Mary K.; Gray, Ronald H.; Kirk, Gregory D.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Ocama, Ponsiano; Serwadda, David] Makerere Univ, Coll Hlth Sci, Kampala, Uganda. [Kiggundu, Valerian; Bbosa, Francis; Boaz, Iga; Reynolds, Steven J.; Serwadda, David] Rakai Hlth Sci Program, Entebbe, Uganda. [Balagopal, Ashwin; Reynolds, Steven J.; Kirk, Gregory D.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Redd, AD (reprint author), NIAID, Rangos Bldg Room 527,855 North Wolfe St, Baltimore, MD 21205 USA. EM aredd2@jhmi.edu FU Division of Intramural Research, NIAID; Office of AIDS research, NIH, NICHD [F31HD063345]; NIAID [5P30HD06826, U01AI075115]; Henry M. Jackson Foundation; Fogarty Foundation [5D43TW00010]; Bill and Melinda Gates Foundation [22006.03]; Office of Cyberinfrastructure and Computational Biology (OCICB), NIAID FX Institutional Review Board approvals were obtained from the Uganda Virus Research Institute's Scientific and Ethics Committee, the Uganda National Council for Science and Technology, and the Institutional Review Boards of collaborating U.S. institutions (National Institutes of Health and Johns Hopkins University). This study was supported by the Division of Intramural Research, NIAID, the Office of AIDS research, NIH, NICHD (grant F31HD063345), NIAID (grants 5P30HD06826, U01AI075115), Henry M. Jackson Foundation, Fogarty Foundation (5D43TW00010), and the Bill and Melinda Gates Foundation (grant 22006.03). The authors with to thank the Office of Cyberinfrastructure and Computational Biology (OCICB), NIAID for support. NR 18 TC 12 Z9 12 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUL PY 2013 VL 29 IS 7 BP 1026 EP 1030 DI 10.1089/aid.2013.0004 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 163ZP UT WOS:000320378300007 PM 23548102 ER PT J AU Shea, N Prasad, V AF Shea, Neil Prasad, Vinay TI Open Issues with Open Access Publication SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Shea, Neil] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Shea, N (reprint author), Northwestern Univ, Dept Med, Chicago, IL 60611 USA. NR 8 TC 6 Z9 6 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD JUL PY 2013 VL 126 IS 7 BP 563 EP 564 DI 10.1016/j.amjmed.2012.11.027 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 167RE UT WOS:000320649800018 PM 23787194 ER PT J AU Thomashow, MA Shimbo, D Parikh, MA Hoffman, EA Vogel-Claussen, J Hueper, K Fu, J Liu, CY Bluemke, DA Ventetuolo, CE Doyle, MF Barr, RG AF Thomashow, Michael A. Shimbo, Daichi Parikh, Megha A. Hoffman, Eric A. Vogel-Claussen, Jens Hueper, Katja Fu, Jessie Liu, Chia-Ying Bluemke, David A. Ventetuolo, Corey E. Doyle, Margaret F. Barr, R. Graham TI Endothelial Microparticles in Mild Chronic Obstructive Pulmonary Disease and Emphysema The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE chronic obstructive pulmonary disease; emphysema; antigens, CD31; endothelium; pulmonary disease ID AIR-FLOW OBSTRUCTION; PROGENITOR CELLS; LUNG-FUNCTION; GROWTH-FACTOR; UP-REGULATION; COPD; APOPTOSIS; SMOKERS; STANDARDIZATION; DYSFUNCTION AB Rationale: Basic research implicates alveolar endothelial cell apoptosis in the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. However, information on endothelial microparticles (EMPs) in mild COPD and emphysema is lacking. Objectives: We hypothesized that levels of CD31(+) EMPs phenotypic for endothelial cell apoptosis would be elevated in COPD and associated with percent emphysema on computed tomography (CT). Associations with pulmonary microvascular blood flow (PMBF), diffusing capacity, and hyperinflation were also examined. Methods: The Multi-Ethnic Study of Atherosclerosis COPD Study recruited participants with COPD and control subjects age 50-79 years with greater than or equal to 10 pack-years without clinical cardiovascular disease. CD31(+) EMPs were measured using flow cytometry in 180 participants who also underwent CTs and spirometry. CD62E(+) EMPs phenotypic for endothelial cell activation were also measured. COPD was defined by standard criteria. Percent emphysema was defined as regions less than 2950 Hounsfield units on full-lung scans. PMBF was assessed on gadolinium-enhanced magnetic resonance imaging. Hyperinflation was defined as residual volume/total lung capacity. Linear regression was used to adjust for potential confounding factors. Measurements and Main Results: CD31(+) EMPs were elevated in COPD compared with control subjects (P = 0.03) and were notably increased in mild COPD (P = 0.03). CD31(+) EMPs were positively related to percent emphysema (P = 0.045) and were inversely associated with PMBF (P = 0.047) and diffusing capacity (P =/ 0.01). In contrast, CD62E(+) EMPs were elevated in severe COPD (P = 0.003) and hyperinflation (P = 0.001). Conclusions: CD31(+) EMPs, suggestive of endothelial cell apoptosis, were elevated in mild COPD and emphysema. In contrast, CD62E(+) EMPs indicative of endothelial activation were elevated in severe COPD and hyperinflation. C1 [Thomashow, Michael A.; Shimbo, Daichi; Parikh, Megha A.; Fu, Jessie; Barr, R. Graham] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Barr, R. Graham] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Hoffman, Eric A.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Vogel-Claussen, Jens; Hueper, Katja; Liu, Chia-Ying; Bluemke, David A.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Vogel-Claussen, Jens; Hueper, Katja] Hannover Med Sch, Dept Radiol, Hannover, Germany. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Ventetuolo, Corey E.] Brown Univ, Dept Med, Alpert Sch, Providence, RI 02912 USA. [Doyle, Margaret F.] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. RP Barr, RG (reprint author), Columbia Univ, Med Ctr, Presbyterian Hosp 9 East 105,630 West 18th St, New York, NY 10032 USA. EM rgb9@mail.cumc.columbia.edu RI Hueper, Katja/J-9566-2016; OI Hueper, Katja/0000-0002-3195-4400; Ventetuolo, Corey /0000-0002-4223-4775; Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health [R01-HL093081, R01-HL077612, R01-HL075476, N01-HC95159-HC95169, UL1 RR024156] FX Supported by National Institutes of Health R01-HL093081, R01-HL077612, R01-HL075476, and N01-HC95159-HC95169, UL1 RR024156. NR 50 TC 40 Z9 41 U1 0 U2 16 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 1 PY 2013 VL 188 IS 1 BP 60 EP 68 DI 10.1164/rccm.201209-1697OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 173SW UT WOS:000321100500016 PM 23600492 ER PT J AU Woodrow, CJ Dahlstrom, S Cooksey, R Flegg, JA Le Nagard, H Mentre, F Murillo, C Menard, D Nosten, F Sriprawat, K Musset, L Quashie, NB Lim, P Fairhurst, RM Nsobya, SL Sinou, V Noedl, H Pradines, B Johnson, JD Guerin, PJ Sibley, CH Le Bras, J AF Woodrow, Charles J. Dahlstroem, Sabina Cooksey, Richard Flegg, Jennifer A. Le Nagard, Herve Mentre, France Murillo, Claribel Menard, Didier Nosten, Francois Sriprawat, Kanlaya Musset, Lise Quashie, Neils B. Lim, Pharath Fairhurst, Rick M. Nsobya, Sam L. Sinou, Veronique Noedl, Harald Pradines, Bruno Johnson, Jacob D. Guerin, Philippe J. Sibley, Carol H. Le Bras, Jacques TI High-Throughput Analysis of Antimalarial Susceptibility Data by the WorldWide Antimalarial Resistance Network (WWARN) In Vitro Analysis and Reporting Tool SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PLASMODIUM-FALCIPARUM SUSCEPTIBILITY; DRUG-SENSITIVITY; PHARMACODYNAMIC PROPERTIES; ARTEMISININ RESISTANCE; WESTERN CAMBODIA; RICH PROTEIN; MALARIA; QUININE; MEFLOQUINE; INVITRO AB Assessment of in vitro susceptibility is a fundamental component of antimalarial surveillance studies, but wide variations in the measurement of parasite growth and the calculation of inhibitory constants make comparisons of data from different laboratories difficult. Here we describe a Web-based, high-throughput in vitro analysis and reporting tool (IVART) generating inhibitory constants for large data sets. Fourteen primary data sets examining laboratory-determined susceptibility to artemisinin derivatives and artemisinin combination therapy partner drugs were collated from 11 laboratories. Drug concentrations associated with half-maximal inhibition of growth (IC(50)s) were determined by a modified sigmoid E-max model-fitting algorithm, allowing standardized analysis of 7,350 concentration-inhibition assays involving 1,592 isolates. Examination of concentration-inhibition data revealed evidence of apparent paradoxical growth at high concentrations of nonartemisinin drugs, supporting amendment of the method for calculating the maximal drug effect in each assay. Criteria for defining more-reliable IC(50)s based on estimated confidence intervals and growth ratios improved correlation coefficients for the drug pairs mefloquine-quinine and chloroquine-desethylamodiaquine in 9 of 11 and 8 of 8 data sets, respectively. Further analysis showed that maximal drug inhibition was higher for artemisinins than for other drugs, particularly in ELISA (enzyme-linked immunosorbent assay)-based assays, a finding consistent with the earlier onset of action of these drugs in the parasite life cycle. This is the first high-throughput analytical approach to apply consistent constraints and reliability criteria to large, diverse antimalarial susceptibility data sets. The data also illustrate the distinct biological properties of artemisinins and underline the need to apply more sensitive approaches to assessing in vitro susceptibility to these drugs. C1 [Woodrow, Charles J.; Cooksey, Richard; Flegg, Jennifer A.; Guerin, Philippe J.; Sibley, Carol H.] Univ Oxford, Nuffield Dept Clin Med, WorldWide Antimalarial Resistance Network WWARN, Churchill Hosp,Ctr Trop Med, Oxford, England. [Woodrow, Charles J.] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand. [Dahlstroem, Sabina; Le Bras, Jacques] Hop Bichat Claude Bernard, WorldWide Antimalarial Resistance Network WWARN I, F-75877 Paris 18, France. [Le Nagard, Herve; Mentre, France] Univ Paris Diderot, INSERM, UMR S 738, Paris, France. [Murillo, Claribel] Int Ctr Med Res & Training CIDEIM, Cali, Colombia. [Menard, Didier] Inst Pasteur Cambodia, Malaria Mol Epidemiol Unit, Phnom Penh, Cambodia. [Nosten, Francois; Sriprawat, Kanlaya] Shoklo Malaria Res Unit, Mae Sot, Tai, Thailand. [Musset, Lise] Inst Pasteur, Ctr Natl Reference Chimioresistance Paludisme Reg, Parasitol Lab, Cayenne, French Guiana. [Quashie, Neils B.] Univ Ghana, Sch Med, Ctr Trop Clin Pharmacol & Therapeut, Accra, Ghana. [Quashie, Neils B.] Univ Ghana, Noguchi Mem Inst Med Res, Dept Epidemiol, Accra, Ghana. [Lim, Pharath; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Lim, Pharath] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Nsobya, Sam L.] Makerere Univ, Dept Med, Kampala, Uganda. [Sinou, Veronique] Aix Marseille Univ, UMR MD3, Marseille, France. [Noedl, Harald] Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria. [Pradines, Bruno] Inst Rech Biomed Armees, Unite Parasitol, Marseille, France. [Pradines, Bruno] Aix Marseille Univ, URMITE, UM63, CNRS 7278,IRD 198,INSERM 1095, Marseille, France. [Pradines, Bruno] Ctr Natl Reference Paludisme, Marseille, France. [Johnson, Jacob D.] Walter Reed Project, US Army Med Res Unit, Kisumu, Kenya. [Sibley, Carol H.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Le Bras, Jacques] Univ Paris 05, Paris, France. [Le Bras, Jacques] IRD, UMR 216, Paris, France. RP Woodrow, CJ (reprint author), Univ Oxford, Nuffield Dept Clin Med, WorldWide Antimalarial Resistance Network WWARN, Churchill Hosp,Ctr Trop Med, Oxford, England. EM charlie@tropmedres.ac RI Menard, Didier/O-3294-2013; OI Menard, Didier/0000-0003-1357-4495; Flegg, Jennifer/0000-0002-8809-726X; Nosten, Francois/0000-0002-7951-0745; Guerin, Philippe/0000-0002-6008-2963; Woodrow, Charles/0000-0002-5134-7165 FU Bill and Melinda Gates Foundation; Intramural Research Program of NIAID, NIH FX WWARN is supported by a Bill and Melinda Gates Foundation grant. This work was supported in part by the Intramural Research Program of NIAID, NIH. NR 54 TC 13 Z9 13 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUL PY 2013 VL 57 IS 7 BP 3121 EP 3130 DI 10.1128/AAC.02350-12 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 161YG UT WOS:000320229600028 PM 23612201 ER PT J AU Kim, JH Xu, EY Sacks, DB Lee, J Shu, LM Xia, B Kong, ANT AF Kim, Jung-Hwan Xu, Eugenia Y. Sacks, David B. Lee, Jonghun Shu, Limin Xia, Bing Kong, Ah-Ng Tony TI Identification and Functional Studies of a New Nrf2 Partner IQGAP1: A Critical Role in the Stability and Transactivation of Nrf2 SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID TRANSCRIPTION FACTOR NRF2; ANTIOXIDANT RESPONSE ELEMENT; CANCER CHEMOPREVENTION; INDUCIBLE EXPRESSION; BINDING-PROTEIN; NUCLEAR EXPORT; CELL-DEATH; GENE; CALCIUM; STRESS AB Aims: Nuclear factor-erythroid-related factor 2 (Nrf2) is a critical transcriptional factor that is used in regulating cellular defense against oxidative stress. This study is aimed at investigating new interacting protein partners of Nrf2 using One-strep tag pull-down coupled with LTQ Orbitrap LC/MS/MS, and at examining the impact on Nr2 signaling by the newly identified IQ motif containing GTPase activating protein 1 (IQGAP1). Results: Using the One-strep tag pull-down and LTQ Orbitrap LC/MS/MS, we identified IQGAP1 as a new Nrf2 interacting partner. Direct interactions between IQGAP1 and Nrf2 proteins were verified using in vitro glutathione S-transferase (GST) pull-down, transcription/translation assays, and in vivo utilizing Nrf2 overexpressing cells. Coexpression of Dsredmono-IQGAP1 and eGFP-Nrf2 increased the stability of eGFP-Nrf2 and enhanced the expression of Nrf2-target gene heme oxygenase-1 (HO-1). To confirm the functional role of IQGAP1 on Nrf2, knock-downed IQGAP1 using siIQGAP1 attenuated the expression of endogenous Nrf2, HO-1 proteins, and Nrf2-target genes GSTpi, GCLC, and NAD(P) H: quinone oxidoreductase 1 (NQO-1). Furthermore, the stability of Nrf2 was dramatically decreased in IQGAP1-deficient mouse embryonic fibroblast (MEF) cells. Since IQGAP1 signaling could be mediated by calcium, treating the cells with calcium showed the translocation of IQGAP1/Nrf2 complex into the nucleus, suggesting that IQGAP1 may play a critical role in Nrf2 stability. Interestingly, consistent with calcium signaling for IQGAP1, treating the cells with calcium functionally enhanced Nrf2-mediated antioxidant responsive element-transcription activity and enhanced the expression of the endogenous Nrf2-target gene HO-1. Innovation: In the aggregate, our current study identifies and functionally characterizes a new Nrf2 partner protein IQGAP1, which may contribute to Nrf2's regulation of antioxidant enzymes such as HO-1. Conclusion: IQGAP1 may play a critical role in the stability and transactivation of Nrf2. Antioxid. Redox Signal. 19, 89-101. C1 [Kim, Jung-Hwan; Kong, Ah-Ng Tony] Rutgers State Univ, Ernest Mario Sch Pharm, Ctr Canc Prevent Res, Grad Program Pharmaceut Sci, Piscataway, NJ 08854 USA. [Xu, Eugenia Y.; Lee, Jonghun; Shu, Limin; Kong, Ah-Ng Tony] Rutgers State Univ, Ernest Mario Sch Pharm, Ctr Canc Prevent Res, Dept Pharmaceut, Piscataway, NJ 08854 USA. [Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Xia, Bing] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ USA. RP Kong, ANT (reprint author), Rutgers State Univ, Ernest Mario Sch Pharm, Ctr Canc Prevent Res, Dept Pharmaceut, 160 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM kongt@pharmacy.rutgers.edu OI Lee, Jong Hun/0000-0002-3083-7595; Sacks, David/0000-0003-3100-0735 FU National Institutes of Health [R01 CA94828, 2R01CA118947]; Intramural Research Program of the National Institutes of Health FX This work was supported by National Institutes of Health grants R01 CA94828 and 2R01CA118947 to A.N.K. and by the Intramural Research Program of the National Institutes of Health to D.B.S. NR 58 TC 11 Z9 11 U1 2 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUL PY 2013 VL 19 IS 2 BP 89 EP 101 DI 10.1089/ars.2012.4586 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 166WY UT WOS:000320591600002 PM 22793650 ER PT J AU Martin-Montalvo, A de Cabo, R AF Martin-Montalvo, Alejandro de Cabo, Rafael TI Mitochondrial Metabolic Reprogramming Induced by Calorie Restriction SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID HUMAN SKELETAL-MUSCLE; EXTENDS LIFE-SPAN; GENETICALLY HETEROGENEOUS MICE; OXYGEN SPECIES PRODUCTION; SMALL-MOLECULE ACTIVATORS; GREEN TEA POLYPHENOL; FEMALE SHR MICE; CAENORHABDITIS-ELEGANS; OXIDATIVE STRESS; SACCHAROMYCES-CEREVISIAE AB Significance: Calorie restriction (CR) is a known intervention that delays most aging processes. Most of the beneficial effects of CR are mediated by improved maintenance of mitochondrial performance in aged individuals. The control of mitochondrial biogenesis, apoptosis, and protein turnover is required for healthy aging. CR is able to induce molecular mechanisms that preserve oxidative capacity and decrease oxidative damage. Recent Advances and Critical Issues: Published data indicate that peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is activated in old animals under CR conditions compared to ad libitum counterparts, enhancing mitochondrial biogenesis. Molecular regulation of PGC-1 alpha has recently attracted significant research interest. We discuss the master regulators of energy metabolism such as AMP-activated protein kinase and sirtuin 1 among others that have been demonstrated to activate mitochondrial biogenesis through increased PGC-1 alpha activity at transcriptional and post-translational levels. Additionally, we describe the latest findings that explain how CR promotes mitochondrial efficiency and decreases mitochondrial-derived oxidative damage. Future Directions: Understanding the beneficial mitochondrial changes conferred by CR will aid design of therapies for age-related diseases and help slow the aging process. Given the difficulty for humans to adhere to CR, we also explore new molecules that have been proposed during the last years to mimic the CR phenotype and their potential as future therapeutics. C1 [Martin-Montalvo, Alejandro; de Cabo, Rafael] NIA, Expt Gerontol Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP de Cabo, R (reprint author), NIA, Expt Gerontol Sect, Translat Gerontol Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM decabora@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; , rafael/0000-0003-2830-5693 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work has been supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. We thank Jessica Curtis for editing the article. NR 94 TC 28 Z9 28 U1 2 U2 27 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUL PY 2013 VL 19 IS 3 BP 310 EP 319 DI 10.1089/ars.2012.4866 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 172XO UT WOS:000321040300009 PM 22901095 ER PT J AU Kuhn, JH Radoshitzky, SR Bavari, S Jahrling, PB AF Kuhn, Jens H. Radoshitzky, Sheli R. Bavari, Sina Jahrling, Peter B. TI The International Code of Virus Classification and Nomenclature (ICVCN): proposal for text changes for improved differentiation of viral taxa and viruses SO ARCHIVES OF VIROLOGY LA English DT Article ID SPECIES NAMES; TAXONOMY AB The International Committee on Taxonomy of Viruses (ICTV) is responsible for the classification of viruses into taxa. Importantly, the ICTV is currently not responsible for the nomenclature of viruses or their subclassification into strains, lineages, or genotypes. ICTV rules for classification of viruses and nomenclature of taxa are laid out in a code, the International Code of Virus Classification and Nomenclature (ICVCN). The most recent version of the Code makes it difficult for the unfamiliar reader to distinguish between viruses and taxa, thereby often giving the impression that certain Rules apply to viruses. Here, Code text changes are proposed to address this problem. C1 [Kuhn, Jens H.; Jahrling, Peter B.] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, DCR, NIH, Frederick, MD 21702 USA. [Radoshitzky, Sheli R.; Bavari, Sina] US Army Med Res Inst Infect Dis, Frederick, MD USA. RP Kuhn, JH (reprint author), NIAID, Integrated Res Facil Ft Detrick IRF Frederick, DCR, NIH, B-8200 Res Plaza, Frederick, MD 21702 USA. EM kuhnjens@mail.nih.gov RI Kuhn, Jens H./B-7615-2011 OI Kuhn, Jens H./0000-0002-7800-6045 FU NIAID [HHSN272200200016I] FX The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, the US Department of Defense, the US Department of the Army, or of the institutions and companies affiliated with the authors. JHK performed this work as an employee of Tunnell Consulting, Inc., a subcontractor to Battelle Memorial Institute under its prime contract with NIAID, under Contract No. HHSN272200200016I. NR 12 TC 0 Z9 0 U1 2 U2 10 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PD JUL PY 2013 VL 158 IS 7 BP 1621 EP 1629 DI 10.1007/s00705-012-1582-6 PG 9 WC Virology SC Virology GA 173GN UT WOS:000321066600025 PM 23417351 ER PT J AU Lim, S Hong, J Liu, CT Hivert, MF White, CC Murabito, JM O'Donnell, CJ Dupuis, J Florez, JC Meigs, JB AF Lim, Soo Hong, Jaeyoung Liu, Ching-Ti Hivert, Marie-France White, Charles C. Murabito, Joanne M. O'Donnell, Christopher J. Dupuis, Josee Florez, Jose C. Meigs, James B. TI Common variants in and near IRS1 and subclinical cardiovascular disease in the Framingham Heart Study SO ATHEROSCLEROSIS LA English DT Article DE IRS1; 2q36.3; Genetic association; Subclinical atherosclerosis; Ankle-brachial index ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; INSULIN-RESISTANCE; METABOLIC SYNDROME; LINKAGE ANALYSIS; RISK; ATHEROSCLEROSIS; LOCI; CALCIFICATION; METAANALYSIS AB Objective: Common variants at the 2q36.3-IRS1 locus are associated with insulin resistance (IR), type 2 diabetes (T2D) and coronary artery disease (CAD) in large-scale association studies. We tested the hypothesis that variants at this locus are associated with subclinical atherosclerosis traits. Methods: We studied 2740 Framingham Heart Study participants (54.9% women; mean age 57.8 years) with measures of coronary artery or abdominal aortic calcium, internal and common carotid intima-media thickness, and ankle-brachial index (ABI). We tested 1) four SNPs previously shown to be associated with IR (rs2972146, rs2943650), T2D (rs2943641) or CAD (rs2943634) and 2) any SNP at 2q36.3-IRS1, for association with subclinical atherosclerosis traits, adjusting for atherosclerosis risk factors. We set type 1 error rate for test 1) as 0.05/5 traits - P < 0.01, and for test 2) as 0.05 divided by the effective number of independent tests, divided by 5 for the number of traits analyzed. Results: We found no association between the four known SNPs and subclinical atherosclerosis, but identified one SNP (rs10167219, r(2) with rs2943634 = 0.07) at 2q36.3 that was significantly associated with ABI (corrected P = 0.009). However, rs10167219 was not associated with ABI (P = 0.70) in 35,404 participants in a published ABI association study. Conclusion: Common variants at the 2q36.3-IRS1 locus were not associated with subclinical atherosclerosis traits in this study which was adequately powered to find associations with moderate effect size. Although IR and T2D may be mechanistically linked to CAD via subclinical atherosclerosis, an alternate mechanism for the IR-T2D-CAD associations at 2q36.3-IRS1 must be postulated. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Lim, Soo; Hivert, Marie-France; Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Lim, Soo; Hivert, Marie-France; O'Donnell, Christopher J.; Florez, Jose C.; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Unit, Boston, MA 02114 USA. [Lim, Soo] Seoul Natl Univ, Bundang Hosp, Dept Internal Med, Coll Med, Songnam, South Korea. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Hong, Jaeyoung; Liu, Ching-Ti; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hivert, Marie-France] Univ Sherbrooke, Div Endocrinol & Metab, Dept Med, Sherbrooke, PQ J1K 2R1, Canada. [White, Charles C.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Murabito, Joanne M.; O'Donnell, Christopher J.; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Dept Med, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jmeigs@partners.org OI Murabito, Joanne/0000-0002-0192-7516; Dupuis, Josee/0000-0003-2871-3603 FU National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) [2R01DK078616, K24 DK080140]; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195, N02-HL-6-4278]; Boston University Linux Cluster for Genetic Analysis (LinGA); National Institutes of Health National Center for Research Resources Shared Instrumentation Grant [1S10RR163736-01A1] FX This study was funded by the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) 2R01DK078616, K24 DK080140 (Dr. Meigs), the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract Nos. N01-HC-25195, N02-HL-6-4278), and the Boston University Linux Cluster for Genetic Analysis (LinGA) funded by the National Institutes of Health National Center for Research Resources Shared Instrumentation Grant (1S10RR163736-01A1). The funding agency had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The sole responsibility for the content of this manuscript lies with the authors. NR 32 TC 6 Z9 6 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JUL PY 2013 VL 229 IS 1 BP 149 EP 154 DI 10.1016/j.atherosclerosis.2013.03.037 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 166XU UT WOS:000320594700024 PM 23659870 ER PT J AU Ge, Y Cheng, S Larson, MG Ghorbani, A Martin, RP Klein, RJ O'Donnell, CJ Vasan, RS Shawe, SY Wang, TJ Cohen, KS AF Ge, Yin Cheng, Susan Larson, Martin G. Ghorbani, Anahita Martin, Roderick P. Klein, Rachael J. O'Donnell, Christopher J. Vasan, Ramachandran S. Shawe, Stanley Y. Wang, Thomas J. Cohen, Kenneth S. TI Circulating CD31+leukocyte frequency is associated with cardiovascular risk factors SO ATHEROSCLEROSIS LA English DT Article DE Epidemiology; CD31; Leukocytes; Endothelial cells; Cardiovascular risk factors ID ENDOTHELIAL PROGENITOR CELLS; ISCHEMIC VASCULAR-DISEASE; CORONARY-HEART-DISEASE; BONE-MARROW; CD31(+) CELLS; VASCULOGENIC CELLS; MONONUCLEAR-CELLS; HUMAN BLOOD; T-CELLS; ANGIOGENESIS AB Objectives: CD31 identifies a heterogeneous population of cells in the blood, consisting of mature leukocytes and platelets, as well as smaller numbers of endothelial and progenitor cells. Because unfractionated CD31+ blood cells have demonstrated angiogenic properties in vivo, we hypothesized that circulating CD31+ cells would be related to the presence of cardiovascular risk factors in humans. Methods and results: We studied 1487 participants, free of cardiovascular disease, from the Framingham Offspring Study. Using anti-human CD31 and CD45 antibodies, distinct CD31+/CD45+ leukocyte populations were enumerated in blood samples by FACS analysis. We used linear regression analyses to investigate the relation of each cell phenotype with cardiovascular risk factors. We identified 3 distinct leukocyte populations: CD31 -, CD31 dim, and CD31 bright cells. Using forward/side scatter analyses, CD31 - and CD31 dim cells mapped to lymphoid gates while CD31 bright cells were monocytoid. In multivariable analyses, higher frequency of CD31 bright cells was associated with older age, male sex, HDL cholesterol, and CRP (all P < 0.01). In contrast, CD31 dim was inversely associated with age, male sex, CRP, and smoking (all P < 0.01). Framingham Risk Score was positively associated with CD31 bright frequency (P = 0.002), and negatively associated with CD31 dim frequency (P = 0.020). Conclusions: CD31+ staining identifies 2 major leukocyte populations, CD31 bright and CD31 dim, which demonstrated significant and opposite associations with cardiovascular risk in humans. Further research is needed to define the biological and potential therapeutic roles of CD31+ subpopulations in vascular disease. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Ge, Yin] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Cheng, Susan; Larson, Martin G.; O'Donnell, Christopher J.; Vasan, Ramachandran S.; Wang, Thomas J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Cheng, Susan] Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiovasc Div, Boston, MA 02115 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Ghorbani, Anahita; O'Donnell, Christopher J.; Shawe, Stanley Y.; Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Martin, Roderick P.] Genzyme Corp, Cambridge, MA USA. [Martin, Roderick P.; Klein, Rachael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Shawe, Stanley Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Cohen, Kenneth S.] Univ Chicago, Med Ctr, Sect Hematol Oncol, Chicago, IL 60637 USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, Nashville, TN 37235 USA. RP Cohen, KS (reprint author), Univ Chicago, Med Ctr, Sect Hematol Oncol, 5841 S Maryland Ave,MC 2115, Chicago, IL 60637 USA. EM tjwang@partners.org; kcohen@medicine.bsd.uchicago.edu OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health; Boston University School of Medicine; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195, R01-HL083197, R01-HL93328, K99-HL107642]; Ellison Foundation FX From the Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine. This work was supported in part by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), grant R01-HL083197 (TJW), R01-HL93328 (RSV), and K99-HL107642 (SC). Dr. Cheng is supported in part by a grant from the Ellison Foundation. NR 33 TC 6 Z9 7 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JUL PY 2013 VL 229 IS 1 BP 228 EP 233 DI 10.1016/j.atherosclerosis.2013.04.017 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 166XU UT WOS:000320594700037 PM 23701996 ER PT J AU Kreisl, WC Lyoo, CH McGwier, M Snow, J Jenko, KJ Kimura, N Corona, W Morse, CL Zoghbi, SS Pike, VW McMahon, FJ Turner, RS Innis, RB AF Kreisl, William C. Lyoo, Chul Hyoung McGwier, Meghan Snow, Joseph Jenko, Kimberly J. Kimura, Nobuyo Corona, Winston Morse, Cheryl L. Zoghbi, Sami S. Pike, Victor W. McMahon, Francis J. Turner, R. Scott Innis, Robert B. CA Biomarkers Consortium Pet TI In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's disease SO BRAIN LA English DT Article DE Alzheimer's disease; mild cognitive impairment; neuroinflammation; positron emission tomography ID MILD COGNITIVE IMPAIRMENT; PERIPHERAL BENZODIAZEPINE-RECEPTOR; POSITRON-EMISSION-TOMOGRAPHY; PITTSBURGH COMPOUND-B; HUMAN CEREBRAL-CORTEX; HUMAN BRAIN; EARLY-ONSET; 18 KDA; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES AB Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with C-11-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with C-11-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, C-11-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater C-11-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. C-11-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. C-11-PBR28 binding also inversely correlated with grey matter volume. Early-onset (< 65 years) patients had greater C-11-PBR28 binding than late-onset patients, and in parietal cortex and striatum C-11-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between C-11-PBR28 and C-11-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased C-11-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. C-11-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease. C1 [Kreisl, William C.; Lyoo, Chul Hyoung; McGwier, Meghan; Jenko, Kimberly J.; Kimura, Nobuyo; Morse, Cheryl L.; Zoghbi, Sami S.; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Snow, Joseph] NIMH, Off Clin Director, Bethesda, MD 20892 USA. [Corona, Winston; McMahon, Francis J.] NIMH, Human Genet Branch, Bethesda, MD 20892 USA. [Turner, R. Scott] Georgetown Univ, Memory Disorders Program, Washington, DC USA. RP Kreisl, WC (reprint author), NIMH, 10 Ctr Dr,Rm B1-D43, Bethesda, MD 20892 USA. EM kreislw@mail.nih.gov RI Turner, Raymond/G-2263-2011; OI Turner, Raymond/0000-0001-7534-2935; McMahon, Francis/0000-0002-9469-305X FU Intramural Research Program of the National Institute of Mental Health-National Institutes of Health (IRP-NIMH-NIH); NIMH; Foundation for the NIH Biomarkers Consortium; EMD Serono; Glaxo Smith Kline; Lilly; Merck; Pfizer, Inc.; Roche FX This project was funded in part by the Intramural Research Program of the National Institute of Mental Health-National Institutes of Health (IRP-NIMH-NIH), and as a public-private partnership supported by the NIMH and the Foundation for the NIH Biomarkers Consortium (www.biomarkersconsortium.org) for the project 'Measuring neuroinflammation in Alzheimer's disease and mild cognitive impairment with 11C-PBR28 PET'. This project was submitted to the Biomarkers Consortium Neuroscience Steering Committee for execution and was managed by a Biomarkers Consortium Project Team that includes members from academia, Government, and the pharmaceutical industry. This work was supported by EMD Serono, Glaxo Smith Kline, Lilly, Merck, Pfizer, Inc., and Roche. We thank the Project Team for their contributions: Edilio Borroni (Roche), Linda Brady (NIMH), Thomas Finn (FDA), Richard Hargreaves (Merck), Robert Innis (NIMH), Walter Koroshetz (NINDS), William Kreisl (NIMH), Timothy McCarthy (Pfizer), P. David Mozley (Merck), Susanne Ostrowitzki (Roche), Victor Pike (NIMH), Eugenni Rabiner (GSK), Mark Shearman (EMD Serono), Judith Siuciak (FNIH), Cyrille Sur (Merck), Johannes Tauscher (Lilly). NR 54 TC 81 Z9 82 U1 1 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD JUL PY 2013 VL 136 BP 2228 EP 2238 DI 10.1093/brain/awt145 PN 7 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 173EF UT WOS:000321060200027 PM 23775979 ER PT J AU Angstadt, AY Berg, A Zhu, JJ Miller, P Hartman, TJ Lesko, SM Muscat, JE Lazarus, P Gallagher, CJ AF Angstadt, Andrea Y. Berg, Arthur Zhu, Junjia Miller, Paige Hartman, Terryl J. Lesko, Samuel M. Muscat, Joshua E. Lazarus, Philip Gallagher, Carla J. TI The effect of copy number variation in the phase II detoxification genes UGT2B17 and UGT2B28 on colorectal cancer risk SO CANCER LA English DT Article DE UGT2B17; UGT2B28; colorectal cancer risk; phase II detoxification; copy number variation ID UDP-GLUCURONOSYLTRANSFERASE 2B17; PROSTATE-CANCER; DELETION POLYMORPHISM; GLUCURONIDATION; EXPRESSION; MEAT; MEN; REGRESSION; ASPIRIN; ADULTS AB BACKGROUND Genetic polymorphisms in combination with the Western-style diet, physical inactivity, smoking, excessive alcohol consumption, and obesity have been hypothesized to affect colorectal cancer (CRC) risk. Metabolizers of environmental carcinogenic and endogenous compounds affecting CRC risk include the phase II detoxification UDP-glucuronosyltransferase (UGT) enzymes UGT2B17 and UGT2B28, which are 2 of the most commonly deleted genes in the genome. METHODS To study the effect of UGT2B17 and UGT2B28 copy number variation (CNV) on CRC risk, 665 Caucasian CRC cases and 621 Caucasian controls were genotyped who had completed extensive demographics and lifestyle questionnaires. RESULTS A significant association between the UGT2B17 deletion genotype (0/0) and decreased CRC risk was found when the entire population was analyzed (P=.044). Stratification by sex yielded a decreased risk (P=.020) in men with the UGT2B17 deletion (0/0), but no association was observed in women (P=.724). A significant association between UGT2B17 (0/0) and decreased risk for rectal (P=.0065) but not colon cancer was found. No significant association was found between UGT2B28 CNV and CRC risk. CONCLUSIONS The UGT2B17 deletion genotype (0/0) was associated with a decreased CRC risk in a Caucasian population. After sex stratification, the association was observed in men but not in women, which is consistent with previous findings that men have higher UGT2B17 expression and activity than women. Because UGT2B17 metabolizes certain nonsteroidal anti-inflammatory drugs and flavonoids with antioxidative properties, individuals with a gene deletion may have higher levels of these protective dietary components. Cancer 2013;119:2477-2485. (c) 2013 American Cancer Society. C1 [Angstadt, Andrea Y.; Berg, Arthur; Zhu, Junjia; Muscat, Joshua E.; Lazarus, Philip; Gallagher, Carla J.] Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Miller, Paige] NCI, Rockville, MD USA. [Hartman, Terryl J.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Lesko, Samuel M.] Northeast Reg Canc Inst, Scranton, PA USA. [Lazarus, Philip; Gallagher, Carla J.] Penn State Coll Med, Dept Pharmacol, Hershey, PA USA. RP Gallagher, CJ (reprint author), Penn State Univ, Dept Publ Hlth Sci, Coll Med, 500 Univ Dr,CH69, Hershey, PA 17033 USA. EM cgallagher@hmc.psu.edu OI Berg, Arthur/0000-0002-4097-7348 FU National Institute of Health [R00 CA 131477]; PA Department of Health CURE FX This study was funded by National Institute of Health grant R00 CA 131477 and PA Department of Health CURE. NR 39 TC 14 Z9 14 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUL 1 PY 2013 VL 119 IS 13 BP 2477 EP 2485 DI 10.1002/cncr.28009 PG 9 WC Oncology SC Oncology GA 165FT UT WOS:000320469400019 PM 23575887 ER PT J AU Patel, A Tiwari, AK Chufan, EE Sodani, K Anreddy, N Singh, S Ambudkar, SV Stephani, R Chen, ZS AF Patel, Atish Tiwari, Amit K. Chufan, Eduardo E. Sodani, Kamlesh Anreddy, Nagaraju Singh, Satyakam Ambudkar, Suresh V. Stephani, Ralph Chen, Zhe-Sheng TI PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE PD173074; ABC transporter; ABCB1; Fibroblast growth factor receptor; Multidrug resistance; Tyrosine kinase inhibitor ID TYROSINE KINASE INHIBITORS; MEDIATED MULTIDRUG-RESISTANCE; SUBFAMILY-B MEMBER-1; P-GLYCOPROTEIN; IN-VITRO; MOLECULAR-MECHANISMS; ANTICANCER DRUGS; ABC TRANSPORTERS; POTENT MODULATOR; BINDING AB Specific tyrosine kinase inhibitors were recently reported to modulate the activity of ABC transporters, leading to an increase in the intracellular concentration of their substrate drugs. In this study, we determine whether PD173074, a specific fibroblast growth factor receptor (FGFR) inhibitor, could reverse ABC transporter-mediated multidrug resistance. 3-(4,5-Dimethylthiazol-yl)-2,5-diphenyllapatinibrazolium bromide assay was used to determine the effect of PD173074 on reversal of ABC transporter-mediated multidrug resistance (MDR). In addition, [H-3]-paclitaxel accumulation/efflux assay, western blotting analysis, ATPase, and photoaffinity labeling assays were done to study the interaction of PD173074 on ABC transporters. PD173074 significantly sensitized both ABCB1-transfected and drug-selected cell lines overexpressing this transporter to substrate anticancer drugs colchicine, paclitaxel, and vincristine. This effect of PD173074 is specific to ABCB1, as no significant interaction was detected with other ABC transporters such as ABCC1 and ABCG2. The observed reversal effect seems to be primarily due to the decreased active efflux of [H-3]-paclitaxel in ABCB1 overexpressing cells observed in efflux assay. In addition, no significant change in the ABCB1 expression was observed when ABCB1 overexpressing cells were exposed to 5 mu M PD173074 for up to 3 days, thereby further suggesting its role in modulating the function of the transporter. In addition, PD173074 stimulated the ATPase activity of ABCB1 in a concentration-dependent manner, indicating a direct interaction with the transporter. Interestingly, PD173074 did not inhibit photolabeling of ABCB1 with [I-125]-iodoarylazidoprazosin (IAAP), showing that it binds at a site different from that of IAAP in the drug-binding pocket. Here, we report for the first time, PD173074, an inhibitor of the FGFR, to selectively reverse ABCB1 transporter-mediated MDR by directly blocking the efflux function of the transporter. C1 [Patel, Atish; Tiwari, Amit K.; Sodani, Kamlesh; Anreddy, Nagaraju; Singh, Satyakam; Stephani, Ralph; Chen, Zhe-Sheng] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA. [Chufan, Eduardo E.; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chen, ZS (reprint author), St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Queens, NY 11439 USA. EM chenz@stjohns.edu RI Patel, Atish/J-4699-2014; OI Singh, Satyakam/0000-0001-9115-3296; Anreddy, Nagaraju/0000-0001-8914-8404; Patel, Atish/0000-0002-5549-9166; TIWARI, AMIT/0000-0002-7427-7155 FU NIH [1R15CA143701]; RayBiotech, Inc; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Drs. Michael M. Gottesman (NCI, NIH, Bethesda, MD, USA) for KB-3-1 cells, Shinichi Akiyama (Kagoshima University, Japan) for the KB-C2 cell lines, Susan E. Bates and Robert W. Robey (NIH, USA) for the FTC, HEK293/pcDNA3.1, HEK293/ABCB1, H460, and H460/MX20 cell lines. Dr. Tanaji Talele and Rishil J Kathawala (St. John's University) for carefully reading and editing the manuscript. This work was supported by funds from NIH (No. 1R15CA143701) and RayBiotech, Inc to Z.S. Chen. E.E. Chufan and S.V. Ambudkar were supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 49 TC 16 Z9 17 U1 0 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUL PY 2013 VL 72 IS 1 BP 189 EP 199 DI 10.1007/s00280-013-2184-z PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 170XU UT WOS:000320889300019 PM 23673445 ER PT J AU Zhang, Y Choksi, S Chen, K Pobezinskaya, Y Linnoila, I Liu, ZG AF Zhang, Yan Choksi, Swati Chen, Kun Pobezinskaya, Yelena Linnoila, Ilona Liu, Zheng-Gang TI ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages SO CELL RESEARCH LA English DT Article DE ROS; alternatively activated M2 macrophages; macrophage differentiation; inflammation; tumorigenesis ID NADPH OXIDASE; LUNG TUMORIGENESIS; T-CELLS; INFLAMMATION; CSF; PROLIFERATION; POLARIZATION; METASTASIS; EXPRESSION; AUTOPHAGY AB Differentiation to different types of macrophages determines their distinct functions. Tumor-associated macrophages (TAMs) promote tumorigenesis owing to their proangiogenic and immune-suppressive functions similar to those of alternatively activated (M2) macrophages. We report that reactive oxygen species (ROS) production is critical for macrophage differentiation and that inhibition of superoxide (O2-) production specifically blocks the differentiation of M2 macrophages. We found that when monocytes are triggered to differentiate, O2- is generated and is needed for the biphasic ERK activation, which is critical for macrophage differentiation. We demonstrated that ROS elimination by butylated hydroxyanisole (BHA) and other ROS inhibitors blocks macrophage differentiation. However, the inhibitory effect of ROS elimination on macrophage differentiation is overcome when cells are polarized to classically activated (M1), but not M2, macrophages. More importantly, the continuous administration of the ROS inhibitor BHA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by blocking ROS can be a potentially effective method for cancer treatment. C1 [Zhang, Yan; Choksi, Swati; Chen, Kun; Pobezinskaya, Yelena; Linnoila, Ilona; Liu, Zheng-Gang] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chen, Kun] Nanjing Univ, Sch Life Sci, Nanjing 210093, Jiangsu, Peoples R China. RP Liu, ZG (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, 37 Convent Dr,RM1130, Bethesda, MD 20892 USA. EM zgliu@helix.nih.gov FU Center for Cancer Research, NCI, NIH FX We thank AA Molinolo (NIH/NIDCR) for his expertise in histopathology and the National Institutes of Health Blood Bank for elutriated monocytes. We also thank Dr JJ Yin (NCI/CCBB) for helping set up the breast cancer xenograft model, V Diaz (NIH/NINDS) for the mouse imaging and B Barreff (NCI/CCBB) for helping with analysis of mouse image data. This study was supported by the Intramural Research Program of The Center for Cancer Research, NCI, NIH. NR 48 TC 52 Z9 52 U1 3 U2 39 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 J9 CELL RES JI Cell Res. PD JUL PY 2013 VL 23 IS 7 BP 898 EP 914 DI 10.1038/cr.2013.75 PG 17 WC Cell Biology SC Cell Biology GA 173WT UT WOS:000321113700009 PM 23752925 ER PT J AU Mi, QS Kenny, JJ AF Mi, Qing-Sheng Kenny, James J. TI Types of tolerance seen in autoreactive phosphocholine-specific B cells are dependent on the idiotype of the receptors expressed SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Article DE B cells; idiotype; phosphocholine; Streptococcus pneumoniae; tolerance ID VARIABLE REGION GENE; HEAVY-CHAIN LOCUS; TRANSGENIC MICE; REPERTOIRE; ANTIBODIES; SELECTION; KAPPA; DELETION; BINDING; FORMS AB Phosphocholine (PC) is the immunodominant epitope found on the surface of a number of microorganisms, including Streptococcus pneumoniae (SPn), and is thought to play a vital role in the pathogenesis of SPn. B cells expressing M167H kappa 24L immunoglobulin receptors specific for PC have been shown to be autoreactive in that they undergo clonal deletion in both X-linked immune-deficient and Rag(-/-) mice. We have now shown that B cells expressing M603H kappa 8L PC-specific receptors also delete in Rag(-/-) mice, whereas those expressing T15H kappa 22L transgenes do not delete. However, T15H kappa 22L B cells are lost in normal heterozygous transgenic mice because they cannot compete with normal B cells. These data indicate that M167H kappa 24L and M603H kappa 8L PC-specific B cells are recognizing an autoantigen expressed on membranes which causes them to downregulate their receptors and clonally delete, while T15H kappa 22L B cells are tolerized by a soluble form of PC-antigen which results in their being trapped in the spleen. Thus, the types of tolerance seen in autoreactive PC-specific B cells are dependent on the idiotype of the receptors expressed. C1 [Mi, Qing-Sheng] Henry Ford Hlth Syst, Henry Ford Immunol Program, Detroit, MI USA. [Mi, Qing-Sheng] Henry Ford Hlth Syst, Dept Dermatol, Detroit, MI USA. [Mi, Qing-Sheng] Henry Ford Hlth Syst, Dept Internal Med, Detroit, MI USA. [Kenny, James J.] NIH, Immunol Lab, Gerontol Res Inst, Baltimore, MD USA. [Kenny, James J.] NIH, Gerontol Res Inst, Baltimore, MD USA. RP Mi, QS (reprint author), Henry Ford Hlth Syst, Dept Dermatol, Henry Ford Immunol Program, 1 Ford Pl, Detroit, MI 48202 USA. EM qmi1@hfhs.org FU Gerontology Research Institute, NIA, NIH FX We are grateful to Dr Klaus Rajewsky for providing T15i KI mice and mu KO mice, to Dr Ursula Storb for M167H chain mice and M167H kappa 24L mice, and to J. Latham Claflin for M603 H and Kappa 8 L transgenic mice. We thank Randy Fisher, Anna Lustig and Dr Louis Razanka for technical assistance. This work was supported by the Gerontology Research Institute, NIA, NIH. NR 23 TC 0 Z9 0 U1 0 U2 0 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD JUL PY 2013 VL 10 IS 4 BP 311 EP 316 DI 10.1038/cmi.2013.17 PG 6 WC Immunology SC Immunology GA 173WK UT WOS:000321112400006 PM 23624878 ER PT J AU Burbelo, PD Swedo, SE Thurm, A Bayat, A Levin, AE Marques, A Iadarola, MJ AF Burbelo, Peter D. Swedo, Susan E. Thurm, Audrey Bayat, Ahmad Levin, Andrew E. Marques, Adriana Iadarola, Michael J. TI Lack of Serum Antibodies against Borrelia burgdorferi in Children with Autism SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID LYME-DISEASE; DISORDERS AB It has been proposed that Borrelia burgdorferi infection is present in similar to 25% of children with autism spectrum disorders. In this study, antibodies against Borrelia burgdorferi were assessed in autistic (n = 104), developmentally delayed (n = 24), and healthy control (n = 55) children. No seropositivity against Borrelia burgdorferi was detected in the children with and without autism. There was no evidence of an association between Lyme disease and autism. C1 [Burbelo, Peter D.; Bayat, Ahmad; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. [Swedo, Susan E.; Thurm, Audrey] NIMH, Dept Pediat & Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Levin, Andrew E.] Immunetics Inc, Boston, MA USA. [Marques, Adriana] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Burbelo, PD (reprint author), Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. EM burbelop@nidcr.nih.gov FU Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institute of Mental Health; Division of Intramural Research National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institute of Mental Health, and by the Division of Intramural Research National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 12 TC 2 Z9 2 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD JUL PY 2013 VL 20 IS 7 BP 1092 EP 1093 DI 10.1128/CVI.00643-12 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 170MV UT WOS:000320857300020 PM 23658391 ER PT J AU Tran, TM Li, SP Doumbo, S Doumtabe, D Huang, CY Dia, S Bathily, A Sangala, J Kone, Y Traore, A Niangaly, M Dara, C Kayentao, K Ongoiba, A Doumbo, OK Traore, B Crompton, PD AF Tran, Tuan M. Li, Shanping Doumbo, Safiatou Doumtabe, Didier Huang, Chiung-Yu Dia, Seydou Bathily, Aboudramane Sangala, Jules Kone, Younoussou Traore, Abdrahamane Niangaly, Moussa Dara, Charles Kayentao, Kassoum Ongoiba, Aissata Doumbo, Ogobara K. Traore, Boubacar Crompton, Peter D. TI An Intensive Longitudinal Cohort Study of Malian Children and Adults Reveals No Evidence of Acquired Immunity to Plasmodium falciparum Infection SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE preerythrocytic immunity; endemic population; Plasmodium falciparum; infection risk; malaria ID MODERATE SEASONAL TRANSMISSION; SICKLE-CELL TRAIT; REAL-TIME PCR; MALARIA VACCINE; NORTHERN GHANA; PROTECTION; SPOROZOITES; PARASITE; INFANTS; TRIAL AB Background. In experimental models of human and mouse malaria, sterilizing liver stage immunity that blocks progression of Plasmodium infection to the symptomatic blood stage can be readily demonstrated. However, it remains unclear whether individuals in malaria-endemic areas acquire such immunity. Methods. In Mali, 251 healthy children and adults aged 4-25 years who were free of blood-stage Plasmodium infection by polymerase chain reaction (PCR) were enrolled in a longitudinal study just prior to an intense 6-month malaria season. Subsequent clinical malaria episodes were detected by weekly active surveillance and self-referral. Asymptomatic P. falciparum infections were detected by blood-smear microscopy and PCR analysis of dried blood spots that had been collected every 2 weeks for 7 months. Results. As expected, the risk of clinical malaria decreased with increasing age (log-rank test, P =.0038). However, analysis of PCR data showed no age-related differences in P. falciparum infection risk (log-rank test, P =.37). Conclusions. Despite years of exposure to intense P. falciparum transmission, there is no evidence of acquired, sterile immunity to P. falciparum infection in this population, even as clinical immunity to blood-stage malaria is clearly acquired. Understanding why repeated P. falciparum infections do not induce sterile protection may lead to insights for developing vaccines that target the liver stage in malaria-endemic populations. C1 [Tran, Tuan M.; Li, Shanping; Crompton, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Huang, Chiung-Yu] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Doumbo, Safiatou; Doumtabe, Didier; Dia, Seydou; Bathily, Aboudramane; Sangala, Jules; Kone, Younoussou; Traore, Abdrahamane; Niangaly, Moussa; Dara, Charles; Kayentao, Kassoum; Ongoiba, Aissata; Doumbo, Ogobara K.; Traore, Boubacar] Univ Sci Tech & Technol Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali. RP Crompton, PD (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook 2,Rm 125,12441 Parklawn Dr, Rockville, MD 20852 USA. EM pcrompton@niaid.nih.gov RI Crompton, Peter/N-1130-2016 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 40 TC 49 Z9 50 U1 2 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2013 VL 57 IS 1 BP 40 EP 47 DI 10.1093/cid/cit174 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 171JU UT WOS:000320923700008 PM 23487390 ER PT J AU Rotger, M Glass, TR Junier, T Lundgren, J Neaton, JD Poloni, ES van 't Wout, AB Lubomirov, R Colombo, S Martinez, R Rauch, A Gunthard, HF Neuhaus, J Wentworth, D van Manen, D Gras, LA Schuitemaker, H Albini, L Torti, C Jacobson, LP Li, XH Kingsley, LA Carli, F Guaraldi, G Ford, ES Sereti, I Hadigan, C Martinez, E Arnedo, M Egana-Gorrono, L Gatell, JM Law, M Bendall, C Petoumenos, K Rockstroh, J Wasmuth, JC Kabamba, K Delforge, M De Wit, S Berger, F Mauss, S Sierra, MD Losso, M Belloso, WH Leyes, M Campins, A Mondi, A De Luca, A Bernardino, I Barriuso-Iglesias, M Torrecilla-Rodriguez, A Gonzalez-Garcia, J Arribas, JR Fanti, I Gel, S Puig, J Negredo, E Gutierrez, M Domingo, P Fischer, J Fatkenheuer, G Alonso-Villaverde, C Macken, A Woo, J McGinty, T Mallon, P Mangili, A Skinner, S Wanke, CA Reiss, P Weber, R Bucher, HC Fellay, J Telenti, A Tarr, PE AF Rotger, Margalida Glass, Tracy R. Junier, Thomas Lundgren, Jens Neaton, James D. Poloni, Estella S. van 't Wout, Angelique B. Lubomirov, Rubin Colombo, Sara Martinez, Raquel Rauch, Andri Guenthard, Huldrych F. Neuhaus, Jacqueline Wentworth, Deborah van Manen, Danielle Gras, Luuk A. Schuitemaker, Hanneke Albini, Laura Torti, Carlo Jacobson, Lisa P. Li, Xiuhong Kingsley, Lawrence A. Carli, Federica Guaraldi, Giovanni Ford, Emily S. Sereti, Irini Hadigan, Colleen Martinez, Esteban Arnedo, Mireia Egana-Gorrono, Lander Gatell, Jose M. Law, Matthew Bendall, Courtney Petoumenos, Kathy Rockstroh, Juergen Wasmuth, Jan-Christian Kabamba, Kabeya Delforge, Marc De Wit, Stephane Berger, Florian Mauss, Stefan de Paz Sierra, Mariana Losso, Marcelo Belloso, Waldo H. Leyes, Maria Campins, Antoni Mondi, Annalisa De Luca, Andrea Bernardino, Ignacio Barriuso-Iglesias, Monica Torrecilla-Rodriguez, Ana Gonzalez-Garcia, Juan Arribas, Jose R. Fanti, Iuri Gel, Silvia Puig, Jordi Negredo, Eugenia Gutierrez, Mar Domingo, Pere Fischer, Julia Faetkenheuer, Gerd Alonso-Villaverde, Carlos Macken, Alan Woo, James McGinty, Tara Mallon, Patrick Mangili, Alexandra Skinner, Sally Wanke, Christine A. Reiss, Peter Weber, Rainer Bucher, Heiner C. Fellay, Jacques Telenti, Amalio Tarr, Philip E. CA MAGNIFICENT Consortium INSIGHT Swiss HIV Cohort Study TI Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV infection; coronary artery disease; genetics; traditional risk factors; antiretroviral therapy ID MIDDLE-AGED ADULTS; MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; INFECTED INDIVIDUALS; HEART-DISEASE; PROTEASE INHIBITORS; DIABETES-MELLITUS; COHORT; ASSOCIATION; HISTORY AB Background. Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods. In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. Results. A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9x10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), >= 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. Conclusions. In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD. C1 [Rotger, Margalida; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Fellay, Jacques; Telenti, Amalio] Univ Lausanne, Univ Hosp Ctr, Inst Microbiol, CH-1015 Lausanne, Switzerland. [Glass, Tracy R.; Bucher, Heiner C.] Univ Basel Hosp, Basel Inst Clin Epidemiol & Biostat, Basel, Switzerland. [Junier, Thomas] Swiss Inst Bioinformat, Lausanne, Switzerland. [Junier, Thomas; Fellay, Jacques] Ecole Polytech Fed Lausanne, CH-1015 Lausanne, Switzerland. [Lundgren, Jens] Univ Copenhagen, DK-1168 Copenhagen, Denmark. [Neaton, James D.; Neuhaus, Jacqueline; Wentworth, Deborah] Univ Minnesota, Minneapolis, MN USA. [van 't Wout, Angelique B.; van Manen, Danielle; Gras, Luuk A.; Schuitemaker, Hanneke; Reiss, Peter] AIDS Therapy Evaluat Netherlands, Amsterdam, Netherlands. [Rauch, Andri; Guenthard, Huldrych F.; Weber, Rainer; Bucher, Heiner C.; Fellay, Jacques; Telenti, Amalio; Tarr, Philip E.] Swiss HIV Cohort Study, Bern, Switzerland. [Tarr, Philip E.] Univ Basel, Kantonsspital Baselland, Bruderholz, Bern, Switzerland. [Poloni, Estella S.] Univ Geneva, Dept Genet & Evolut, Lab Anthropol, Bern, Switzerland. [Guenthard, Huldrych F.; Weber, Rainer] Univ Zurich, Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, Bern, Switzerland. [Rauch, Andri] Univ Hosp Bern, Div Infect Dis, CH-3010 Bern, Switzerland. [Albini, Laura; Torti, Carlo] Univ Brescia, Dept Infect Dis, Catanzaro, Italy. [Torti, Carlo] Magna Graecia Univ Catanzaro, Infect Dis Unit, Catanzaro, Italy. [Carli, Federica; Guaraldi, Giovanni] Univ Modena & Reggio Emilia, Modena, Italy. [Ford, Emily S.; Sereti, Irini; Hadigan, Colleen] Intramural Natl Inst Allergy & Infect Dis Cohort, Bethesda, MD USA. [Martinez, Esteban; Arnedo, Mireia; Egana-Gorrono, Lander; Gatell, Jose M.] Hosp Clin IDIBAPS, Barcelona, Spain. [Law, Matthew; Bendall, Courtney; Petoumenos, Kathy] Univ New S Wales, Kirby Inst, Australian HIV Observat Database, Darlinghurst, NSW, Australia. [Rockstroh, Juergen; Wasmuth, Jan-Christian] Univ Hosp Bonn, Bonn, Germany. [Kabamba, Kabeya; Delforge, Marc; De Wit, Stephane] St Pierre Univ Hosp, Brussels, Belgium. [Berger, Florian; Mauss, Stefan] Ctr HIV Hepatogastroenterol Dusseldorf, Dusseldorf, Germany. [de Paz Sierra, Mariana; Losso, Marcelo; Belloso, Waldo H.] Cohorte LATINA Argentinian Component, Buenos Aires, DF, Argentina. [Leyes, Maria; Campins, Antoni] Univ Hosp Son Espases, Palma De Mallorca, Spain. [Mondi, Annalisa; De Luca, Andrea] Univ Cattolica Sacro Cuore, Rome, Italy. [Bernardino, Ignacio; Barriuso-Iglesias, Monica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, Jose R.] Univ Hosp La Paz, Madrid, Spain. [Bernardino, Ignacio; Barriuso-Iglesias, Monica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, Jose R.] IdiPAZ Biobanco, Madrid, Spain. [Gel, Silvia; Puig, Jordi; Negredo, Eugenia] Univ Hosp Germans Trias & Pujol, Badalona, Spain. [Gutierrez, Mar; Domingo, Pere] Autonomous Univ Barcelona, Univ Hosp Santa Creu & St Pau Cohort, Barcelona, Spain. [Fischer, Julia; Faetkenheuer, Gerd] Univ Hosp Cologne, Cologne, Germany. [Alonso-Villaverde, Carlos] Hosp Santa Tecla & St Pau, Tarragona, Spain. [Macken, Alan; Mallon, Patrick] Univ Coll Dublin, Sch Med & Med Sci, Dublin, Ireland. [Woo, James] St James Hosp, Dublin, Ireland. [McGinty, Tara] Mater Misericordiae Univ Hosp, Dublin, Ireland. [Mangili, Alexandra; Skinner, Sally; Wanke, Christine A.] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Tarr, PE (reprint author), Univ Basel, Kantonsspital Baselland, Infect Dis Serv, CH-4101 Bruderholz, Switzerland. EM philip.tarr@unibas.ch RI Infektiologie, USZ/A-6921-2011; SHCS, int. coll. A/G-4083-2011; De Luca, Andrea/G-8810-2011; Fellay, Jacques/A-6681-2009; Arribas, Jose/A-1595-2015; SHCS, all/G-4072-2011; Pantaleo, Giuseppe/K-6163-2016; Rizzardini, Giuliano/K-9458-2016; perno, carlo federico/O-1544-2016; Weber, Rainer/D-5175-2012; gunthard, huldrych/F-1724-2011; Glass, Tracy/D-5046-2017; OI Ippolito, Giuseppe/0000-0002-1076-2979; Ford, Emily/0000-0001-7358-798X; Tebano, Gianpiero/0000-0003-1891-4823; Lundgren, Jens/0000-0001-8901-7850; Guaraldi, Giovanni/0000-0002-5724-3914; Poloni, Estella S./0000-0002-8465-003X; CAUDA, Roberto/0000-0002-1498-4229; Egana Gorrono, Lander/0000-0002-0378-7844; Cranston, Ross/0000-0002-2687-6217; Fellay, Jacques/0000-0002-8240-939X; Arribas, Jose/0000-0002-7410-9450; Rizzardini, Giuliano/0000-0002-5183-7818; gunthard, huldrych/0000-0002-1142-6723; Glass, Tracy/0000-0001-7075-9803; Becker, James/0000-0003-4425-4726 FU Swiss National Science Foundation (SNF) [324730_127631/1]; Swiss HIV Cohort Study (SNF) [33CS30_134277, 599]; Universities of Geneva and Lausanne; Intramural Research Program of the National Institute of Allergy and Infectious Diseases; Gilead Sciences and Merck Sharp & Dohme Switzerland; Instituto de Salud Carlos III, Spanish Health Ministry [RETIC RD09/0076/00073]; Farmaindustria, through the Cooperation Program in Clinical and Translational Research of the Community of Madrid Red de Investigacion en SIDA [ISCIII- RETIC RD06/0006/1017, ISCIII-MA06/0164] FX This work was supported by the Swiss National Science Foundation (SNF; project 324730_127631/1), the Swiss HIV Cohort Study (SNF grant 33CS30_134277, SHCS project 599), an INFECTIGEN grant from the Universities of Geneva and Lausanne (to P. E. T.), the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, and unrestricted grants from Gilead Sciences and Merck Sharp & Dohme Switzerland to the SHCS research foundation. The IdiPAZ Biobank is supported by Instituto de Salud Carlos III, Spanish Health Ministry (RETIC RD09/0076/00073) and Farmaindustria, through the Cooperation Program in Clinical and Translational Research of the Community of Madrid Red de Investigacion en SIDA grant (ISCIII- RETIC RD06/0006/1017, ISCIII-MA06/0164). NR 39 TC 19 Z9 20 U1 1 U2 28 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2013 VL 57 IS 1 BP 112 EP 121 DI 10.1093/cid/cit196 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 171JU UT WOS:000320923700017 PM 23532479 ER PT J AU Martini, S Nair, V Patel, SR Eichinger, F Nelson, RG Weil, EJ Pezzolesi, MG Krolewski, AS Randolph, A Keller, BJ Werner, T Kretzler, M AF Martini, Sebastian Nair, Viji Patel, Sanjeevkumar R. Eichinger, Felix Nelson, Robert G. Weil, E. Jennifer Pezzolesi, Marcus G. Krolewski, Andrzej S. Randolph, Ann Keller, Benjamin J. Werner, Thomas Kretzler, Matthias TI From Single Nucleotide Polymorphism to Transcriptional Mechanism A Model for FRMD3 in Diabetic Nephropathy SO DIABETES LA English DT Article ID GENOME-WIDE ASSOCIATION; BONE MORPHOGENETIC PROTEIN-7; CHRONIC KIDNEY-DISEASE; PROMOTER ANALYSIS; FUNCTIONAL-CHARACTERIZATION; NETWORK ANALYSIS; GENETIC-FACTORS; EXPRESSION; IDENTIFICATION; MELLITUS AB Genome-wide association studies have proven to be highly effective at defining relationships between single nucleotide polymorphisms (SNPs) and clinical phenotypes in complex diseases. Establishing a mechanistic link between a noncoding SNP and the clinical outcome is a significant hurdle in translating associations into biological insight. We demonstrate an approach to assess the functional context of a diabetic nephropathy (DN)-associated SNP located in the promoter region of the gene FRMD3. The approach integrates pathway analyses with transcriptional regulatory pattern-based promoter modeling and allows the identification of a transcriptional framework affected by the DN-associated SNP in the FRMD3 promoter. This framework provides a testable hypothesis for mechanisms of genomic variation and transcriptional regulation in the context of DN. Our model proposes a possible transcriptional link through which the polymorphism in the FRMD3 promoter could influence transcriptional regulation within the bone morphogenetic protein (BMP)-signaling pathway. These findings provide the rationale to interrogate the biological link between FRMD3 and the BMP pathway and serve as an example of functional genomics-based hypothesis generation. C1 [Martini, Sebastian; Nair, Viji; Patel, Sanjeevkumar R.; Eichinger, Felix; Randolph, Ann; Werner, Thomas; Kretzler, Matthias] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Martini, Sebastian; Nair, Viji; Patel, Sanjeevkumar R.; Eichinger, Felix; Randolph, Ann; Werner, Thomas; Kretzler, Matthias] Univ Michigan, Dept Nephrol, Ann Arbor, MI 48109 USA. [Nelson, Robert G.; Weil, E. Jennifer] NIDDK, NIH, Phoenix, AZ USA. [Pezzolesi, Marcus G.; Krolewski, Andrzej S.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Pezzolesi, Marcus G.; Krolewski, Andrzej S.] Joslin Diabet Ctr, Clin Div, Boston, MA 02215 USA. [Keller, Benjamin J.] Eastern Michigan Univ, Dept Comp Sci, Ypsilanti, MI 48197 USA. [Werner, Thomas] Genomatix Software GmbH, Munich, Germany. RP Kretzler, M (reprint author), Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. EM kretzler@umich.edu FU National Institutes of Health [R01-DK058549, K01-DK090125]; O'Brien Renal Center [P30-DK081943]; National Center for Integrative Bioinformatics [U54-DA021519]; Federal Ministry of Education and Research, Germany [01EX1021L] FX This study was supported in part by National Institutes of Health grants R01-DK058549 to A.S.K. and K01-DK090125 to M.G.P., by the O'Brien Renal Center (P30-DK081943) and the National Center for Integrative Bioinformatics (U54-DA021519) to M.K., and from the Federal Ministry of Education and Research, Germany (01EX1021L) to T.W. NR 47 TC 18 Z9 19 U1 0 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2013 VL 62 IS 7 BP 2605 EP 2612 DI 10.2337/db12-1416 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 173KA UT WOS:000321077200049 PM 23434934 ER PT J AU Garm, C Moreno-Villanueva, M Burkle, A Larsen, LA Bohr, VA Christensen, K Stevnsner, T AF Garm, Christian Moreno-Villanueva, Maria Buerkle, Alexander Larsen, Lisbeth Aagaard Bohr, Vilhelm A. Christensen, Kaare Stevnsner, Tinna TI Genetic and environmental influence on DNA strand break repair: A twin study SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE DNA repair; single-strand break repair; double-strand break repair; gamma-H2AX; heritability; twins ID MUTAGEN SENSITIVITY; BLOOD MONONUCLEAR; INDUCED APOPTOSIS; HUMAN-LYMPHOCYTES; HERITABILITY; AGE; DAMAGE; LONGEVITY; RADIATION; CANCER AB Accumulation of DNA damage deriving from exogenous and endogenous sources has significant consequences for cellular survival, and is implicated in aging, cancer, and neurological diseases. Different DNA repair pathways have evolved in order to maintain genomic stability. Genetic and environmental factors are likely to influence DNA repair capacity. In order to gain more insight into the genetic and environmental contribution to the molecular basis of DNA repair, we have performed a human twin study, where we focused on the consequences of some of the most abundant types of DNA damage (single-strand breaks), and some of the most hazardous lesions (DNA double-strand breaks). DNA damage signaling response (Gamma-H2AX signaling), relative amount of endogenous damage, and DNA-strand break repair capacities were studied in peripheral blood mononuclear cells from 198 twins (94 monozygotic and 104 dizygotic). We did not detect genetic effects on the DNA-strand break variables in our study. Environ. Mol. Mutagen. 54:414-420, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Garm, Christian; Stevnsner, Tinna] Univ Aarhus, Danish Ctr Mol Gerontol, DK-8000 Aarhus C, Denmark. [Garm, Christian; Stevnsner, Tinna] Univ Aarhus, Danish Aging Res Ctr, Dept Mol Biol & Genet, DK-8000 Aarhus C, Denmark. [Garm, Christian; Larsen, Lisbeth Aagaard; Christensen, Kaare] Univ Southern Denmark, Inst Publ Hlth, Epidemiol Unit, Danish Aging Res Ctr, Odense, Denmark. [Moreno-Villanueva, Maria; Buerkle, Alexander] Univ Konstanz, Dept Biol, Mol Toxicol Grp, Constance, Germany. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Christensen, Kaare] Odense Univ Hosp, Dept Clin Biochem & Pharmacol, Odense, Denmark. [Christensen, Kaare] Odense Univ Hosp, Dept Clin Genet, Odense, Denmark. RP Stevnsner, T (reprint author), Univ Aarhus, Dept Mol Biol & Genet, Lab DNA Repair & Aging, CF Moellers Alle 3, DK-8000 Aarhus C, Denmark. EM tvs@mb.au.dk FU Danish Agency for Science, Technology and Innovation [09-063256]; VELUX Foundation; Ausschuss fur Forschungsfragen; University of Konstanz FX Grant sponsors: Danish Agency for Science, Technology and Innovation; Grant number: 09-063256. The VELUX Foundation. Ausschuss fur Forschungsfragen, University of Konstanz. NR 27 TC 6 Z9 6 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD JUL PY 2013 VL 54 IS 6 BP 414 EP 420 DI 10.1002/em.21791 PG 7 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 176HS UT WOS:000321295400005 PM 23798034 ER PT J AU Bassig, BA Zhang, LP Tang, XJ Vermeulen, R Shen, M Smith, MT Qiu, CY Ge, YC Ji, ZY Reiss, B Hosgood, HD Liu, SW Bagni, R Guo, WH Purdue, M Hu, W Yue, F Li, LY Huang, HL Rothman, N Lan, Q AF Bassig, Bryan A. Zhang, Luoping Tang, Xiaojiang Vermeulen, Roel Shen, Min Smith, Martyn T. Qiu, Chuangyi Ge, Yichen Ji, Zhiying Reiss, Boris Hosgood, H. Dean, III Liu, Songwang Bagni, Rachel Guo, Weihong Purdue, Mark Hu, Wei Yue, Fei Li, Laiyu Huang, Hanlin Rothman, Nathaniel Lan, Qing TI Occupational exposure to trichloroethylene and serum concentrations of IL-6, IL-10, and TNF-alpha SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE trichloroethylene; immunotoxicity; IL-10; TNF-; IL-6; occupational exposure ID NON-HODGKINS-LYMPHOMA; INTERLEUKIN-10 GENE PROMOTER; POLYMORPHISMS INFLUENCE; RISK; SUSCEPTIBILITY; MARKERS; WORKERS; CANCER AB To evaluate the immunotoxicity of trichloroethylene (TCE), we conducted a cross-sectional molecular epidemiology study in China of workers exposed to TCE. We measured serum levels of IL-6, IL-10, and TNF-, which play a critical role in regulating various components of the immune system, in 71 exposed workers and 78 unexposed control workers. Repeated personal exposure measurements were taken in workers before blood collection using 3 M organic vapor monitoring badges. Compared to unexposed workers, the serum concentration of IL-10 in workers exposed to TCE was decreased by 70% (P=0.001) after adjusting for potential confounders. Further, the magnitude of decline in IL-10 was >60% and statistically significant in workers exposed to <12 ppm as well as in workers with exposures 12 ppm of TCE, compared to unexposed workers. No significant differences in levels of IL-6 or TNF- were observed among workers exposed to TCE compared to unexposed controls. Given that IL-10 plays an important role in immunologic processes, including mediating the Th1/Th2 balance, our findings provide additional evidence that TCE is immunotoxic in humans. Environ. Mol. Mutagen. 54:450-454, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Bassig, Bryan A.; Shen, Min; Purdue, Mark; Hu, Wei; Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH,DHHS, Bethesda, MD 20892 USA. [Zhang, Luoping; Smith, Martyn T.; Ji, Zhiying; Guo, Weihong] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Tang, Xiaojiang; Qiu, Chuangyi; Ge, Yichen; Yue, Fei; Li, Laiyu; Huang, Hanlin] Guangdong Poison Control Ctr, Guangzhou, Guangdong, Peoples R China. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Reiss, Boris] Univ Utrecht, Utrecht, Netherlands. [Hosgood, H. Dean, III] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Liu, Songwang] Qiaotou Hosp, Dongguan, Guangdong, Peoples R China. [Bagni, Rachel] NCI, Prot Express Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Lan, Q (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH,DHHS, 9609 Med Ctr Dr,Room 6-E136,MSC 9771, Bethesda, MD 20892 USA. EM qingl@mail.nih.gov RI Hu, Wei/M-3524-2013; Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU NIEHS NIH HHS [P42 ES004705] NR 25 TC 5 Z9 6 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD JUL PY 2013 VL 54 IS 6 BP 450 EP 454 DI 10.1002/em.21789 PG 5 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 176HS UT WOS:000321295400008 PM 23798002 ER PT J AU Kraigher-Krainer, E Lyass, A Massaro, JM Lee, DS Ho, JE Levy, D Kannel, WB Vasan, RS AF Kraigher-Krainer, Elisabeth Lyass, Asya Massaro, Joseph M. Lee, Douglas S. Ho, Jennifer E. Levy, Daniel Kannel, William B. Vasan, Ramachandran S. TI Association of physical activity and heart failure with preserved vs. reduced ejection fraction in the elderly: the Framingham Heart Study SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE Physical activity; Heart failure; Elderly ID BODY-MASS INDEX; RISK-FACTORS; EPIDEMIOLOGY; MEN AB Aims Reduced physical activity is associated with increased risk of heart failure (HF) in middle-aged individuals. We hypothesized that physical inactivity is also associated with greater HF risk in older individuals, and examined if the association was consistent for HF with preserved ejection fraction (HFPEF) vs. HF with a reduced ejection fraction (HFREF). Methods and results We evaluated 1142 elderly participants (mean age 76 years) from the Framingham Study without prior myocardial infarction and who attended a routine examination when daily physical activity was assessed systematically with a questionnaire. A composite score, the physical activity index (PAI), was calculated and modelled as tertiles, and related to incidence of HF, HFPEF, and HFREF on follow-up using proportional hazards regression models adjusting for age and sex, and then additionally for standard HF risk factors. Participants with HF and EF <45% vs. >= 45% were categorized as HFREF and HFPEF, respectively. On follow-up (mean 10 years), 250 participants developed HF (108 with HFPEF, 106 with HFREF, 36 with unavailable EF). In age-and sex-adjusted models, the middle and highest PAI tertiles were associated with a 15-56% lower risk of any HF, of HFREF, and of HFPEF, with a graded response across tertiles. In multivariable models, the association of higher PAI with lower risk of any HF and with HFPEF was maintained, whereas the association with HFREF was attenuated. Conclusions Our study of an older community-based sample extends to the elderly and to HFPEF previous findings of a protective effect of physical activity on HF risk. C1 [Kraigher-Krainer, Elisabeth] Med Univ Graz, Dept Cardiol, Graz, Austria. [Lyass, Asya; Massaro, Joseph M.; Lee, Douglas S.; Ho, Jennifer E.; Levy, Daniel; Kannel, William B.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Lyass, Asya] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Lee, Douglas S.] Univ Toronto, Inst Clin Evaluat Sci, Toronto, ON, Canada. [Lee, Douglas S.] Univ Toronto, Toronto Gen Hosp, Toronto, ON M5G 1L7, Canada. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu RI Lee, Douglas/J-4315-2014; OI Massaro, Joseph/0000-0002-2682-4812; Ho, Jennifer/0000-0002-7987-4768; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung and Blood Institute [NO1-HC-25195] FX The National Heart, Lung and Blood Institute (contract no. NO1-HC-25195). NR 14 TC 22 Z9 22 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1388-9842 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD JUL PY 2013 VL 15 IS 7 BP 742 EP 746 DI 10.1093/eurjhf/hft025 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 170MW UT WOS:000320857400008 PM 23435761 ER PT J AU Lima, BR Nussenblatt, RB Sen, HN AF Lima, Breno R. Nussenblatt, Robert B. Sen, H. Nida TI Pharmacogenetics of drugs used in the treatment of ocular inflammatory diseases SO EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY LA English DT Review DE inflammation; pharmacogenetics; scleritis; uveitis ID RENAL-TRANSPLANT PATIENTS; GLUCOCORTICOID-RECEPTOR POLYMORPHISMS; JUVENILE IDIOPATHIC ARTHRITIS; HL-A 27; MYCOPHENOLATE-MOFETIL; RHEUMATOID-ARTHRITIS; POSTERIOR UVEITIS; BEHCETS-DISEASE; IMMUNOSUPPRESSIVE DRUGS; NONINFECTIOUS UVEITIS AB Introduction: Ocular inflammatory diseases comprise uveitis, scleritis, and inflammation of adjacent structures of the eye. Therapy may be challenging and often involves corticosteroids and immunomodulatory agents. Areas covered: This review describes the genes involved in noninfectious ocular inflammatory diseases and focuses on pharmacogenetic studies regarding different classes of anti-inflammatory drugs used in the management of uveitis, including corticosteroids, antimetabolites, calcineurin inhibitors, alkylating agents, and biological agents. Expert opinion: Pharmacogenetics holds the promise of a personalized medicine with potential to customize treatment that can achieve the best clinical response and avoid toxicity. Several polymorphisms in various genes involved in the metabolism of drugs commonly utilized in the treatment of ocular inflammatory diseases have been described. Most promising is the polymorphism in thiopurinemethyltransferase gene for which a genotype analysis can reveal slow metabolizers of azathioprine and help avoid serious drug toxicity. Although pharmacogenetic studies with specific focus on ocular inflammatory diseases are lacking, knowledge from studies in rheumatologic diseases and transplant medicine can provide a platform for future research. Prospective clinical studies are needed to determine the clinical significance of such polymorphisms and their true effect on drug metabolism and side effects. C1 [Lima, Breno R.; Nussenblatt, Robert B.; Sen, H. Nida] NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. EM senh@nei.nih.gov NR 96 TC 3 Z9 3 U1 1 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1742-5255 J9 EXPERT OPIN DRUG MET JI Expert Opin. Drug Metab. Toxicol. PD JUL PY 2013 VL 9 IS 7 BP 875 EP 882 DI 10.1517/17425255.2013.783818 PG 8 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 164ZA UT WOS:000320450600006 PM 23521173 ER PT J AU Werder, E Mendola, P Mannisto, T O'Loughlin, J Laughon, SK AF Werder, Emily Mendola, Pauline Maennistoe, Tuija O'Loughlin, Jennifer Laughon, S. Katherine TI Effect of maternal chronic disease on obstetric complications in twin pregnancies in a United States cohort SO FERTILITY AND STERILITY LA English DT Article DE Twins; obstetric complications; assisted reproductive technology (ART) ID ASSISTED REPRODUCTIVE TECHNOLOGY; PERINATAL OUTCOMES; MULTIPLE BIRTHS; RISK-FACTOR; TRENDS; POPULATION; DELIVERY; OBESITY; WOMEN; AGE AB Objective: To evaluate the effect of maternal chronic disease on obstetric complications among twin pregnancies. Design: Multicenter, retrospective, observational study. Setting: Clinical centers (19 hospitals). Patient(s): Twin pregnancies (n = 4,821) delivered >= 23 weeks of gestation and classified by maternal chronic disease (either none or any of the following: asthma, depression, hypertension, diabetes, and heart, thyroid, gastrointestinal or renal disease). Intervention(s): None. Main Outcome Measure(s): Gestational age at delivery, gestational hypertension, pre-eclampsia, gestational diabetes, placental abruption, placenta previa, hemorrhage, chorioamnionitis, maternal postpartum fever, premature rupture of membranes, labor onset (spontaneous vs. nonspontaneous), route of delivery, and maternal admission to intensive care unit. Result(s): Women with chronic disease delivered earlier (mean gestational length, 34.1 vs. 34.6 weeks) and were less likely to have term birth (risk ratio 0.80; 95% confidence interval 0.70-0.90). Cesarean delivery after spontaneous labor (risk ratio 1.20; 95% confidence interval 1.05-1.37) was also increased with chronic disease. No statistically significant effects were observed for other complications studied. Women who used assisted reproductive technology were more likely to hemorrhage, independent of chronic disease, but other findings were generally similar to the non- assisted reproductive technology sample. Conclusion(s): Chronic disease was associated with additional risk of earlier delivery and cesarean section after spontaneous labor in a nationwide sample of US twin pregnancies. (C) 2013 by American Society for Reproductive Medicine. C1 [Werder, Emily; Mendola, Pauline; Maennistoe, Tuija; O'Loughlin, Jennifer; Laughon, S. Katherine] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD 20852 USA. [Werder, Emily] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [O'Loughlin, Jennifer] Commonwealth Med Coll, Scranton, PA 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,Room 7B03F, Rockville, MD 20852 USA. EM pauline.mendola@nih.gov OI Mannisto, Tuija/0000-0002-6382-9153; Mendola, Pauline/0000-0001-5330-2844; Grantz, Katherine/0000-0003-0276-8534 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health. NR 36 TC 2 Z9 2 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUL PY 2013 VL 100 IS 1 BP 142 EP + DI 10.1016/j.fertnstert.2013.01.153 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 173AJ UT WOS:000321049400028 PM 23541402 ER PT J AU Louis, GMB Peterson, CM Chen, Z Croughan, M Sundaram, R Stanford, J Varner, MW Kennedy, A Giudice, L Fujimoto, VY Sun, LP Wang, L Guo, Y Kannan, K AF Louis, Germaine M. Buck Peterson, C. Matthew Chen, Zhen Croughan, Mary Sundaram, Rajeshwari Stanford, Joseph Varner, Michael W. Kennedy, Anne Giudice, Linda Fujimoto, Victor Y. Sun, Liping Wang, Lei Guo, Ying Kannan, Kurunthachalam TI Bisphenol A and phthalates and endometriosis: the Endometriosis: Natural History, Diagnosis and Outcomes Study SO FERTILITY AND STERILITY LA English DT Article DE Bisphenol A; endometriosis; endocrine disrupting chemicals; epidemiology; phthalates ID ENDOCRINE-DISRUPTING CHEMICALS; HIGH PLASMA-CONCENTRATIONS; DIOXIN-LIKE COMPOUNDS; HUMAN EXPOSURE; POLYCHLORINATED-BIPHENYLS; PELVIC ENDOMETRIOSIS; ITALIAN WOMEN; ASSOCIATION; SOCIETY; METABOLITES AB Objective: To explore the relation between bisphenol A and 14 phthalate metabolites and endometriosis. Design: Matched cohort design. Setting: Fourteen clinical centers. Patient(s): The operative cohort comprised 495 women undergoing laparoscopy/laparotomy, whereas the population cohort comprised 131 women matched on age and residence. Intervention(s): None. Main Outcome Measure(s): Surgically visualized or pelvic magnetic resonance imaging diagnosed endometriosis in the two cohorts, respectively. Result(s): Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression adjusting for age, body mass index, and creatinine. In the population cohort, six phthalate metabolites-mono-n-butyl phthalate, mono-[(2-carboxymethyl) hexyl] phthalate, mono (2-ethyl-5-carboxyphentyl) phthalate, mono (2-ethylhexyl) phthalate, mono (2-ethyl-5-hydroxyhexyl) phthalate, and mono (2-ethyl-5-oxohexyl) phthalate-were significantly associated with an approximately twofold increase in the odds of an endometriosis diagnosis. Two phthalates were associated with endometriosis in the operative cohort when restricting to visualized and histologic endometriosis (monooctyl phthalate; OR 1.38; 95% CI 1.10-1.72) or when restricting comparison women to those with a postoperative diagnosis of a normal pelvis [mono (2-ethylhexyl) phthalate; OR 1.35; 95% CI 1.03-1.78]. Conclusion(s): Select phthalates were associated with higher odds of an endometriosis diagnosis for women with magnetic resonance imaging-diagnosed endometriosis. The lack of consistency of findings across cohorts underscores the impact of methodology on findings. (C) 2013 by American Society for Reproductive Medicine. C1 [Louis, Germaine M. Buck; Chen, Zhen; Sundaram, Rajeshwari; Sun, Liping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Peterson, C. Matthew; Varner, Michael W.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Stanford, Joseph] Univ Utah, Dept Family Med, Salt Lake City, UT USA. [Kennedy, Anne] Univ Utah, Dept Radiol, Salt Lake City, UT 84132 USA. [Croughan, Mary; Giudice, Linda; Fujimoto, Victor Y.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Wang, Lei; Guo, Ying; Kannan, Kurunthachalam] SUNY Albany, New York State Dept Hlth, Div Environm Hlth Sci, Wadsworth Ctr, Albany, NY 12222 USA. [Wang, Lei; Guo, Ying; Kannan, Kurunthachalam] SUNY Albany, Dept Environm Hlth Sci, Albany, NY 12222 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Bvld,Room 7B03, Rockville, MD 20852 USA. EM louisg@mail.nih.gov RI Varner, Michael/K-9890-2013; OI Varner, Michael/0000-0001-9455-3973; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Women's Reproductive Health Foundation; University of Utah Department of Radiology; Amirsys Inc.; Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [NO1-DK-6-3428, NO1-DK-6-3427, 10001406-02] FX G.M.B.L. has nothing to disclose. C.M.P. has nothing to disclose. Z.C. has nothing to disclose. M.C. has nothing to disclose. R.S. has nothing to disclose. J.S. reports a consultancy with Swiss Diagnostics and grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Women's Reproductive Health Foundation. M.W.V. has nothing to disclose. A.K. reports a grant from the University of Utah Department of Radiology; honoraria from the University of California-Davis and Siemens; and royalties and payment for development of educational materials from Amirsys Inc. L.G. reports board membership in the World Endometriosis Research Foundation and royalties from the textbook Endometriosis: Science and Practice. V.Y.F. has nothing to disclose. L.S. has nothing to disclose. L.W. has nothing to disclose. Y.G. has nothing to disclose. K.K. has nothing to disclose.; This study was funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). Ethicon Endo-Surgery donated the HARMONIC ACE 36P scalpel blades for use in the study through a signed Materials Transfer Agreement with the University of Utah and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 67 TC 11 Z9 11 U1 11 U2 42 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUL PY 2013 VL 100 IS 1 BP 162 EP + DI 10.1016/j.fertnstert.2013.03.026 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 173AJ UT WOS:000321049400030 ER PT J AU Wolff, EF Vahidi, N Alford, C Richter, K Widra, E AF Wolff, Erin Foran Vahidi, Nima Alford, Connie Richter, Kevin Widra, Eric TI Influences on endometrial development during intrauterine insemination: clinical experience of 2,929 patients with unexplained infertility SO FERTILITY AND STERILITY LA English DT Article DE Endometrium; intrauterine insemination; assisted reproductive technologies ID IN-VITRO FERTILIZATION; INTRACYTOPLASMIC SPERM INJECTION; LOW-DOSE ASPIRIN; EMBRYO-TRANSFER; PREGNANCY RATES; LOCAL INJURY; THICKNESS; IMPLANTATION; CYCLES; IVF AB Objective: To characterize relationships associated with adverse endometrial development in patients undergoing IUI for unexplained infertility. Design: A retrospective review of 2,929 patients from 2004-2011. Setting: Large metropolitan infertility practice. Patient(s): Patients with unexplained infertility undergoing first IUI cycle at age less than 43 years, with a total motile sperm count >= 8 million. Intervention(s): Clomiphene citrate (CC) with FSH stimulation followed by IUI. Main Outcome Measure(s): Endometrial thickness, serum E-2 (in picograms per milliliter) levels on the day of hCG trigger administration, body mass index (BMI) (in kilograms per meter squared), total motile sperm, follicle number, and clinical pregnancy. Result(s): Of the 2,929 patients who met the inclusion criteria, 466 (15.9 %) achieved a clinical pregnancy. Pregnancy rates (PRs) increased significantly with increasing endometrial thickness on the day of hCG administration and with increasing serum E2 level, but were not significantly related to age, BMI, or follicle numbers according to multiple logistic regression modeling. Peak endometrial thickness declined with age and increasing E-2 levels. The BMI was associated with thicker endometrium, but it was also associated with lower peak E-2 levels. Conclusion(s): The impact of "endometrial factor" infertility may be underappreciated in IUI therapy. Targeted therapies to optimize the endometrium represent an important new area to improve in current fertility success rates. (C)2013 by American Society for Reproductive Medicine. C1 [Wolff, Erin Foran; Vahidi, Nima] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Reprod Regenerat Med, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Wolff, Erin Foran; Richter, Kevin; Widra, Eric] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Alford, Connie] South Florida Inst Reprod Med, Naples, FL USA. RP Wolff, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 1E-3140, Bethesda, MD 20892 USA. EM wolffe@mail.nih.gov FU Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported, in part, by the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 28 TC 3 Z9 4 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUL PY 2013 VL 100 IS 1 BP 194 EP + DI 10.1016/j.fertnstert.2013.03.023 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 173AJ UT WOS:000321049400033 PM 23579008 ER PT J AU Burger, J Gochfeld, M AF Burger, Joanna Gochfeld, Michael TI Selenium and mercury molar ratios in commercial fish from New Jersey and Illinois: Variation within species and relevance to risk communication SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Mercury; Selenium; Selenium:mercury molar ratios; Risk balancing ID METHYLMERCURY EXPOSURE; BRAZILIAN AMAZON; OXIDATIVE STRESS; TROPHIC POSITION; METHYL MERCURY; PUBLIC-HEALTH; MOUSE-BRAIN; TOXICITY; CONSUMPTION; DIETARY AB There is an emerging consensus that people consuming large amounts of fish with selenium:mercury ratios below 1 are at higher risk from mercury toxicity. As the relative amount of selenium increases compared to mercury, risk may be lowered, but it is unclear how much excess selenium is required. It would be useful if the selenium:mercury ratio was relatively consistent within a species, but this has not been the case in our studies of wild-caught fish. Since most people in developed countries and urban areas obtain their fish and other seafood commercially, we examined selenium:mercury molar ratios in commercial fish purchased in stores and fish markets in central New Jersey and Chicago. There was substantial interspecific and intraspecific variation in molar ratios. Across species the selenium:mercury molar ratio decreased with increasing mean mercury levels, but selenium variation also contributed to the ratio. Few samples had selenium:mercury molar ratios below 1, but there was a wide range in ratios, complicating the interpretation for use in risk management and communication. Before ratios can be used in risk management, more information is needed on mercury:selenium interactions and mutual bioavailability, and on the relationship between molar ratios and health outcomes. Further, people who are selenium deficient may be more at risk from mercury toxicity than others. (c) 2013 Elsevier Ltd. All rights reserved. C1 [Burger, Joanna] Rutgers State Univ, Div Life Sci, Piscataway, NJ 08854 USA. [Burger, Joanna; Gochfeld, Michael] Rutgers State Univ, Environm & Occupat Hlth Sci Inst, Piscataway, NJ 08854 USA. [Burger, Joanna; Gochfeld, Michael] Rutgers State Univ, Consortium Risk Evaluat Stakeholder Participat, Piscataway, NJ 08854 USA. [Gochfeld, Michael] Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. [Gochfeld, Michael] NIEHS, Ctr Environm Exposures & Dis, Piscataway, NJ 08854 USA. RP Burger, J (reprint author), Rutgers State Univ, Div Life Sci, 604 Allison Rd, Piscataway, NJ 08854 USA. EM burger@biology.rutgers.edu FU Office of Science, Research and Technology of the New Jersey Department of Environmental Protection; NIEHS Center Grant [P30ES005022]; Consortium for Risk Evaluation with Stakeholder Participation (Department of Energy) [DE-FC01-06EW07053]; Chicago Tribune; EOHSI FX We particularly thank A. Stern for his role in our initial study of mercury in commercial fish, C. Jeitner, M. Donio, and T. Pittfield for field, laboratory and manuscript assistance, and Sam Roe of the Chicago Tribune for collecting the samples in his region. B. Buckley, P. Copeland, M. Lemire, K. Mahaffey, D. Mergler, N. Ralston, C. Safina, R. Schoeny, A. Stern, and H. Zarbl provided valuable discussion on mercury, selenium, and the selenium-mercury interactions. This research was partly supported by the Office of Science, Research and Technology of the New Jersey Department of Environmental Protection, the NIEHS Center Grant (P30ES005022), the Consortium for Risk Evaluation with Stakeholder Participation (Department of Energy, #DE-FC01-06EW07053), Chicago Tribune, and EOHSI. This study of commercial fish was exempt under Rutgers University Animal Use protocols. The views and conclusions expressed in this paper are solely those of the authors, and do not reflect the funding agencies. NR 91 TC 15 Z9 16 U1 4 U2 49 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD JUL PY 2013 VL 57 BP 235 EP 245 DI 10.1016/j.fct.2013.03.021 PG 11 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 165QL UT WOS:000320498300030 PM 23541437 ER PT J AU Costanzo, ME McArdle, JJ Swett, B Nechaev, V Kemeny, S Xu, J Braun, AR AF Costanzo, Michelle E. McArdle, Joseph J. Swett, Bruce Nechaev, Vladimir Kemeny, Stefan Xu, Jiang Braun, Allen R. TI Spatial and temporal features of superordinate semantic processing studied with fMRI and EEG SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE semantic processing; modality independent; superordinate categorization; fMRI; ERP ID EVENT-RELATED POTENTIALS; INDEPENDENT COMPONENT ANALYSIS; PARIETAL CORTEX; HUMAN BRAIN; TIME-COURSE; OBJECT CATEGORIZATION; MULTIPLE SEMANTICS; FUNCTIONAL-ANATOMY; WORD REPETITION; ANGULAR GYRUS AB The relationships between the anatomical representation of semantic knowledge in the human brain and the timing of neurophysiological mechanisms involved in manipulating such information remain unclear. This is the case for superordinate semantic categorization-the extraction of general features shared by broad classes of exemplars (e.g., living vs. non-living semantic categories). We proposed that, because of the abstract nature of this information, input from diverse input modalities (visual or auditory, lexical or non-lexical) should converge and be processed in the same regions of the brain, at similar time scales during superordinate categorization-specifically in a network of heteromodal regions, and late in the course of the categorization process. In order to test this hypothesis, we utilized electroencephalography and event related potentials (EEG/ERP) with functional magnetic resonance imaging (fMRI) to characterize subjects' responses as they made superordinate categorical decisions (living vs. non-living) about objects presented as visual pictures or auditory words. Our results reveal that, consistent with our hypothesis, during the course of superordinate categorization, information provided by these diverse inputs appears to converge in both time and space: fMRI showed that heteromodal areas of the parietal and temporal cortices are active during categorization of both classes of stimuli. The ERP results suggest that superordinate categorization is reflected as a late positive component (LPC) with a parietal distribution and long latencies for both stimulus types. Within the areas and times in which modality independent responses were identified, some differences between living and non-living categories were observed, with a more widespread spatial extent and longer latency responses for categorization of non-living items. C1 [Costanzo, Michelle E.; McArdle, Joseph J.; Swett, Bruce; Nechaev, Vladimir; Kemeny, Stefan; Xu, Jiang; Braun, Allen R.] Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bethesda, MD 20892 USA. [Costanzo, Michelle E.] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [McArdle, Joseph J.] Army Res Lab, Translat Neurosci Branch, Human Res & Engn Directorate, Aberdeen Proving Ground, Aberdeen, MD USA. [Swett, Bruce] EOIR Technol Inc, Lorton, VA USA. [Xu, Jiang] PAREXEL Early Phase Clin, Centreville, VA USA. RP Braun, AR (reprint author), Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bldg 10,Room 5D-37, Bethesda, MD 20892 USA. EM brauna@nidcd.nih.gov RI chen, zhu/K-5923-2013 FU Intramural Program of NIDCD FX This work was supported by the Intramural Program of NIDCD. NR 82 TC 6 Z9 6 U1 1 U2 20 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 1 PY 2013 VL 7 AR 293 DI 10.3389/fnhum.2013.00293 PG 13 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 174XW UT WOS:000321192300001 PM 23847490 ER PT J AU Lee, MR Gallen, CL Ross, TJ Kurup, P Salmeron, BJ Hodgkinson, CA Goldman, D Stein, EA Enoch, MA AF Lee, M. R. Gallen, C. L. Ross, T. J. Kurup, P. Salmeron, B. J. Hodgkinson, C. A. Goldman, D. Stein, E. A. Enoch, M. A. TI A preliminary study suggests that nicotine and prefrontal dopamine affect cortico-striatal areas in smokers with performance feedback SO GENES BRAIN AND BEHAVIOR LA English DT Article DE COMT Val158Met; fMRI; nicotine; prefrontal dopamine; reward processing; smoking cessation treatment ID CATECHOL-O-METHYLTRANSFERASE; COMT VAL(158)MET POLYMORPHISM; TOBACCO CRAVING QUESTIONNAIRE; VAL(108/158) MET GENOTYPE; SMOKING-CESSATION; GENETIC-VARIATION; WORKING-MEMORY; HUMAN BRAIN; REWARD; ASSOCIATION AB Nicotine and tonic dopamine (DA) levels [as inferred by catechol-O-methyl tranferase (COMT) Val158Met genotype] interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotinexCOMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotinexCOMT genotype interaction for BOLD signal during performance feedback in cortico-striatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, area associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy. C1 [Lee, M. R.; Ross, T. J.; Kurup, P.; Salmeron, B. J.; Stein, E. A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Gallen, C. L.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Hodgkinson, C. A.; Goldman, D.; Enoch, M. A.] NIAAA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 90034 USA. RP Lee, MR (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM leemary@mail.nih.gov RI Goldman, David/F-9772-2010; Salmeron, Betty Jo/M-1793-2016; OI Goldman, David/0000-0002-1724-5405; Salmeron, Betty Jo/0000-0003-1699-9333; Ross, Thomas/0000-0002-7745-3572 FU Intramural Research Program of the NIDA; Intramural Research Program of the NIAAA FX This research was supported by the Intramural Research Programs of the NIDA and NIAAA. M.-A.E. and D.G. are members of the International Behavioral and Neural Genetics Society. NR 57 TC 3 Z9 3 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JUL PY 2013 VL 12 IS 5 BP 554 EP 563 DI 10.1111/gbb.12027 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 174VM UT WOS:000321184700008 PM 23433232 ER PT J AU Le, TN Elsea, SH Romero, R Chaiworapongsa, T Francis, GL AF Le, Trang N. Elsea, Sarah H. Romero, Roberto Chaiworapongsa, Tinnakorn Francis, Gary L. TI Prolactin Receptor Gene Polymorphisms Are Associated with Gestational Diabetes SO GENETIC TESTING AND MOLECULAR BIOMARKERS LA English DT Article ID LACTATION; POPULATION; PREGNANCY; MELLITUS AB Aims: Human placental lactogen (hPL) acts via the prolactin receptor (PRLR) on maternal beta-cells to mediate increases in beta-cell mass and function during normal pregnancy. This interaction between hPL and PRLR is essential to maintain normal glucose homeostasis and to address the increased metabolic demands of pregnancy. Given the importance of the PRLR-hPL axis in pancreatic islet cell adaptation to pregnancy, we hypothesized that genetic variation in the PRLR gene could influence risk of development of gestational diabetes mellitus (GDM). DNA samples from 96 mothers affected by GDM and 96 unaffected cases were genotyped for 8 selected single nucleotide polymorphisms (SNPs) in PRLR. Results: Significant associations were identified in two SNPs analyzed. The minor alleles of PRLR SNPs rs10068521 and rs9292578 were more frequently observed in GDM cases than controls and were associated with a 2.36-fold increased risk for GDM in those carrying the minor allele. Conclusion: SNPs of the PRLR gene 5' UTR and promoter region are associated with increased risk for GDM in a population of Chilean subjects. C1 [Le, Trang N.; Elsea, Sarah H.; Francis, Gary L.] Virginia Commonwealth Univ, Childrens Hosp Richmond, Dept Pediat, Richmond, VA 23298 USA. [Elsea, Sarah H.] Virginia Commonwealth Univ, Childrens Hosp Richmond, Dept Human & Mol Genet, Richmond, VA 23298 USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Romero, Roberto; Chaiworapongsa, Tinnakorn] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. [Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. RP Le, TN (reprint author), Virginia Commonwealth Univ, Childrens Hosp Richmond, Dept Pediat, POB 980140, Richmond, VA 23298 USA. EM tle@mcvh-vcu.edu FU A.D. Williams Fund, of the Virginia Commonwealth University [648973]; VCU CTSA [UL1RR031990]; Division of Intramural Research, National Institute of Child Health and Human Development, National Institutes of Health FX This study was supported by the A.D. Williams Fund, Grant Number 648973, of the Virginia Commonwealth University, the VCU CTSA UL1RR031990, and in part by the Division of Intramural Research, National Institute of Child Health and Human Development, National Institutes of Health. NR 20 TC 7 Z9 7 U1 1 U2 9 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1945-0265 J9 GENET TEST MOL BIOMA JI Genet. Test. Mol. Biomark. PD JUL PY 2013 VL 17 IS 7 BP 567 EP 571 DI 10.1089/gtmb.2013.0009 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 175PP UT WOS:000321243400010 PM 23651351 ER PT J AU Hutchison, ER Kawamoto, EM Taub, DD Lal, A Abdelmohsen, K Zhang, YQ Wood, WH Lehrmann, E Camandola, S Becker, KG Gorospe, M Mattson, MP AF Hutchison, Emmette R. Kawamoto, Elisa M. Taub, Dennis D. Lal, Ashish Abdelmohsen, Kotb Zhang, Yongqing Wood, William H., III Lehrmann, Elin Camandola, Simonetta Becker, Kevin G. Gorospe, Myriam Mattson, Mark P. TI Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes SO GLIA LA English DT Article DE miR-181; inflammation; LPS; MeCP2; XIAP ID NF-KAPPA-B; ISCHEMIC BRAIN-INJURY; PARKINSONS-DISEASE; APOPTOSIS PROTEINS; ALZHEIMERS-DISEASE; GROWTH-FACTOR; GLIOMA-CELLS; EXPRESSION; GENE; DIFFERENTIATION AB Inflammation is a common component of acute injuries of the central nervous system (CNS) such as ischemia, and degenerative disorders such as Alzheimer's disease. Glial cells play important roles in local CNS inflammation, and an understanding of the roles for microRNAs in glial reactivity in injury and disease settings may therefore lead to the development of novel therapeutic interventions. Here, we show that the miR-181 family is developmentally regulated and present in high amounts in astrocytes compared to neurons. Overexpression of miR-181c in cultured astrocytes results in increased cell death when exposed to lipopolysaccharide (LPS). We show that miR-181 expression is altered by exposure to LPS, a model of inflammation, in both wild-type and transgenic mice lacking both receptors for the inflammatory cytokine TNF-. Knockdown of miR-181 enhanced LPS-induced production of pro-inflammatory cytokines (TNF-, IL-6, IL-1, IL-8) and HMGB1, while overexpression of miR-181 resulted in a significant increase in the expression of the anti-inflammatory cytokine IL-10. To assess the effects of miR-181 on the astrocyte transcriptome, we performed gene array and pathway analysis on astrocytes with reduced levels of miR-181b/c. To examine the pool of potential miR-181 targets, we employed a biotin pull-down of miR-181c and gene array analysis. We validated the mRNAs encoding MeCP2 and X-linked inhibitor of apoptosis as targets of miR-181. These findings suggest that miR-181 plays important roles in the molecular responses of astrocytes in inflammatory settings. Further understanding of the role of miR-181 in inflammatory events and CNS injury could lead to novel approaches for the treatment of CNS disorders with an inflammatory component. C1 [Hutchison, Emmette R.; Kawamoto, Elisa M.; Camandola, Simonetta; Mattson, Mark P.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Hutchison, Emmette R.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Taub, Dennis D.; Abdelmohsen, Kotb; Zhang, Yongqing; Wood, William H., III; Lehrmann, Elin; Becker, Kevin G.; Gorospe, Myriam] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Lal, Ashish] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Kawamoto, Elisa/E-3485-2012; OI Kawamoto, Elisa/0000-0001-8637-414X; Lehrmann, Elin/0000-0002-9869-9475; abdelmohsen, Kotb/0000-0001-6240-5810; Becker, Kevin/0000-0002-6794-6656 FU Intramural Research Program of the National Institute on Aging FX Grant sponsor: Intramural Research Program of the National Institute on Aging. NR 63 TC 70 Z9 75 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 J9 GLIA JI Glia PD JUL PY 2013 VL 61 IS 7 BP 1018 EP 1028 DI 10.1002/glia.22483 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 171NK UT WOS:000320935900002 PM 23650073 ER PT J AU Binukumar, BK Shukla, V Amin, ND Reddy, P Skuntz, S Grant, P Pant, HC AF Binukumar, B. K. Shukla, Varsha Amin, Niranjana D. Reddy, Preethi Skuntz, Suzanne Grant, Philip Pant, Harish C. TI Topographic regulation of neuronal intermediate filaments by phosphorylation, role of peptidyl-prolyl isomerase 1: significance in neurodegeneration SO HISTOCHEMISTRY AND CELL BIOLOGY LA English DT Review DE Neurofilaments; Phosphorylation; Kinases; Phosphatase; Neurodegeneration; Pin1; Alzheimer's disease; Topographic ID AMYOTROPHIC-LATERAL-SCLEROSIS; CYCLIN-DEPENDENT KINASE-5; CDK5 INHIBITORY PEPTIDE; ALZHEIMERS-DISEASE HIPPOCAMPUS; ACTIVATED PROTEIN-KINASE; NEUROFILAMENT PROTEINS; AXONAL-TRANSPORT; MOUSE MODEL; INCREASED EXPRESSION; CEREBROSPINAL-FLUID AB The neuronal cytoskeleton is tightly regulated by phosphorylation and dephosphorylation reactions mediated by numerous associated kinases, phosphatases and their regulators. Defects in the relative kinase and phosphatase activities and/or deregulation of compartment-specific phosphorylation result in neurodegenerative disorders. The largest family of cytoskeletal proteins in mammalian cells is the superfamily of intermediate filaments (IFs). The neurofilament (NF) proteins are the major IFs. Aggregated forms of hyperphosphorylated tau and phosphorylated NFs are found in pathological cell body accumulations in the central nervous system of patients suffering from Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The precise mechanisms for this compartment-specific phosphorylation of cytoskeletal proteins are not completely understood. In this review, we focus on the mechanisms of neurofilament phosphorylation in normal physiology and neurodegenerative diseases. We also address the recent breakthroughs in our understanding the role of different kinases and phosphatases involved in regulating the phosphorylation status of the NFs. In addition, special emphasis has been given to describe the role of phosphatases and Pin1 in phosphorylation of NFs. C1 [Binukumar, B. K.; Shukla, Varsha; Amin, Niranjana D.; Reddy, Preethi; Skuntz, Suzanne; Grant, Philip; Pant, Harish C.] NINDS, Lab Neuronal Cytoskeletal Prot Regulat Sect, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINDS, Lab Neuronal Cytoskeletal Prot Regulat Sect, NIH, Bethesda, MD 20892 USA. EM binukumarbk@gmail.com; Panth@ninds.nih.gov FU NIH, National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Programs of the NIH, National Institute of Neurological Disorders and Stroke. NR 72 TC 8 Z9 8 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0948-6143 J9 HISTOCHEM CELL BIOL JI Histochem. Cell Biol. PD JUL PY 2013 VL 140 IS 1 BP 23 EP 32 DI 10.1007/s00418-013-1108-7 PG 10 WC Cell Biology; Microscopy SC Cell Biology; Microscopy GA 173GY UT WOS:000321067800004 PM 23793952 ER PT J AU Yao, JH Bliton, J Summers, RM AF Yao, Jianhua Bliton, John Summers, Ronald M. TI Automatic Segmentation and Measurement of Pleural Effusions on CT SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Biomedical image processing; pleural effusion (PE) ID IMAGE SEGMENTATION; ULTRASONOGRAPHY; FLUID AB Pleural effusion is an important biomarker for the diagnosis of many diseases. We develop an automated method to evaluate pleural effusion on CT scans, the measurement of which is prohibitively time consuming when performed manually. The method is based on parietal and visceral pleura extraction, active contour models, region growing, Bezier surface fitting, and deformable surface modeling. Twelve CT scans with three manual segmentations were used to validate the automatic segmentation method. The method was then applied on 91 additional scans for visual assessment. The segmentation method yielded a correlation coefficient of 0.97 and a Dice coefficient of 0.72 +/- 0.13 when compared to a professional manual segmentation. The visual assessment estimated 83% cases with negligible or small segmentation errors, 14% with medium errors, and 3% with large errors. C1 [Yao, Jianhua; Bliton, John; Summers, Ronald M.] NIH, Bethesda, MD 20892 USA. RP Yao, JH (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM jyao@cc.nih.gov; jnbliton@gmail.com; rms@nih.gov FU Intramural Research Program of the National Institutes of Health, Clinical Center FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, Clinical Center. Asterisk indicates corresponding author. NR 26 TC 4 Z9 4 U1 1 U2 6 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD JUL PY 2013 VL 60 IS 7 BP 1834 EP 1840 DI 10.1109/TBME.2013.2243446 PG 7 WC Engineering, Biomedical SC Engineering GA 168MF UT WOS:000320709500008 PM 23372069 ER PT J AU Estes, JD AF Estes, Jacob D. TI Pathobiology of HIV/SIV-associated changes in secondary lymphoid tissues SO IMMUNOLOGICAL REVIEWS LA English DT Review DE T cells; AIDS; lymph nodes; inflammation; fibrosis AB Acquired immunodeficiency syndrome (AIDS) is principally a disease of lymphoid tissues (LTs), due to the fact that the main target cell of human immunodeficiency virus (HIV) is the CD4+ T lymphocyte that primarily resides within organs of the immune system. The impact of HIV infection on secondary LTs, in particular lymph nodes, is critical to delineate, as these immune organs are the principal sites for initiating and facilitating immune responses and are critical for lymphocyte homeostatic maintenance and survival. The underlying structural elements of LTs, fibroblastic reticular cell (FRC) network, not only form the architectural framework for these organs, but also play in integral role in the production and storage of cytokines needed for T-cell survival. There is an interdependent relationship between the FRC stromal network and CD4+ T lymphocytes for their survival and maintenance that is progressively disrupted during HIV disease. HIV infection results in profound pathological changes to LTs induced by persistent chronic immune activation and inflammation that leads to progressive collagen deposition and fibrosis disrupting and damaging the important FRC network. In this review, I focus on the process, mechanisms, and the implications of pathological damage to important secondary LTs, combining what we have learned from HIV-infected individuals as well as the invaluable knowledge gained from studies in non-human primate simian immunodeficiency virus infection models. C1 [Estes, Jacob D.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA. RP Estes, JD (reprint author), SAIC Frederick Inc, Retroviral Immunopathol Sect, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, 1050 Boyles St,Bldg 535,Rm 411, Frederick, MD 21702 USA. EM estesj@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX I would like to thank Allen Kane with SPGM at the Frederick National Laboratory for Cancer Research for generation of the figures and Jeff Lifson for critically reading the manuscript and thoughtful input. This project has been funded with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The author has no conflict of interest to declare. NR 115 TC 19 Z9 20 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD JUL PY 2013 VL 254 BP 65 EP 77 DI 10.1111/imr.12070 PG 13 WC Immunology SC Immunology GA 164EE UT WOS:000320390900005 PM 23772615 ER EF